product name is cn 600 tg omega-3-acid triglycerides. ingredient to be applied in parenteral formulations. description of the omega-3-acid triglycerides (cn 600 tg) is a pale-yellow liquid comprised of a minimum of 30 per cent eicosapentaenoic acid (epa) and a minimum of 20 per cent docosahexaenoic acid (dha) presented as triglycerides (ph. eur. 1352 current ed.). the content of epa and dha triglycerides is a minimum 50 per cent and the content of total omega-3-acid triglycerides is a minimum 60 per cent. tocopherol is added as an antioxidant.. the product is manufactured in norway. the compendial name of the product is omega-3-acid triglycerides. packet sizes are 0,11kg aluminium bottle 190kg steel drums. the benefits of the product are this api, eicosapentaenoic acid and docosahexaenoic acid, mainly as triglycerides, complies with the european pharmacopoeia (ph eur.). we have over 20 years of production and research experience in omega-3-based pharmaceuticals..
product name is dexpanthenol ph. eur.. dexpanthenol for various therapeutic efficacy. description of the dexpanthenol ph.eur. is supplied as a colorless to slightly yellowish, viscous liquid or semicrystalline substance.. the product is manufactured in germany. the compendial name of the product is (+)-panthenol; dexpanthenol; n-pantoyl-3-propanolamine. packet sizes are 0,25kg aluminum drums 200kg steel drums 25kg steel drums 25kg plastic drums not specified. the benefits of the product are dexpanthenol increases the healing of wounds, stimulates the epithelization, and has anti-inflammatory properties  injectable vitamin preparations with dexpanthenol are used for completing parenteral nutrition..
product name is ibuprofen 25. fine grade ibuprofen. description of the all ibuprofen grades are supplied as white or almost white crystalline powder or colorless crystals with a characteristic odor.. the product is manufactured in usa. the compendial name of the product is ibuprofen_x000d_ (2rs)-2[4-(2-methylpropyl)phenyl]propanoic acid. packet sizes are 0,5kg plastic bottle 20kg fiber drum 50kg fiber drums. the benefits of the product are recommended for suspension  the mean particle size is about 25 μm (d (0.5) = 20-33 μm)  bulk density: approximately 0.3 g/ml  tapped density: approximately 0.48 g/ml.
product name is ibuprofen 38. powder grade ibuprofen with controlled particle size. description of the all ibuprofen grades are supplied as white or almost white crystalline powder or colorless crystals with a characteristic odor.. the product is manufactured in usa. the compendial name of the product is ibuprofen_x000d_ (2rs)-2[4-(2-methylpropyl)phenyl]propanoic acid. packet sizes are 0,5kg plastic bottle 50kg fiber drums 51,5kg fiber drums. the benefits of the product are the mean particle size is about 38 μm (d (0.5) = 33-45 μm)  bulk density: approximately 0.33 g/ml  tapped density: approximately 0.6 g/ml..
product name is ibuprofen 50. powder grade ibuprofen with controlled particle size. description of the all ibuprofen grades are supplied as white or almost white crystalline powder or colorless crystals with a characteristic odor.. the product is manufactured in usa. the compendial name of the product is ibuprofen, _x000d_ (2rs)-2-[4-(2-methylpropyl)phenyl]propanoic acid. packet sizes are 0,5kg plastic bottle 50kg fiber drums 62,8kg fiber drums not specified. the benefits of the product are the mean particle size is about 50 μm (d (0.5) = 45-60 μm)  bulk density: approximately 0.34 g/ml  tapped density: approximately 0.6 g/ml.
product name is ibuprofen 70. powder grade ibuprofen with controlled particle size. description of the all ibuprofen grades are supplied as white or almost white crystalline powder or colorless crystals with a characteristic odor.. the product is manufactured in usa. the compendial name of the product is ibuprofen_x000d_ (2rs)-2[4-(2-methylpropyl)phenyl]propanoic acid. packet sizes are 0,5kg plastic bottle 50kg fiber drums. the benefits of the product are the mean particle size is about 70 μm (d (0.5) = 60-85 μm)  bulk density: approximately 0.38 g/ml  tapped density: approximately 0.68 g/ml.
product name is ibuprofen dc 85 w. direct compressible grade with 85% ibuprofen. description of the the product is supplied as white granules, free-flowing, homogeneous material. it contains 85 % ibuprofen and 15 % of the following pharmaceutical inactive ingredients: croscarmellose sodium (ph. eur., usp quality), microcrystalline cellulose (ph. eur., usp, jp quality), and colloidal silicon dioxide (ph. eur., usp quality).. the product is manufactured in usa. packet sizes are 2kg metal pail 50kg fiber drums. the benefits of the product are sieve analysis  min. 15% retained on 0.85 mm sieve  min. 45% retained on 0.3 mm sieve  bulk density: approximately 0.55 g/ml.  tapped density: approximately 0.64 g/ml  angle of repose: 33°    ibuprofen dc 85 w is able to be compressed into tablets with minimum amount of lubricant.  excellent tablet engraving  maximizes production speed while minimizing stickiness  allows for smaller tablet sizes compared to those with pure ibuprofen which are easier to swallow.
product name is ibuprofen sodium dihydrate. salt form of ibuprofen. description of the the product is supplied as white to almost white powder.. the product is manufactured in usa. packet sizes are 0,5kg plastic bottle 50kg fiber drums. the benefits of the product are it dissolves more quickly in vitro and is absorbed more rapid (shorter tmax and faster onset of action) than conventional ibuprofen  it causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen  white to almost white powder containing asay 98.0 to 102% on anhydrous basis  e-dmf an us-dmf are both available.
product name is k85ee - cep-accepting markets. omega-3-acid ethyl esters (k85ee) as an active pharmaceutical ingredient (api), specified for cep-accepting markets. description of the omega-3-acid ethyl esters (k85ee) is a light-yellow liquid comprised of 430-495 mg/g eicosapentaenoic acid (epa) and 347-403 mg/g docosahexaenoic acid (dha). the content of epa and dha ethyl esters is 800-880 mg/g and the content of total omega-3-acid ethyl esters is a minimum of 90 per cent. tocopherol is added as an antioxidant. k85ee is a highly concentrated, unsaturated oil. it oxidizes readily in contact with air and is, therefore, filled in drums purged with nitrogen. it is well suited for use in soft gelatin capsules as the sole fill material.. the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 90 (ph.eur.), omega-3-acid ethyl esters (usp). packet sizes are 0,11kg aluminium bottle 190kg steel drums. the benefits of the product are this api complies with the european pharmacopoeia (ph eur.).  k85ee is documented in a cep  k85ee is used as an active ingredient in finished drug products according to a documented and approved indication after approval by the concerned medicinal authority. the exact indication may be different in different markets  long history of use in the finished drug product omacor®/lovaza™, the first fda- and eu-approved omega-3-based prescription drug   our sustainable sourcing and production contribute to reduction of our customers carbon footprint  the combination of technology and our know-how ensures an efficient production with a high utilization of the raw material.
product name is k85ee omega-3-acid ethyl esters - us market. omega-3-acid ethyl esters (k85ee) as an active pharmaceutical ingredient (api), specified for the us market. description of the k85ee omega-3-acid ethyl esters (k85ee) is a light-yellow liquid comprised of 430-495 mg/g eicosapentaenoic acid (epa) and 347-403 mg/g docosahexaenoic acid (dha). the content of epa and dha ethyl esters is 800-880 mg/g and the content of total omega-3-acid ethyl esters is a minimum of 90 per cent. tocopherol is added as an antioxidant. k85ee is a highly concentrated, unsaturated oil. it oxidizes readily in contact with air and is, therefore, filled in drums purged with nitrogen. it is well suited for use in soft gelatin capsules as the sole fill material.. the product is manufactured in norway. the compendial name of the product is compendial name:  omega-3-acid ethyl esters 90 (ph.eur.), omega-3-acid ethyl esters (usp). packet sizes are 0,11kg aluminium bottle 190kg steel drum. the benefits of the product are this api complies with the us pharmacopoeia (usp)  k85ee is documented in a us-dmf  k85ee is used as an active ingredient in finished drug products according to a documented and approved indication after approval by the concerned medicinal authority. the exact indication may be different in different markets  long history of use in the finished drug product omacor®/lovaza™, the first fda- and eu-approved omega-3-based prescription drug  our sustainable sourcing and production contribute to reduction of our customers carbon footprint  the combination of technology and our know-how ensures an efficient production with a high utilization of the raw material.
product name is k85ee omega-3-acid ethylesters -  global market, except japan and us. omega-3-acid ethyl esters (k85ee) as an active pharmaceutical ingredient (api), specified for the global market except japan and us. description of the omega-3-acid ethyl esters (k85ee) is a light-yellow liquid comprised of 430-495 mg/g eicosapentaenoic acid (epa) and 347-403 mg/g docosahexaenoic acid (dha). the content of epa and dha ethyl esters is 800-880 mg/g and the content of total omega-3-acid ethyl esters is a minimum of 90 per cent. tocopherol is added as an antioxidant. k85ee is a highly concentrated, unsaturated oil. it oxidizes readily in contact with air and is, therefore, filled in drums purged with nitrogen. it is well suited for use in soft gelatin capsules as the sole fill material.. the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 90 (ph.eur.), omega-3-acid ethyl esters (usp). packet sizes are 0,11kg aluminium bottle 190kg steel drums. the benefits of the product are this api complies with the european pharmacopoeia (ph eur.), us pharmacopoeia (usp)  k85ee is documented in a cep  k85ee is used as an active ingredient in finished drug products according to a documented and approved indication after approval by the concerned medicinal authority. the exact indication may be different in different markets  long history of use in the finished drug product omacor®/lovaza™, the first fda- and eu-approved omega-3-based prescription drug  our sustainable sourcing and production contribute to reduction of our customers carbon footprint  the combination of technology and our know-how ensures an efficient production with a high utilization of the raw material.
product name is k85ee omega-3-acid ethylesters - japanese market. omega-3-acid ethyl esters (k85ee) as an active pharmaceutical ingredient (api), specified for the japanese market. description of the k85ee omega-3-acid ethylesters (k85ee) is a light-yellow liquid comprised of 430-495 mg/g eicosapentaenoic acid (epa) and 347-403 mg/g docosahexaenoic acid (dha). the content of epa and dha ethyl esters is 800-880 mg/g and the content of total omega-3-acid ethyl esters is a minimum of 90 per cent. tocopherol is added as an antioxidant. k85ee is a highly concentrated, unsaturated oil. it oxidizes readily in contact with air and is, therefore, filled in drums purged with nitrogen. it is well suited for use in soft gelatin capsules as the sole fill material.. the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 90 (ph.eur.), omega-3-acid ethyl esters (usp). packet sizes are 0,11kg aluminium bottle 190kg steel drums. the benefits of the product are k85ee is used as an active ingredient in finished drug products according to a documented and approved indication after approval by the concerned medicinal authority. the exact indication may be different in different marketslong history of use in the finished drug product omacor®/lovaza™, the first fda- and eu-approved omega-3-based prescription drugour sustainable sourcing and production contribute to reduction of our customers carbon footprintthe combination of technology and our know-how ensures an efficient production with a high utilization of the raw material.
product name is kollicoat® ir. the true multitalent for various pharmaceutical applications. description of the kollicoat® ir is a white to faintly yellow free-flowing powder. the polymer consists of 75% polyvinyl alcohol units and 25% polyethylene glycol units. the product also contains approx. 0.3% colloidal anhydrous silica to improve its flow properties. as a result of its structure, the polymer dissolves very readily in acidic, neutral and alkaline aqueous media.. the product is manufactured in germany. the compendial name of the product is macrogol poly(vinyl alcohol)grafted copolymer (ph. eur.), ethylene gylcol and vinyl alcohol graft copolymer (usp-nf). packet sizes are 0,5kg plastic bottle not specified 20kg plastic drums. the benefits of the product are water-soluble film former for instant release coatings  high pigment-loading capacity  excellent wet binder  easy processing due to low solution viscosity and very fast dissolution  no peroxide formation.
product name is kollicoat® mae 100 p. reliable, high-performance enteric film coating material. description of the kollicoat® mae 100 p is a white redispersible powder with a faint characteristic odor. the partially neutralized carboxyl groups in the powder make it easy to redisperse in water without further auxiliaries. kollicoat® mae 100 p coating contains 0.7% sodium lauryl sulphate (usp) and 2.3% polysorbate 80 (ph.eur.) as emulsifying agents. the fatty acids used in the manufacture of polysorbate 80 are of vegetable origin. kollicoat® mae 100 p coating is a weakly acidic copolymer that dissolves at a ph above 5.5. it is also soluble in dilute alkaline solutions.. the product is manufactured in germany. the compendial name of the product is metacrylic acid-ethyl acrylate copolymer (1:1) type b (ph. eur.)_x000d_ partially-neutralized methacrylic acid and ethyl acrylate copolymer (usp-nf). packet sizes are 1kg plastic bottle 20kg fiberboard boxes. the benefits of the product are excellent resistance to gastric fluids  rapid release at ph values greater than 5.5  pore former for sustained release formulation for highly water soluble drug  easy and efficient processing.
product name is kollicoat® mae 100-55. a complete match – just better. description of the kollicoat® mae 100-55 is a white redispersible powder with a faint characteristic odor. _x000d_ the product contains 0.7% sodium lauryl sulphate (usp) and 2.3% polysorbate 80 (ph. eur.) as emulsifying agents. the fatty acids used in the manufacture of polysorbate 80 are of vegetable origin. the product is a weakly acidic copolymer that dissolves at a ph above 5.5._x000d_ kollicoat® mae 100-55 is a weakly acidic copolymer that dissolves at a ph above 5.5. kollicoat® mae 100-55 dissolves in methanol  and ethanol to yield clear to slightly cloudy solutions. it is also soluble in dilute alkaline solutions.. the product is manufactured in germany. the compendial name of the product is methacrylic acid - ethyl acrylate copolymer (1:1), type a (ph. eur.); methacrylic acid and ethyl acrylate copolymer (usp-nf); dried methacrylic acid copolymer ld (jpe). packet sizes are 0,5kg plastic bottle 1kg plastic bottle 20kg fiberboard boxes. the benefits of the product are direct substitution in commercial enteric release formulations based on methacrylic acid-ethylacrylate copolymer with an opening ph >5.5  easier handling due to dust-free material.
product name is kollicoat® mae 30 dp. ready to use enteric coating polymer for aqueous coating. description of the kollicoat® mae 30 dp is an aqueous dispersion with a solids content of 30% (w/w). the low viscosity product has a weak characteristic odor and a milky white or slightly yellowish appearance. based on the solid substance the dispersion consists of about 97% (w/w) methacrylic acid and ethylacrylate copolymer (1:1), 2.3% (w/w) polysorbate 80 and 0.7% (w/w) sodium lauryl sulfate. kollicoat®  mae 30 dp is miscible with water in any ratio while retaining its milky-white appearance. the polymer is insoluble in aqueous buffer systems with an acidic ph value between 1 and 5 and dissolves at ph-values of 5.5 and higher. the main application is enteric coating of solid oral dosage forms.. the product is manufactured in germany. the compendial name of the product is methyacryl acid and ethyl acrylate copolymer dispersion(usp), methacrylic acid copolymer ld (jpe), methacrylic acid-ethyl acrylate copolymer dispersion 30 per cent (ph. eur.). packet sizes are 530kg composite ibc 1000kg composite ibc 1kg plastic bottle 25kg plastic jerrycans not specified. the benefits of the product are excellent resistance to gastric fluids  rapid release at ph >5.5  easy and efficient processing.
product name is kollicoat® protect. effective and reliable moisture protection for your api. description of the kollicoat® protect is a composition of 55-65% polyvinyl alcohol-polyethylene glycol graft copolymer, 35-45% polyvinyl alcohol and 0.1-0.3% silicon dioxide as processing aid. it is a white to off-white, free-flowing powder. it rapidly dissolves in water. the aqueous solution has a relatively low viscosity and can be readily prepared.. the product is manufactured in germany. the compendial name of the product is polyvinyl alcohol graft polyethylene glycol copolymer and polyvinyl alcohol (pva). packet sizes are 0,5kg plastic bottle 25kg plastic drums. the benefits of the product are highly water-impermeable instant release coating  ideal for moisture-sensitive active ingredients  improves stability of formulation  easy preparation at room temperature and no plasticizer required.
product name is kollicoat® smartseal 100 p. the best in class polymer for taste masking and moisture protection applications via aqueous or solvent coating. description of the kollicoat® smartseal 100 p is a spray dried powder of a methyl methacrylate (mma)and diethylaminoethyl methacrylate (deaema) copolymer. the molar ratio of the monomers mma and deaema in the copolymer is 7:3. the powder contains approx. 2% macrogol cetostearyl ether and approx. 2.5% sodium lauryl sulfate. it is white and has a pleasant characteristic odor.. the product is manufactured in germany. packet sizes are 15kg fiberboard boxes 1kg plastic bottle. the benefits of the product are effective taste masking at low excipient levels/ thinner films  excellent flowability and less dusting for a safe processing environment  no irritant and toxic sls is required during processing  no fishy smell.
product name is kollicoat® smartseal 30 d. the first water-based polymer dispersion for taste-masking and moisture barrier applications. description of the kollicoat® smartseal is insoluble in water (neutral ph) and dissolves quickly under protonation at ph-values of 5.5 and below due to the defined number of basic functional groups. it is a co-polymer comprising methyl methacrylate (mma) and diethylaminoehtylmethacrylate (deaema) in the ratio 6:4. kollicoat smartseal 30 d is an aqueous polymer dispersion (latex) with a faint characteristic odor. it contains approx. 0.6 % macrogol cetostearylether 20 and approx. 0.8% sodium laurylsulfate.. the product is manufactured in germany. packet sizes are 1kg plastic bottle 25kg plastic jerrycans. the benefits of the product are effective taste masking at low coating levels  instant release of active ingredients below ph 5.5  effective sealing against moisture  pleasant smell for processing environments.
product name is kollicoat® sr 30 d. the coating polymer for ph-independent sustained release formulations. description of the kollicoat® sr 30 d is an aqueous dispersion with a solids content of 30%. the low viscosity product has a weak characteristic odor and a milky white or slightly yellowish appearance. the dispersion consists of about 27% polyvinyl acetate, 2.7% povidone and 0.3% sodium lauryl sulfate. kollicoat® sr 30 d is miscible with water in any ratio while retaining its milky-white appearance. mixing the product with ethanol or isopropyl alcohol in a 1:5 ratio produces a slightly turbid and somewhat viscous solution; a solution in acetone is more turbid. on addition of further organic solvents the polymer precipitates out but then dissolves when further solvent is added. it is insoluble in dilute alkaline or acidic solutions.. the product is manufactured in germany. the compendial name of the product is poly (vinyl acetate)dispersion 30 per cent (ph. eur.)_x000d_ polyvinyl acetate dispersion (usp). packet sizes are 1kg plastic bottle 25kg plastic jerrycans. the benefits of the product are amenable as a wet binder for granulation processes and/or and coating applications for sustained release  drug release profile can be easily optimized with compatible pore formers  low viscous aqueous dispersion of polyvinyl acetate for easy homogenization/mixing   high binding capacity and plasticity lead to robust films in tablets and pellets  due to the polymer's high plasticity and flexibility, drug release from pellets and tablets are not significantly affected by compression force  provides moderate taste-masking in multiple dosage forms.
product name is kollicream® 3c. a mild, emollient, solubilizer and skin penetration enhancer for dermal applications. description of the kollicream® 3c is a clear, mildly yellowish, medium polar oil; it has a slightly fatty odor. due to its high spreading value the product is suited for the use in pharmaceutical skin care preparations such as low fatting emulsions and skin oils.. the product is manufactured in germany. the compendial name of the product is cocoyl caprylocaprate (ph.eur.). packet sizes are 0,5kg plastic bottle 175kg steel drums 800kg composite ibc. the benefits of the product are medium spreadability  enhanced skin penetrability  extremely mild upon application  solvent for lipophilic drugs.
product name is kollicream® cp 15. a rich high melting point emollient for dermal applications. description of the kollicream® cp 15 is supplied in the form of white coarse pellets. on account of its body giving characteristics this wax is applied in  pharmaceutical emulsions.. the product is manufactured in germany. the compendial name of the product is cetyl palmitate 15 (ph.eur.). packet sizes are 0,5kg plastic bottle 20kg plastic film bags. the benefits of the product are slow spreading with rich feeling  solvent for lipophilic drugs.
product name is kollicream® do. a medium spreading emollient and solubilizer. description of the kollicream® do is a clear, slightly yellowish polar oil with characteristic odor. on account of the medium spreading value, the product is suitable for application in pharmaceutical skin care preparations, such as low fattening emulsions and skin oils.. the product is manufactured in germany. the compendial name of the product is decyl oleate (ph.eur.), decyl oleate (inci). packet sizes are 0,5kg plastic bottle 175kg steel drums. the benefits of the product are medium spreadability  solvent for lipophilic drugs  enhances skin penetration.
product name is kollicream® ipm. a fast spreading emollient with broad penetration enhancement properties for dermal applications. description of the kollicream® ipm is a clear, colorless, almost odorless oil of medium polarity. on account of its high spreading value, the product is suitable for the application in pharmaceutical skin care preparations such as low-fatting emulsions and skin oils. kollicream® ipm has a good solubilizing capacity for lipid-soluble active agents; it can serve as a dermatological carrier.. the product is manufactured in germany. the compendial name of the product is isopropyl myristate (ph.eur.), isopropyl myristate (usp/nf),1-methylethyl tetradecanoate. packet sizes are 0,5kg plastic bottle 175kg steel drums 850kg composite ibc. the benefits of the product are fast spreading with light & fresh feeling  solvent for lipophilic drugs  enhances skin penetration.
product name is kollicream® oa. a medium spreading emollient with penetration enhancement for dermal applications. description of the kollicream® oa  is a clear, slightly yellowish, almost odorless weak polar oil. kollicream® oa is suited for application in pharmaceutical skin care preparations, such as low-fatting emulsions and skin oils.. the product is manufactured in germany. the compendial name of the product is oleyl alcohol (ph.eur.), oleyl alcohol (usp/nf). packet sizes are 0,5kg plastic bottle 175kg steel drums 850kg composite ibc. the benefits of the product are medium spreadability  solvent for lipophilic drugs  enhances skin penetration.
product name is kollicream® od. a medium spreading emollient and provides good skin penetration for topical applications. description of the kollicream® od is a clear, slightly yellow, odorless oil of low polarity. on account of its medium spreading value, the product can be universally applied in pharmaceutical skin care preparations, such as slightly fatting emulsions and skin oils. due to its chemical structure, kollicream® od is stable to hydrolysis and can therefore be used without any problems both in the alkaline and the acid range.. the product is manufactured in germany. the compendial name of the product is octyldodecanol (ph.eur., usp/nf). packet sizes are 0,5kg plastic bottle 175kg steel drums. the benefits of the product are medium spreadability  extremely mild upon application  solvent for lipophilic drugs  enhances skin penetration  it is stable against acid and base hydrolysis  effective in exceptionally wide ph range.
product name is kollidon® 12 pf. endotoxin controlled, low molecular weight pvp-based solubilizers. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp. packet sizes are 0,5kg plastic pail 25kg plastic drums 50kg plastic drums. the benefits of the product are endotoxin tested within validated limits  particularly suitable for dissolvable microneedles  suitable as solubilizer and crystallization inhibitor  peroxeal® packaging for minimizing peroxide formation.
product name is kollidon® 17 pf. endotoxin controlled, low molecular weight pvp-based solubilizer for various pharmaceutical applications. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp. packet sizes are 0,5kg plastic pail 50kg plastic drums. the benefits of the product are highly water soluble povidone  endotoxin tested  suitable as solubilizer and crystallization inhibitor  peroxeal® packaging for minimizing peroxide formation.
product name is kollidon® 25 - 25kg. the original povidone – medium-molecular povidone is used in various pharmaceutical formulation. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp. packet sizes are 0,5kg plastic pail 25kg fiberboard boxes 0,5kg plastic bottle. the benefits of the product are standard binder in the pharmaceutical industry  easy processing due to low viscosity of the polymer solutions  low peroxide level due to peroxeal® packaging  numerous application options: binder, pore former, stabilizer, thickener, as solubilizing agent, crystallization inhibitor and many more.
product name is kollidon® 25 - 50kg. the original povidone – medium-molecular povidone is used in various pharmaceutical formulation. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp. packet sizes are 0,5kg plastic pail 50kg plastic drums. the benefits of the product are standard binder in the pharmaceutical industry  easy processing due to low viscosity of the polymer solutions  low peroxide level due to peroxeal® packaging  numerous application options: binder, pore former, stabilizer, thickener, as solubilizing agent, crystallization inhibitor and many more.
product name is kollidon® 30 - origin china. the original povidone – medium-molecular povidone is used in various pharmaceutical formulation. description of the the soluble kollidon 30 origin china is supplied as almost white, free-flowing powder or flakes.. the product is manufactured in china. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp.. packet sizes are 0,5kg plastic pail 50kg plastic drums. the benefits of the product are standard binder in the pharmaceutical industry  easy processing due to low viscosity of the polymer solutions  low peroxide level due to peroxeal® packaging  numerous application options (e.g. solubilizer, pore former).
product name is kollidon® 30 - origin germany 25kg. the original povidone – medium-molecular povidone is used in various pharmaceutical formulation. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp, e-number: 1201. packet sizes are 0,5kg plastic pail 25kg fiberboard boxes. the benefits of the product are standard binder in the pharmaceutical industry  easy processing due to low viscosity of the polymer solutions  low peroxide level due to peroxeal® packaging  numerous application options (e.g. solubilizer, pore former).
product name is kollidon® 30 - origin germany 50kg. the original povidone – medium-molecular povidone is used in various pharmaceutical formulation. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp, e-number: 1201. packet sizes are 0,5kg plastic pail 50kg plastic drums. the benefits of the product are standard binder in the pharmaceutical industry  easy processing due to low viscosity of the polymer solutions  low peroxide level due to peroxeal® packaging  numerous application options (e.g. solubilizer, pore former).
product name is kollidon® 30 - origin usa. the original povidone – medium-molecular povidone is used in various pharmaceutical formulation. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder.  they have a slight characteristic odor and are practically tasteless.  because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in usa. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp. packet sizes are 1kg pe-bottle 50kg pe-drum, removable head. the benefits of the product are standard binder in the pharmaceutical industry  easy processing due to low viscosity of the polymer solutions  low peroxide level due to peroxeal® packaging  numerous application options (e.g. solubilizer, pore former).
product name is kollidon® 30 lp. our original, kollidon® 30 in a low peroxide grade – protecting your oxygen-sensitive active ingredient longer.. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp. packet sizes are 0,5kg plastic pail 25kg fiberboard boxes. the benefits of the product are the original pvp from the industry’s most experienced team  particularly suitable for oxygen-sensitive apis – opening the door for new applications  consistently high quality for reliable performance and formulation stability  cutting-edge peroxeal™ packaging concept for even greater stability  built-in peroxide protection limits peroxides even after the packaging is opened.
product name is kollidon® 90 f. a highly effective water soluble binder. description of the all soluble grades of kollidon® are supplied in the form of an almost white free-flowing powder. they have a slight characteristic odor and are practically tasteless. because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.. the product is manufactured in germany. the compendial name of the product is povidone, povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone), pvp, e-number: 1201. packet sizes are 0,5kg plastic pail 25kg fiberboard boxes. the benefits of the product are strongest binding performance resulting in coarse and strong granules  low peroxide level due to peroxeal® packaging  numerous application options (e.g. thickening agent)  consistently high quality for reliable performance and formulation stability  suitable for the direct compression of tablets without granulation  high molecular povidone with a broad range of applications.
product name is kollidon® cl. super-disintegrants and dissolution enhancers. description of the kollidon® cl crosslinked polymer is supplied as fine white or almost white powder. it has a slight characteristic odor and is practically tasteless. it is insoluble in all of the usual solvents.. the product is manufactured in germany. the compendial name of the product is crospovidone, crospovidonum, insoluble polyvinylpyrrolidone, crosslinked pvp. packet sizes are 0,5kg plastic pail 40kg plastic drums. the benefits of the product are super-disintegrant and dissolution enhancers to improve release characteristics of tablets, capsules and granules  exceptionally fast release of active ingredients in solid dosage forms.
product name is kollidon® cl-f. super-disintegrants and dissolution enhancers. description of the kollidon® cl-f is supplied as fine white or almost white powder. it has a slight characteristic odor and is practically tasteless. it is insoluble in all of the usual solvents.. the product is manufactured in germany. the compendial name of the product is crospovidone, crospovidonum, insoluble polyvinylpyrrolidone, crosslinked pvp. packet sizes are 0,25kg plastic pail 0,5kg plastic pail 30kg plastic drums. the benefits of the product are improved tablet strength and surface quality due to smaller particle size  strong disintegration power in combination with a smooth tablet surface  ideal for small tablet formulation  suitable for wet granulation processes  bioavailability increase of selected hardly soluble active ingredients  consistently high quality for reliable performance and formulation stability.
product name is kollidon® cl-m. micronized grade super-disintegrants and dissolution enhancers. description of the kollidon® cl-m is supplied as fine white or almost white powder. it has a slight characteristic odor and is practically tasteless. it is insoluble in all of the usual solvents.. the product is manufactured in germany. the compendial name of the product is crospovidone, crospovidonum, insoluble polyvinylpyrrolidone, crosslinked pvp. packet sizes are 0,25kg plastic pail 30kg plastic drums. the benefits of the product are micronized grade with finest particles  stabilizer for oral and topical suspensions  improvement of drug release characteristics of tablets, capsules and granules  particularly suitable for small tables, granules and pellets.
product name is kollidon® cl-sf. super-disintegrants and dissolution enhancers. description of the kollidon® cl-sf is supplied as fine white or almost white powder. it has a slight characteristic odor and is practically tasteless. it is insoluble in all of the usual solvents.. the product is manufactured in germany. the compendial name of the product is crospovidone, crospovidonum, insoluble polyvinylpyrrolidone, crosslinked pvp. packet sizes are 0,25kg plastic pail 30kg plastic drums. the benefits of the product are its super fine particle size leads to a creamy mouth feel in odt formulations  high binding efficiency for increased tablet strength coupled with rapid disintegration properties.
product name is kollidon® sr. ph independent sustained release polymer. description of the kollidon® sr is a mixture of 80% of polyvinyl acetate and 19% povidone (kollidon® 30) in a physical mixture. approximately 0.8% of sodium lauryl sulphate and about 0.2% of silica are used as stabilizers. it is supplied as slightly yellowish, free-flowing powder. kollidon® sr polymer is insoluble in water and very soluble in n-methylpyrrolidone.. the product is manufactured in germany. the compendial name of the product is povidone and polyvinyl acetate. packet sizes are 0,5kg plastic film bags 0,5kg plastic bottle 0,3kg plastic bottle 20kg plastic drums. the benefits of the product are sprayable polymeric film former  flexible  wash resistant.
product name is kollidon® va 64. a copovidone used as dry binder in tablets, as matrix formers for amorphous solid dispersions. description of the kollidon® va 64 is a white or slightly yellowish, free-flowing powder with a faint characteristic odor and practically no taste. it readily dissolves in all hydrophilic solvents. solutions of more than 10 % concentration can be prepared in water, ethanol, isopropanol, methylene chloride, glycerol and propylene glycol. it is less soluble in ether, cyclic, aliphatic and alicyclic hydrocarbons.. the product is manufactured in germany. the compendial name of the product is copovidone, copolyvidone, vp/vac copolymer 60/40, copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4 by mass. packet sizes are 0,5kg plastic bottle 35kg plastic drums 0,5kg plastic pail. the benefits of the product are it provides erodible instant release matrix  it is a solubilizer, dispersant, crystallization inhibitor and matrix former  for direct compression, roller compaction and wet granulation, suitable for markets with higher humidity exposure   it has excellent stability throughout the extrusion process  a coarse powder provides a dust free handling, good flowability and faster extruder feeding  recently obtained gras/sa status (generally recognized as safe/self-affirmed) by the u.s. food & drug administration (fda) for use in food and nutritional supplements e.g. vitamin and mineral tablets.
product name is kollidon® va 64 fine. highly effective dry binder. description of the kollidon® va 64 fine is a white or slightly yellowish powder with a faint characteristic odor and practically no taste. it readily dissolves in all hydrophilic solvents. solutions of more than 10 % concentration can be prepared in water, ethanol, isopropanol, methylene chloride, glycerol and propylene glycol. it is less soluble in ether, cyclic, aliphatic and alicyclic hydrocarbons.. the product is manufactured in germany. the compendial name of the product is copovidone, copolyvidone, vp/vac copolymer 60/40, copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4 by mass.. packet sizes are 0,25kg plastic pail 15kg fiberboard boxes. the benefits of the product are suitable for increasing blend compressibility  highly effective binder even at low concentrations for medium and high dose formulations  very good plasticity combined with fine particle size distribution produce very hard tablets  amenable for processing and storage in all temperature zone markets  recently obtained gras/sa status (generally recognized as safe/self-affirmed) by the u.s. food & drug administration (fda) for use in food and nutritional supplements e.g. vitamin and mineral tablets.
product name is kolliphor® cs 12. a non-ionic emulsifier; stable with acidic, basic and ionic excipients. description of the kolliphor® cs 12 is a white, wax-like mass with a mild odor, delivered in pellets. the product can be universally applied as a non-ionic emulsifier for pharmaceutical o/w emulsions.. the product is manufactured in germany. the compendial name of the product is macrogol cetostearyl ether 12 (ph.eur.). packet sizes are 0,5kg plastic bottle 20kg fiberboard boxes. the benefits of the product are shows good sensory properties when formulated into creams  suitable for hot processes and phase inversion technology  stable with acidic, basic and ionic excipients  widely used for pharmaceutical oil-in-water emulsions.
product name is kolliphor® cs 20. non-ionic emulsifier for topical application. description of the kolliphor® cs 20 is supplied in white to slightly yellowish pellets. the product is used as universally applicable, non-ionic emulsifier for the manufacture of pharmaceutical o/w emulsions.. the product is manufactured in germany. the compendial name of the product is macrogol cetostearyl ether 20 (ph.eur.), polyoxyl 20 cetostearyl ether (usp), ceteareth-20 (inci). packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are shows good sensory properties when formulated into creams and lotions  suitable for hot processes and phase inversion technology  stable with acidic, basic, and ionic excipients  widely used as a mild, non-ionic emulsifier for pharmaceutical oil-in-water emulsions.
product name is kolliphor® cs a. an easy-to-use, self-emulsifying cream base. description of the kolliphor® cs a is a product with a faint characteristic odor, which is supplied in pellets. this anionic self emulsifying base is suited for the preparation of pharmaceutical o/w creams and lotions.. the product is manufactured in germany. the compendial name of the product is cetostearyl alcohol (type a), emulsifying (ph.eur.). packet sizes are 0,5kg plastic bottle 20kg plastic film bags. the benefits of the product are anionic emulsifier and consistency factor combination for creams and lotions   self emulsifying wax  convenient and easy-to-use cream base  self-emulsifying system building its own consistency and viscosity  enables many ingredients (or apis) to be stably dispersed.
product name is kolliphor® csl. an easy-to-use, self-emulsifying cream base. description of the kolliphor® csl is a product with a faint characteristic odor, which is supplied in pellets. this anionic self emulsifying base is suited for the preparation of pharmaceutical o/w creams and lotions.. the product is manufactured in germany. packet sizes are 0,5kg plastic bottle 20kg plastic film bags. the benefits of the product are convenient easy to use cream base  many ingredients or api’s can be stably dispersed  combination of sodium lauryl sulfate and sodium cetostearyl sulfate allows for strong self-emulsification.
product name is kolliphor® css. an anionic emulsifier for topical pharmaceutical applications. description of the kolliphor® css is a white to slightly yellowish powder with faint characteristic odor. the product is used as anionic o/w emulsifier for the preparation of pharmaceutical o/w creams and lotions.. the product is manufactured in germany. the compendial name of the product is sodium cetostearyl sulfate (ph.eur.). packet sizes are 0,25kg plastic bottle 12kg paper bags. the benefits of the product are anionic emuslifier with the potential for emulsifying a wide spectrum of oils  suitable for formulating emulsion, creams, and foams  can be used to emulsify biphasic systems.
product name is kolliphor® el. a non-ionic surfactant for various pharmaceutical applications. description of the kolliphor el is a non-ionic solubilizer and emulsifier made by reacting castor oil with ethylene oxide in a molar ratio of 1:35. it is a pale yellow oily liquid that is clear at temperatures above 26 °c. it has a faint but characteristic odor. it forms clear solutions in water. it is also soluble in many organic solvents, e.g. ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethyl acetate, chloroform, carbon tetrachloride, trichloroethylene, toluene and xylene.. the product is manufactured in germany. the compendial name of the product is macrogolglycerol ricinoleate, macrogolglyceroli ricinoleas, polyoxyl 35 castor oil. packet sizes are 0,5kg plastic bottle 60kg steel drums 5kg plastic jerrycans. the benefits of the product are widely used and fully approved solubilizer  good compatibility with other ingredients.
product name is kolliphor® elp. the highly purified solubilizer for oral, parenteral and topical applications. description of the kolliphor elp is a white to yellowish paste or cloudy liquid. it is a non-ionic solubilizer made by reacting castor oil with ethylene oxide in a molar ratio of 1:35. this is followed by a purification process. kolliphor elp forms clear solutions in water and also dissolves in a wide range of organic solvents, such as ethanol, n-propanol, isopropanol, ethyl acetate, chloroform, carbon tetrachloride, trichloroethylene, toluene and xylene.. the product is manufactured in germany. the compendial name of the product is macrogolglycerol ricinoleate, peg-35 castor oil. packet sizes are 0,5kg aluminum bottle 60kg steel drums 0,5kg plastic bottle 5kg composite packaging. the benefits of the product are highly purified kolliphor® el grade (polyoxyl-35-castor oil)  endotoxin controlled  excellent compatibility with other ingredients  purified solubilizer for paclitaxel formulations  especially suitable for formulations containing extremely sensitive apis  compliant with ph. eur. and usp-nfalso stabilizes biologic drug formulations.
product name is kolliphor® hs 15. a nonionic solubilizer with low toxicity for parenteral applications. description of the kolliphor hs 15 is a yellowish white paste at room temperature that becomes a liquid at approximately 30 °c. it dissolves in water, ethanol and 2-propanol to form clear solutions. its solubility in water decreases with increasing temperatures. it is insoluble in liquid paraffin.. the product is manufactured in germany. the compendial name of the product is polyethylene glycol 660 12-hydoxystearate, macrogol-15-hydroxystearate, macrogoli 15 hydroxystearas. packet sizes are 0,5kg plastic bottle 50kg steel drums. the benefits of the product are low histamine release, reduces side-effects  thermal stability, suitable for sterilization  lower hemolytic activity compared to other polyoxyethylene-based surfactants  monographed in ph. eur. and usp-nfalso stabilizes biologic drug formulations.
product name is kolliphor® p 188 bio. designed to meet your needs in quality, consistency, and performance, because every cell counts. description of the kolliphor® p 188 bio is supplied as white to slightly yellowish, coarse grained powder with a waxy consistency. it is freely soluble in ethanol, freely soluble in water (opalescent solution), and is insoluble in diethyl ether, paraffin and fatty oils.. the product is manufactured in usa. the compendial name of the product is polyoxyethylene-polyoxypropylene, alpha-hydro-omega-hydroxypoly(oxyethylene)a poly(oxypropylene)b poly(oxyethylene)a block copolymer, polyethylene-polypropylene glycol, poloxamer 188. packet sizes are 0,5kg plastic bottle 102kg plastic drums 12,5kg plastic pail 25kg plastic drums 5kg plastic pail. the benefits of the product are consistent performance lowers manufacturing risk  additional cell culture & analytical testing  enhanced packaging.
product name is kolliphor® p 188 geismar. a polymeric multi-talent non-ionic polymer suitable for various pharmaceutical applications. description of the kolliphor® p 188 is supplied as white to slightly yellowish, coarse grained powder with a waxy consistency. it is freely soluble in ethanol, freely soluble in water (opalescent solution), and is insoluble in diethyl ether, paraffin and fatty oils.. the product is manufactured in usa. the compendial name of the product is polyoxyethylene-polyoxypropylene, alpha-hydro-omega-hydroxypoly(oxyethylene)a poly(oxypropylene)b poly(oxyethylene)a block copolymer, polyethylene-polypropylene glycol, poloxamer 188. packet sizes are 0,5kg plastic bottle 102kg fiber drums 25kg fiber drums. the benefits of the product are hlb value >24  it used as wetting agents, as emulsifiers and solubilizers  it improves the solubility, absorption and bioavailability of low-solubility actives  aqueous solution containing more than 20% concentration are themoreversible viscosity  also used for hot-melt and spray-drying processes  poloxamers are non-ionic and less irritating upon application.
product name is kolliphor® p 188 micro geismar. a polymeric multi-talent non-ionic polymer suitable for variety of instant and modified release applications. description of the kolliphor® p 188 micro is supplied as white to slightly yellowish microbeads. it is readily soluble in water and ethanol and other mainly polar solvents. it is insoluble in ether, paraffin and fatty oils.. the product is manufactured in usa. the compendial name of the product is polyoxyethylene-polyoxypropylene-block-copolymer, microprilled poloxamer 188. packet sizes are 0,5kg plastic bottle 25kg fiber drums 0,5kg plastic bottle. the benefits of the product are microprilled poloxamers were microprilled to an average particle size of approximately 50 mm  dissolution enhancer for actives in tablets and capsules  lubricant for actives incompatible with mg-stearate, e.g. ibuprofen  polishing agent for film-coated tablets  dispersing/wetting agent  water soluble lubricant, e.g. for effervescent tablets  supports lubrication needs in direct compression and dry granulation production of tablets and capsules.
product name is kolliphor® p 338 geismar. a polymeric multi-talent polymer suitable for various pharmaceutical applications. description of the kolliphor® p 338 is supplied as white or almost white, coarse grained powder with a waxy consistency. it is freely soluble in water (opalescent solution) and ethanol; insoluble in diethyl ether, paraffin and fatty oils.. the compendial name of the product is polyoxyethylene-polyoxypropylene, alpha-hydro-omega-hydroxypoly(oxyethylene)a poly(oxypropylene)b poly(oxyethylene) a block copolymer, polyethylene-polypropylene glycol, poloxamer 338. packet sizes are 0,5kg plastic bottle 80kg fiber drums not specified. the benefits of the product are suitable for a broad range of applications   hlb value >24  it primarily used as thickening agents and gel formers but also as wetting agents, as emulsifiers and solubilizers  it shows characteristic property of thermoreversible gelation upon cooling or heating  the high performance and safety is backed by comprehensive documentation.
product name is kolliphor® p 407 geismar. a polymeric multitalent non-ionic polymer suitable for various pharmaceutical applications. description of the kolliphor® p 407 is supplied as white to slightly yellowish, coarse-grained powder with a waxy consistency. it is soluble in water, ethanol (95%) and isopropanol. it is insoluble in ether, paraffin and fatty oils.. the product is manufactured in usa. the compendial name of the product is polyoxyethylene-polyoxypropylene, alpha-hydro-omega-hydroxypoly(oxyethylene)a poly(oxypropylene)b poly(oxyethylene)a block copolymer, polyethylene-polypropylene glycol, poloxamer 407. packet sizes are 0,5kg plastic bottle 90kg fiber drums. the benefits of the product are hlb value between 18-23  it is primarily used as thickening agents and gel formers but also as wetting agents, as emulsifiers and solubilizers  it shows characteristic property of thermoreversible gelation upon cooling or heating.
product name is kolliphor® p 407 micro geismar. kolliphor® p 407 mico offers effective content uniformity, solubilization and increase oral bioavailability of bioactive. description of the kolliphor® p 407 micro is supplied as white to slightly yellowish microbeads. it is readily soluble in water and ethanol and other mainly polar solvents. it is insoluble in ether, paraffin and fatty oils.. the product is manufactured in usa. the compendial name of the product is polyoxyethylene-polyoxypropylene, alpha-hydro-omega-hydroxypoly(oxyethylene)a poly(oxypropylene)b poly(oxyethylene)a block copolymer, polyethylene-polypropylene glycol, poloxamer 407 microprilled. packet sizes are 0,5kg plastic bottle 25kg fiber drums. the benefits of the product are effective solubilization and increased bioavailability and elimination of dumping  microprilled poloxamers were microprilled to an average particle size of approximately 50 mm  average particle size within the same range as for active ingredients which result in homogenous mixtures for granulation or tabletting.
product name is kolliphor® ps 20. kolliphor® ps 20 is a non-ionic, hydrophilic emulsifier, co-emulsifier and solubilizer. description of the kolliphor® ps 20 is an oily, yellow, clear or slightly opalescent liquid with a faint odor. kolliphor® ps 20 is used as a non-ionic, hydrophilic emulsifier and/or solubilizer for pharmaceutical preparations (creams and ointments).. the product is manufactured in germany. the compendial name of the product is polysorbate 20 (ph.eur., usp/nf), polysorbate 20 (inn), polyoxyethylene 20 sorbitan monolaurate, polyethylene glycol 20 sorbitan ether monolaurate. packet sizes are 0,5kg plastic bottle 190kg steel drums. the benefits of the product are suitable for use as solubilizer and emulsifier  broad ph range  good skin tolerance.
product name is kolliphor® ps 60. kolliphor® ps 60 is a non-ionic, hydrophilic emulsifier, co-emulsifier and solubilizer. description of the kolliphor® ps 60 is a pasty yellow liquid with a faint characteristic odor. kolliphor® ps 60 is used as a non-ionic, hydrophilic emulsifier for pharmaceutical creams and ointments.. the product is manufactured in germany. the compendial name of the product is polysorbate 60 (ph.eur.), polysorbate 60 (usp/nf), polysorbate 60 (jpe), polysorbate 60 (inci). packet sizes are 0,5kg plastic bottle 190kg steel drums. the benefits of the product are suitable for cold processing of semi-solid dosage forms  suitable for solid, semi solid and liquid dosage forms  used as solubilizer in solid, semi-solid and liquid dosage forms or as foam stabilizer  good skin tolerance and broad ph range.
product name is kolliphor® ps 80. kolliphor® ps 80 is a non-ionic, hydrophilic emulsifier, co-emulsifier and solubilizer. description of the kolliphor® ps 80 is an amber liquid with a faint characteristic odor. kolliphor® ps 80 is used as a non-ionic surfactant and oil-in-water emulsifier, as plasticizer in a range of solid dispersions and oral dosage forms. it is a non-ionic, hydrophilic emulsifier with broad ph range applicability and good skin tolerance in topical formulations.. the product is manufactured in germany. the compendial name of the product is polysorbate 80 (ph.eur.), polysorbate 80 (usp/nf), polysorbate 80 (inci). packet sizes are 0,5kg amber glass bottle 190kg steel drums. the benefits of the product are suitable for oral, semi solid and liquid dosage forms as well as softgelsplasticizer in a range of solid dispersions and oral dosage formsbroad ph range applicability and good skin tolerance in topical formulationssolubilizing agent in a variety of pharmaceutical formulations.
product name is kolliphor® rh 40. the standard pharmaceutical non-ionic, oil-in-water solubilizer and emulsifying agent. description of the kolliphor rh 40 is a nonionic solubilizer and emulsifying agent obtained by reacting 40 moles of ethylene oxide with 1 mole of hydrogenated castor oil. the main constituent of kolliphor rh 40 is glycerol polyethylene glycol oxystearate, which, together with fatty acid glycerol polyglycol esters, forms the hydrophobic part of the product. the hydrophilic part consists of polyethylene glycols and glycerol ethoxylate. kolliphor rh 40 is a white to yellowish paste at 20°c.. the product is manufactured in germany. the compendial name of the product is macrogolglycerol hydroxystearate, macrogolglyceroli  hydroxystearas, castor oil, polyoxyl hydrogenated,  polyoxyl 40 hydrogenated castor oil. packet sizes are 0,5kg plastic bottle 60kg steel drums 60kg plastic drums. the benefits of the product are widely used and approved solubilizer  particularly suited for aqueous solutions of fat-soluble vitamins  chemically stable and practically tasteless – perfect for oral applications  suitable for sedds and smdds as it is less digestible in git conditions as compare to other unsaturated ethoxylated surfactants.
product name is kolliphor® sls. a widely used anionic surfactant for various pharmaceutical products. description of the kolliphor® sls is an alkyl sulphate on the basis of a natural, saturated, straight-chain, primary fatty alcohol. its foam and cleansing properties are noteworthy.the product is characterized by a very high active substance matter and a very low content of inorganic salts and unsulfated fatty alcohol.. the product is manufactured in germany. the compendial name of the product is sodium laurilsulfate (ph.eur.), sodium lauryl sulfate (nf), sodium lauryl sulfate (jp), sodium lauryl sulfate (inci),. packet sizes are 0,5kg plastic bottle 25kg paper bags 600kg flexible ibc. the benefits of the product are spray crystallized granular sodium lauryl sulfate, based on a natural saturated straight-chain primary fatty alcohol  extremely efficient excipient throughout the tableting process  widely used ionic solubilizer and high hlb anionic emulsifier  additionally suitable as wetting agent or lubricant  suitable for solid, semi-solid dosage forms and foamsused in biopharma manufacturing for solubilizing inclusion bodies during downstream processing.
product name is kolliphor® sls fine. a fast dissolving and widely used anionic surfactant for various pharmaceutical products. description of the kolliphor® sls fine is a white to off-white powder with faint characteristic odor. the product tends to agglomerate. the agglomerates exhibit a yellowish to brownish color and are completely soluble by heating and stirring. solubilizing, the agglomerates does not influence the product quality. the product is characterized by a very high active substance matter and a very low content of inorganic salts and unsulfated fatty alcohol. preferred areas of application are pharmaceutical emulsion, tablets and cream shampoos.. the product is manufactured in germany. the compendial name of the product is sodium laurilsulfate (ph.eur.), sodium lauryl sulfate (nf), sodium lauryl sulfate (jp), sodium lauryl sulfate (inci),. packet sizes are 0,25kg plastic bottle 15kg paper bags. the benefits of the product are spray-dried fine sodium lauryl sulfate, based on a natural saturated straight-chain primary fatty alcohol  the finer particles for more controlled and efficient solubilization  widely used ionic solubilizer and high hlb anionic emulsifier  additionally suitable as wetting agent or lubricant  suitable for solid, semi-solid dosage forms and foams  particularly suitable for direct compression.
product name is kollisolv peg 1000. semisolid polyethylene glycols with low aldehydes content for various pharmaceutical applications. description of the kollisolv peg 1000 is a white to almost white solid with a waxy or paraffin-like appearance. it is very soluble in water, freely soluble in alcohol, practically insoluble in fatty oils and in mineral oils.. the product is manufactured in usa. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are not specified 0,25kg plastic bottle 204kg steel drums. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation.
product name is kollisolv® gta. versatile water and oil miscible solvent. description of the kollisolv® gta is a clear, colorless, slightly viscous liquid. kollisolv® gta is used as a solubilizer for the production of pharmaceutical preparations.. the product is manufactured in germany. the compendial name of the product is triacetin (ph.eur.), triacetin (usp/nf), glycerol triacetate, 1,2,3-propanetriol triacetate. packet sizes are 0,5kg plastic bottle 235kg steel drums. the benefits of the product are a clear, slightly viscous oily liquid. it is a triester of glycerol and acetic acid  suitable as solvent, plasticizer, solubilizer, and humectant and other applications.
product name is kollisolv® mct 70. medium chain triglyceride based lipids for oral and topical formulations. description of the kollisolv® mct 70 is a clear, slightly yellowish, polar, odorless oil. due to its medium spreading value, the product can be universally applied in pharmaceutical skin care preparations and well-fatting emulsions and skin oils.. the product is manufactured in germany. the compendial name of the product is triglycerides, medium-chain (ph.eur.), medium-chain triglycerides (usp), caprylic/capric triglyceride (inci). packet sizes are 0,5kg plastic bottle 190kg steel drums 850kg composite ibc. the benefits of the product are easy to emulsify  high solubilization capacity for lipophilic drugs  suitable for use as solvent, solubilizer, penetration enhancer, emollient, water-barrier-repairing for lipophilic drugs.
product name is kollisolv® p 124 geismar. a polymeric multi-talent non-ionic polymer suitable for various pharmaceutical applications. description of the kollisolv® p 124 is a milky white paste or a colorless or almost colorless liquid. it is soluble in water and in ethanol, practically insoluble in light petroleum.. the product is manufactured in usa. the compendial name of the product is polyoxyethylene-polyoxypropylene, alpha-hydro-omega-hydroxypoly(oxyethylene)a poly(oxypropylene)b poly(oxyethylene)a block copolymer, polyethylene-polypropylene glycol, poloxamer 124. packet sizes are 0,5kg aluminum bottle 200kg steel drums 0,5kg plastic bottle. the benefits of the product are only monographed poloxamer that is liquid at room temperature  ideal for liquid dosage forms  it has melting point around 16°c and hydrophiilic-lipophilic balance (hlb) value between 12-18  it is used for liquid-filled softgel capsules as a dispersion medium for apis, or as plasticizer for tablet formulations  suitable for softgels, creams, foams, gels and emulsions.
product name is kollisolv® peg 1450. solid polyethylene glycols with low aldehydes content for various pharmaceutical applications. description of the kollisolv peg 1450 is a white to almost white solid with a waxy or paraffin-like appearance. it is very soluble in water, freely soluble in alcohol, practically insoluble in fatty oils and in mineral oils.. the product is manufactured in usa. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are 113kg fiber drums 0,35kg aluminum bottle. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation.
product name is kollisolv® peg 300. liquid polyethylene glycols for various pharmaceutical applications. description of the kollisolv® peg 300 is a colorless and tasteless liquid at room temperature. it is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats.. the product is manufactured in germany. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are 0,5kg plastic bottle 130kg plastic drums. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation.
product name is kollisolv® peg 300 g. liquid polyethylene glycols for various pharmaceutical applications. description of the kollisolv peg 300 g is a colorless and tasteless liquid at room temperature. it is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats.. the product is manufactured in usa. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are not specified 0,25kg plastic bottle 204kg steel drums. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation.
product name is kollisolv® peg 400. liquid polyethylene glycols for various pharmaceutical applications. description of the kollisolv® peg 400 is a colorless and tasteless liquid at room temperature. it is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats.. the product is manufactured in germany. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are 0,5kg plastic bottle 1000kg composite ibc 130kg plastic drums. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation.
product name is kollisolv® peg 400 g. liquid polyethylene glycols for various pharmaceutical applications. description of the kollisolv® peg 400 is a colorless and tasteless liquid at room temperature. it is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats.. the product is manufactured in usa. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are 0,25kg plastic bottle 0,5kg aluminum bottle 204kg steel drums not specified. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation  pharmaceutical grade ipec gmp compliance.
product name is kollisolv® peg 400 la. liquid polyethylene glycols with low aldehydes content for various pharmaceutical applications. description of the kollisolv® peg 400 is a colorless and tasteless liquid at room temperature. it is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats.. the product is manufactured in usa. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are 204kg steel drums. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation  pharmaceutical grade ipec gmp compliance.
product name is kollisolv® peg 600. liquid polyethylene glycols for various pharmaceutical applications. description of the kollisolv® peg 600 is a colorless and tasteless liquid at room temperature. it is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats.. the product is manufactured in usa. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are 0,25kg plastic bottle 0,5kg aluminum bottle 204kg steel drums. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation.
product name is kollisolv® peg 600 la. liquid polyethylene glycols with low aldehydes content for various pharmaceutical applications. description of the kollisolv® peg 600 is a colorless and tasteless liquid at room temperature. it is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats.. the product is manufactured in usa. the compendial name of the product is macrogol, polyglycol, polyoxyethylene and polydiol. packet sizes are 0,25kg glass bottle 204kg steel drums. the benefits of the product are versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  recommended for softgels  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation.
product name is kollisolv® peg 8000. solid polyethylene glycols for various pharmaceutical applications. description of the white or almost white solid with a waxy or paraffin-like appearance. very soluble in water and in methylene chloride, very slightly soluble in alcohol, practically_x000d_ insoluble in fatty oils and in mineral oils.. the product is manufactured in usa. the compendial name of the product is poly(oxyethylene), poly(ethylene oxide), poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy. macrogol 8000. packet sizes are 0,25kg plastic bottle 91kg fiber drums not specified. the benefits of the product are kollisolv® peg 8000 will not support microbial growth, even in aqueous solutions  versatile, water-miscible vehicle used as solvent and solubilizing agent for active substances and excipients in liquid and semisolid preparation  can be paired with basf surfactants (for example kolliphor® rh 40) to promote solubilization of poorly water-soluble apis  can be used for crystallization inhibition with basf polymers (for example kollidon® 12 pf)  can also be used as a chemical intermediate in drug formulation  wide acceptance in pharmaceutical application for over 50 years.
product name is kollisolv® pg. high purity premium solvent for various pharmaceutical formulations. description of the kollisolv pg is a clear, colorless viscous liquid of low volatility with a boiling range of 185 - 189 °c. it is odorless, neutral and hygroscopic. it is miscible in all proportions with water, lower alcohols, esters and ketones.. the product is manufactured in germany. the compendial name of the product is propylene glycol, 1,2-propandiole. packet sizes are 0,5kg aluminum bottle 1000kg composite ibc 220kg plastic drums 0,5kg plastic bottle. the benefits of the product are it is used across a wide range of applications, i.e. as preservative, as solvent or cosolvent, as extractant, as stabilizer, or as carrier for emulsifiers  germacidal properties.
product name is kollisolv® pyr. solvent for parenterals and oral formulations for animal health. description of the kollisolv pyr, 2-pyrrolidone, is a colorless or slightly colored liquid which solidifies at room temperature and has a characteristic odor. it is soluble in water and a number of organic solvents, e.g. ethanol, isopropyl alcohol and aromatic hydrocarbons.. the product is manufactured in germany. packet sizes are 0,5kg glass bottle 200kg composite packaging. the benefits of the product are approved solvent for veterinary use in injectables & oral formulations  versatile solvent with broad miscibility for topical application.
product name is kollitab™ dc 87 l. your new all-in-one tableting solution. description of the kollitab™ dc 87 l is an almost white, odorless, and free-flowing powder. it is a coprocessed excipient based on lactose monohydrate (87%), crospovidone (9%), kollicoat® ir (3%) and sodium stearyl fumarate (1%).. the product is manufactured in eu. the compendial name of the product is lactose monohydrate, crospovidone, peg-pva-copolymer, sodium stearyl fumarate. packet sizes are 1kg plastic bottle (50711206)20kg fiberboard box (50708787). the benefits of the product are kollitab™ dc 87 l is an all-in-one tableting solution that includes a filler, binder, disintegrant and lubricant. it provides superior flowability, achieves high tablet strength when applying a broad range of compression forces (both low and high), and ensures fast tablet disintegration. its “all-in-one” nature enables fast tablet development, simplifies formulation processes, and reduces manufacturing complexity..
product name is kolliwax® ca. a commonly used fatty alcohol as consistency factor. description of the kolliwax® ca is a white to almost white, wax like-mass supplied as free flowing mirco pearls. on account of its consistency giving characteristics kolliwax® ca is mainly used for viscosity regulation in pharmaceutical emulsions. raw material base is coconut oil, palm kernel oil, palm oil and/or palm stearine.. the product is manufactured in germany. the compendial name of the product is cetyl alcohol (ph.eur.), cetyl alcohol (nf), cetanol (jp), cetyl alcohol (inci). packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are helps create a unique softness and creaminess in the end application   due to shorter fatty alcohol chains, product has good sensory properties on skin, flows nicely and has good consistency  superior manufacturing process resulting in improved efficiency and higher purity.
product name is kolliwax® csa 50. a fatty alcohol mixture, preferred for its stability in emulsion formulations. description of the kolliwax® csa 50 is a white to pale yellow, wax like-mass supplied as free flowing mirco pearls. on account of its consistency giving characteristics kolliwax® csa 50 is mainly used for viscosity regulation in pharmaceutical emulsions. raw material base is coconut oil, palm kernel oil, palm oil and/or palm stearine.. the product is manufactured in germany. the compendial name of the product is cetostearyl alcohol (ph.eur.), cetostearyl alcohol (nf), cetostearyl alcohol (jpe), cetearyl alcohol (inci), cetyl stearyl alcohol. packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are compatible with most natural vegetable and animal waxes  creates a more stable matrix, when formulated with emulsifier and water  slightly broader melting point window than kolliwax® ca and kolliwax® sa.
product name is kolliwax® csa 70. a fatty alcohol mixture, preferred for its stability in emulsion formulations. description of the kolliwax® csa 70 is a white to pale yellow, wax like-mass supplied as free flowing mirco pearls. on account of its consistency giving characteristics kolliwax® csa 70 is mainly used for viscosity regulation in pharmaceutical emulsions.. the product is manufactured in germany. the compendial name of the product is cetostearyl alcohol (ph.eur.), cetyl stearyl alcohol, cetearyl alcohol. packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are compatible with most natural vegetable and animal waxes  creates a more stable matrix, when formulated with emulsifier and water  slightly broader melting point window than kolliwax® ca and kolliwax® sa.
product name is kolliwax® gms ii. an emulsifier for oral and topical applications. description of the kolliwax® gms ii is a white to slightly yellowish, hydrophilic wax, which is supplied as powder. on account of its consistency giving characteristics it is mainly used for the viscosity adjustment in pharmaceutical o/w emulsions.. the product is manufactured in germany. the compendial name of the product is glycerol monostearate 40-55 (type ii) (ph.eur.), mono- and di-glycerides (usp/nf). packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are co-emulsifier and low hlb surfactant  innovative solutions for better, more stable formulations  structure building consistency for semi solids  can mitigate stickiness or greasiness.
product name is kolliwax® hco. hydrogenated castor powder for various pharmaceutical applications. description of the kolliwax® hco is a white to slightly yellowish, fine, free-flowing powder. the product is used as retardation component and pressing agent for the preparation of tablets for pharmaceutical application.. the product is manufactured in germany. the compendial name of the product is castor oil, hydrogenated (ph.eur.), hydrogenated castor oil (usp/nf), hydrogenated oil (jp), hydrogenated castor oil (inci). packet sizes are 0,5kg plastic bottle 20kg fiberboard boxes. the benefits of the product are at room temperature it is a hard wax with a high melting point (85-88°c)  unique particle size distribution  is particularly suitable for the formulation of sensitive apis  compatible with several natural vegetable and animal waxes, as well as fatty alcohols to enhance viscosity of topical formulations  suitable as a plasticizer for melt granulation, spray drying, hot melt extrusion.
product name is kolliwax® ma. a consistency factor with low melting point and soft sensory effect. description of the kolliwax® ma is a white to light yellowish hydrophilic wax, which is supplied in pellets. on account of its consistency giving characteristics the product is mainly used for viscosity regulation in pharmaceutical o/w-emulsions.. the product is manufactured in germany. the compendial name of the product is myristyl alcohol (usp/nf). packet sizes are 0,5kg plastic bottle 20kg fiberboard boxes. the benefits of the product are used for multiple topical pharmaceutical applications such as, gel creams, lotions and creams  creates a unique softness and creaminess in an end application  has a lower melting point and consistency factor, with soft and pleasing sensory properties.
product name is kolliwax® s. kolliwax® s can be used for various oral and topical dosage forms. description of the kolliwax® s is a vegetable based stearic/palmitic acid and is a white powder with a typical odor. on account of its consistency giving characteristics the product is mainly used for viscosity regulation in pharmaceutical o/w-emulsions.. the product is manufactured in germany. the compendial name of the product is stearic acid 50 (ph.eur.), stearic acid 50 (usp-nf), stearic acid 50 (jp). packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are compatible to a large number of actives  particularly suitable for sensitive apis  can be used as a lubricant in oral dosage forms, matrix forming agent in sustained-release dosage forms, emulsifying and solubilizing agent in topical formulations and hardening agent in glycerin suppositories.
product name is kolliwax® s fine. kolliwax® s fine can be used for various oral applications. description of the kolliwax® s fine is a vegetable based stearic/palmitic acid and is a fine white powder with a typical odor. on account of its consistency giving characteristics the product is mainly used for viscosity regulation in pharmaceutical o/w-emulsions.. the product is manufactured in germany. the compendial name of the product is stearic acid 50 (ph.eur.), stearic acid 50 (usp-nf), stearic acid 50 (jp). packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are effective alternative to magnesium stearate as lubricant  compatible to a large number of actives  no metallic taste development  particularly suitable for sensitive apis  no metallic taste development.
product name is kolliwax® sa. as lipophilic kolliwax® sa for oral and topical applications. description of the kolliwax® sa is a white to almost white, wax like-mass supplied as free flowing mirco pearls. on account of its consistency giving characteristics kolliwax® sa is mainly used for viscosity regulation in pharmaceutical emulsions.. the product is manufactured in germany. the compendial name of the product is stearyl alcohol (ph.eur.), stearyl alcohol  (usp/nf), 1-octadecanol. packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are pasticizer with included consistency factor functionality  lipophilic lubricant and the first choice for sensitive acidic apis  kolliwax® sa acts as a plasticizer with included consistency factor in solid dispersions. it hardens suppository formulations and adjust their melting points  it is commonly used as viscosity regulator for oil-in-water emulsions and as a ph independent sustained release agent.
product name is kolliwax® sa fine. as lipophilic lubricant. description of the kolliwax® sa fine is a white to almost white, wax like-mass supplied as a fine powder. on account of its consistency giving characteristics kolliwax® sa fine is mainly used for viscosity regulation in pharmaceutical emulsions.. the product is manufactured in germany. the compendial name of the product is stearyl alcohol (ph.eur.), stearyl alcohol  (usp/nf), 1-octadecanol. packet sizes are 0,5kg plastic bottle 25kg plastic film bags. the benefits of the product are pasticizer with included consistency factor functionality  lipophilic lubricant  viscosity regulator with a higher melting point.
product name is l-menthol (flakes). menthol for fresh and minty taste. description of the l-menthol flakes pharma is supplied as white flakes. it is almost not soluble in water, but easily soluble in ethanol or diethylether. it melts around 42 °c. it smells characteristically fresh like peppermint.. the product is manufactured in germany. the compendial name of the product is levomenthol, l-menthol, 3-p-menthanol, hexahydrothymol, menthomenthol. packet sizes are 0,02kg aluminum can 0,5kg aluminum can 10kg fiberboard boxes 20kg fiberboard boxes. the benefits of the product are fresh, mint, cooling; can be used for any creation  nature-identical  antimicrobial activity  potent penetration enhancer in skin delivery  antitussive, nasal decongestant, antihistamine, expectorant, throat irritation relief, topical analgesic, local anesthetic.
product name is ludiflash®. all-in-one solution for tablet. description of the ludiflash® is supplied as white to light yellow granules. it is a mixture of 84.0-92.0% d-mannitol, 4.0-6.0% kollidon® cl-sf, 3.5-6.0% polyvinyl acetate, 0.5-2.0% water and 0.25-0.60% povidone.. the product is manufactured in germany. packet sizes are 1kg plastic bottle 20kg fiberboard boxes 330kg flexible ibc. the benefits of the product are enhances patient compliance by making drugs pleasant to take and taste  makes tablets easy to swallow, even without water  increases acceptance of tablets by the very young and elderly  provides flowability, compressability, hardness and stability in production.
Example formulations Production of granules for 200, 400, 600 and 800 mg forms The following ingredients are placed in a high shear mixer and granulated with water: Ibuprofen 50 60.1% w/w Amount of water: approximately 0.2 kg water per 1 kg __ ibuprofen. Wet sieving (4 mm) and drying in a fluid bed Lactose 18% w/w granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following Corn starch 9% w/w additives to form granules suitable for tableting. Kollicoat IR 3.6% w/w Extra granular material Avicel PH 102 3.6% w/w AcDiSol 4.8% w/w Magnesium stearate 0.6% w/w Aerosil 200 0.3% w/w Coating formulations for Ibuprofen tablets oes Fraction with reference to the Fraction with reference Composition atomised suspension [%] to the dry film [%] Polymer Kollicoat IR 16.0 64 Pigments Talc 6.0 24 Sicovit Red 30 3.0 12 Total 25 100 Amount of water: approximately 0.2 kg water per 1 kg ibuprofen. Wet sieving (4 mm) and drying in a fluid bed granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following additives to form granules suitable for tableting. Corn starch Kollicoat IR Extra granular material Magnesium stearate Coating formulations for Ibuprofen tablets

Handling & Safety Product specification The current version of the product specification is avail- able on RegXcellence or from your local BASF sales representative. Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on MyProduct- World or from your local BASF sales representative. Publications Regulatory & Quality Publications including scientific posters are available on: Please refer to the individual document quality & regu- latory product information (QRPI) which is available on RegXcellence and from your local sales representative The QRPI covers all relevant information including retest dates and storage conditions.
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Racemic Ibuprofen Lysinate (RIBL Racemic Ibuprofen Lysinate (RIBL Chemical information Chemical information Ibuprofen Lysinate (+) (+)- (+ (+ -2-[4-(2-methylpropyl)phenyl]propanoic acid lysinate -Benzeneacetic acid, alpha-methyl-4-(2-methylpropyl) lysinate -p-lsobutylhydratropic acid lysinate -2-p-lsobutylphenylpropionic acid lysinate Empirical formula Molecular weight
Chemical and physical properties White to almost white, very fine crystalline powder witt a high volume. In the literature the solubility of Ibuprofen (acid) in distilled water is reported to be less than 0.1%. The solubility of Ibuprofen Lysinate is 1:5, or about 17%. Particle characterization An example particle size distribution is shown below. The median particle size for RIBL is approximately 10 pm Regulatory status No monographs exist. E-DMF is available upon request.
The term RIBL is the acronym for Racemic Ibuprofen Lysinate. Racemic signifies that the ibuprofen drug substance and the lysine anion are both racemic compounds. RIBL differs from the common ibuprofen acid, gen- erally referred to as ibuprofen, in that it is more rapidly absorbed from the intestinal tract and reaches peak plasma levels and t,,., more quickly. After absorption, RIBL is available in the form of pure ibuprofen acid and is therefore to be handled like ibuprofen. Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, anti- pyretic and anti-inflammatory effects, ibuprofen is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever.? For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. Pharmacokinetics RIBL is readily and quickly absorbed from the gastrointestinal tract.!? The peak plasma level of the free acid is reached within 30 to 60 min (with the free acid ibuprofen, t,,,, was measured between 60 and 120 minutes, depending on the dosage form).: After absorption, there is no difference between RIBL and the free acid.
From a pharmacological point of view, there is no difference between RIBL and the free ibuprofen acid because it is the free acid and not the RIBL salt that is the active form. The mode of action of ibuprofen, while not completely understood, is believed to involve reversible inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have among other properties a powerful effect on the smooth muscles. In case of inflammatory stimuli or blood flow disorders, PGs are synthesized in increased amounts, making the tissues sensitive to the action of other agents such as histamine and kinins. As a result, symptoms like pain and inflammation occur. The in- cidence of fever is raised by the influence of the PGs on the heat regulation center in the hypothalamus. There they scale up the normal set point of 37 C. bats CUe Ta Tort) 1 Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration of Ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990. Hermann, T. W. et al., Bioavailability of Racemic Ibuprofen and its Lysinate from Suppositories in Rabbits, Journal of Pharmaceutical Sciences, 82(11):1102-1111, 1993. U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Neupert, W. et al., Effects of lbuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(5): 986-1000, 2011. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration o ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990.
Ibuprofen Sodium Dihydrate Chemical information Ibuprofen Sodium Dihydrate 2-(4-isobutylphenyl)-propionate sodium dihydrate Chemical name Se IS ee ee ee a en re ae ee ee 31121-93-4 C,,H,,0,Na x 2 H,O 228.26 + 36.03 g/mol Empirical formula Molecular weight
Storage Ibuprofen Sodium Dihydrate should be stored in the original, tightly sealed container. It should be placed ina well-ventilated room at ambient temperature and protected from light. The retest period of Ibuprofen Sodium Dihydrate is 60 months for material stored in the original, unopened containe! and according to our recommendations. Regulatory status Currently there are no monographs describing Ibuprofen Sodium Dihydrate in the major Pharmacopoeias (USP, Ph. Eur.. and JP).
According to the literature, ibuprofen sodium dihydrate dissolves more quickly in vitro and is absorbed into blood plasma more quickly than con- ventional ibuprofen, whereas tolerability and safety profiles of the two APIs are comparable.? In an investigation of the dissolution, plasma pharmacokinetics, and safety of ibuprofen sodium dihydrate versus conventional ibuprofen, the following results were reported:? @ buprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 compared to conventional ibuprofen. @ lbuprofen sodium dihydrate reached the t,,,, significantly earlier than conventional ibuprofen. @ lbuprofen sodium dihydrate showed significantly higher c_, compared to conventional ibuprofen. @ buprofen sodium dihydrate was characterized by significantly higher mean plasma concentration (10 min post-dose) compared to conventional ibuprofen. tax iS the necessary time until the maximum plasma concentration of a drug is reached; this is relevant for the drug onset. Generally, reaching the t_ early is of great advantage for analgesic treatment. According to the literature, the first signs of pain relief occurred significantly earlier in ibuprofen sodium dihydrate treated patients, and pain intensity was reduced to half after 30 min for ibuprofen sodium dihydrate compared to 57 min for conventional ibuprofen. In summary, ibuprofen sodium dihydrate causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen.
The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (CO)) which is responsible for the biosynthesis of prostaglandin (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflamma- tory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as hista- mine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C.? c Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandii Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vas FeYToltote CHI (2) Rc) =\ coal O00 Soergel, F. et al. Pharmacokinetics of Ibuprofen Sodium Dihydrate and Gastrointestinal Tolerability of Short-Term Treatment with a Novel, Rapidly Absorbed Formulation, International Journal of Clinical Pharmacology and Therapeutics. 43(8):140-149, 2005. Schleier, P. et al., Ibuprofen Sodium Dihydrate, an Ibuprofen Formulation with Improved Absorption Characteristics, Provides Faster and Greater Pain Relief than Ibuprofen Acid, International Journal of Clinical Pharmacoloay and Therapeutics. 45(2):89-97. 2007. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandir Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997.
www.pharma.basf.com For sample requests contact us ai pharma-solutions@basf.com Meet your Virtual Pharma Assistants! ZoomLab, RegXcellence, and MyProductWorld, your interactive guides for optimizing drug formulations, navigating quality and regulatory compliance, and browsing ingredients. Learn more and sign up at https://info-mypharma.basf.com/ Inspiring Medicines for Better Lives This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been preparec in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to the extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2021 BASF Corporation. All Rights Reserved.
PronovaPure 46:38 El Chemical names of active ingredient CAS-No. 86227-47-6 EPA ethyl ester 81926-94-5 DHA ethyl ester  Description pe ee gee PronovaPure 46:38 EE is a light yellow fish oil ethyl ester concentrate. PronovaPure 46:38 EE is a light yellow fish oil ethyl ester concentrate. Articles The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Scombridae and Carangidae). The product is an ethyl ester (EE), rich in omega-3 fatty acids. The content of EPA (Eicosapentaenoic acid expressed as EE) and DHA (Docosahexaenoic acid expressed as EE) is min. 800 mg/g. Country of origin
Composition Monographs and Regulations VOUNIPOSIHIOR Ingredients in descending order of weight: Fish oil ethyl ester concentrate, tocopherol-rich extract (E 306). mainly derived from soybean (from identity preserved, not genetically modified origin) ee Ne ae ee eS. PronovaPure 46:38 EE meets the requirements for an omega-3 fatty acid source in most countries. The product complies with the Ph. Eur. monograph on Omega-3-acid ethyl esters 90 (1250). Further, the product conforms to the voluntary GOED monograph in the current version. Fish oil ethyl ester concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed. Ingredients in descending order of weight: Fish oil ethyl ester concentrate, tocopherol-rich extract (E 306). mainly derived from soybean (from identity preserved, not genetically modified origin) Solubility Practically insoluble in water, very soluble in acetone, in ethanol (96 per cent), in heptane and in methanol. Practically insoluble in water, very soluble in acetone, in ethanol (96 per cent), in heptane and in methanol. Specification Stability, Storage and Handling Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 36 months. as ethyl ester Ph. Eur. 1250/2.4.29 EPA (Eicosapentaenoic acid) 430-495 mg/g DHA (Docosahexaenoic acid) 347-403 mg/g EPA & DHA (Eicosapentaenoic 800-880 mg/g & Docosahexaenoic acid) Total Omega-3 content min. 90% (w/w) Applications For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access)  PronovaPure 46:38 EE is intended for use in dietary supplements such as in soft gel capsules. PronovaPure 46:38 EE is intended for use in dietary supplements such as in soft gel capsules. Note Standards PronovaPure 46:38 EE must be handled in accor- dance with the Material Safety Data Sheet. PronovaPure 46:38 EE must be handled in accor- dance with the Material Safety Data Sheet. ee Produced under cGMP and HACCP principles. This document, or any answers or information provided herein b\ BASF, does not constitute a legally binding obligation of BASF. Whik the descriptions, designs, data and information contained herein ar presented in good faith and believed to be accurate, it is provided fo your guidance only. Because many factors may affect processing o application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It doe: not relieve our customers from the obligation to perform a full inspectior of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOF A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OF THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUF TERMS AND CONDITIONS OF SALE. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation ie Cerne gare! cee Ray Caen cat ace cet ee: eaten. OL ING PIOGUCTS UPON Gerivery OF any OIner ODEGADON. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS: DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Kolliphor SLS Fine This technical information gives an overview on the use of Kolliphor SLS and Kolliphor SLS Fine as excipients for solid oral dosage forms.
Rebranding As a result of the integration of former Cognis excipients in the BASF portfolio a rebranding was conducted. The rebranding should increase the reliability and compliance for the supply of pharmaceutical excipients. The following table shows a comparison of old versus new trade names. Table 1: New Tradenames-and former Tradenames Tradename Former Tradename Chemistry Kolliphor SLS Texapon K 12 G PH Sodium Lauryl Sulfate Kolliphor SLS Fine Texapon K 12 P PH Sodium Lauryl Sulfate Tradename Kolliphor SLS Kolliphor SLS Fine Kolliphor SLS Kolliphor SLS Fine Former Tradename Texapon K 12 G PH Texapon K 12 P PH 151-21-3 151-21-3 Chemistry Sodium Lauryl Sulfate Sodium Lauryl Sulfate Table 2: PRD and article numbers of Kolliphor SLS and Kolliphor SLS Fine PRD-No. and Article-No. PRD Article-No. Packaging Kolliphor SLS 30569546 50253852 25 kg 50253851 600 kg Kolliphor SLS Fine 30554762 50253853 15 kg See separate documents: ,Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Table 3 lists all monographs Kolliphor SLS and Kolliphor SLS Fine are meeting. Regulatory Status Table 3: Compendial names Tradename Monographic Names Kolliphor SLS Ph.Eur.: Sodium Laurilsulfate USP/NF: Sodium Lauryl Sulfate JP: Sodium Lauryl Sulfate Kolliphor SLS Fine Ph.Eur.: Sodium Laurilsulfate USP/NF: Sodium Lauryl Sulfate JP: Sodium Lauryl Sulfate Kolliphor SLS Fine has a self-affirmed GRAS status. A kosher certificate is available upon request for both grades. Typical properties Spray-dried sodium alkyl sulfate, based on a natural saturated straight-chain primary fatty alcohol. Production Free flowable powder (Kolliphor SLS Fine) or granules (Kolliphor SLS). Physical Form White to off-white. Faint characteristic odor. Melting point
Solubility information Soluble in hot and cold water, sparingly soluble in ethanol. In high concentrations corrosive to steel. Dust may irritate eyes and respiratory system. Incompatibilities Incompatibilities Figure 1 shows the typical particle size distribution of Kolliphor SLS Fine measured by laser diffraction with a powder module. Particle size distribution Figure 1: Typical Particle size distribution of Kolliphor SLS Fine measured by laser diffraction. Tapped density Picture 1 shows a scanning electron microscopic (SEM) pictures of Kolliphor SLS Fine in two different magnitudes. SEM Picture Picture 1: SEM Picture of Kolliphor SLS Fine.
Application Kolliphor SLS and Kolliphor SLS Fine can be used as solubilizers to enhance the solubility of poorly soluble APIs in both solid and liquid oral dosage forms. Kolliphor SLS grades are also suitable for semi solid dosage form like creams, lotions and gels. Sodium lauryl! sulfate is also very broadly used in oral care formulations. The typical usage concentration as a solubilizer or emulsifier is 0.5-2.5 wt%. Solubilizer Wetting agent in tableting Kolliphor SLS and Kolliphor SLS Fine can reduce tablet disintegration time due to improved wettability of the tablet. Some micronized active drugs require a wetting agent to improve drug dissolution rate if compressed into tablets or filled into hard capsules. As wetting agent the typical usage concentration is 0.5-5 wt%. For this application Kolliphor SLS Fine is often more suitable than Kolliphor SLS. Kolliphor SLS and Kolliphor SLS Fine can be used as tablet lubricant if standard lubricants (magnesium stearate 0.5%) are incompatible with the formulation. Since sodium lauryl sulfate can also increase drug dissolution rate, magnesium stearate cannot be replaced one to one by Kolliphor SLS fine. Kolliphor SLS fine offers a combination of good lubrication effect together with improved tablet/capsule disintegration properties and facilitates manufacturing of modern solid dosage forms. As lubricant the typical usage concentration of Kolliphor SLS or Kolliphor SLS Fine is 2%. Example for use as lubricant ina direct compressible formulation Magnesium stearate is known to form eutectics with the drug substance ibuprofen. During tableting, product can adhere on the punch tips (Roberts et al. 2004) and cause problems in the manufacturing process of ibuprofen tablets. The following example demonstrates how magnesium stearate can be successfully exchanged for Kolliphor SLS Fine as an alternative lubricant and tablet disintegration aid. Table 4: Formulation of a direct compression Ibuprofen tablet Ingredient Name mg per tablet Ibuprofen Ibuprofen 400 Tablettose 80 Lactose monohydrate 350 Vivapur 102 Microcrystalline cellulose 175 Kollidon 30 Polyvinylpyrrolidone K 30 50 Kolliphor SLS Fine Sodium lauryl sulfate 20 Aerosil Fumed silica 5 The present direct compressible tablet formulation is intended as technical example only and does not contain additional tablet disintegrants that facilitate tablet disintegration. All components (except the lubricant) are sieved and blended in a double cone blender for 15 minutes. Kolliphor SLS Fine or alternatively magnesium stearate 0.5% (5 mg per tablet, Microcrystalline cellulose is used for mass correction) are added to the blend and blended for another 5 minutes. Tableting is carried out on an eccentric tablet press equipped with a 18 mm diameter flat faced punch. A concentration of 2% Kolliphor SLS Fine is sufficient to obtain good lubrication results. Tablet breaking force was comparable to magnesium stearate but shows a lower standard deviation indicating homogeneous blending (Figure 2).
Tablet disintegration according to Ph. Eur. in 0.1 N HCl solution indicates shorter disintegration times for tablets lubricated with Kolliphor SLS Fine. Even the time difference between the first and the last tablet disintegrated was shorter for Kolliphor SLS Fine (Figure 3). Ibuprofen drug dissolution experiments have been performed according to USP 33 method <711>, Kolliphor SLS Fine can improve dissolution results of the model drug substance ibuprofen. Although the tablet formulation is not optimized for high drug dissolution rates (absence of additional disintegrants in the formulation) the data can clearly demonstrate the benefit of Kolliphor SLS Fine compared to standard lubricant magnesium stearate in this application. Figure 2: Breaking force and disintegration time of Ibuprofen tablets with Mc stearate compared to Kolliphor SLS Fine. Figure 3: Dissolution of Ibuprofen tablets over time.
Raw material origin Kolliphor SLS and Kolliphor SLS fine are based on vegetable and synthetic raw materials. The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreement. Stability and storage In original sealed containers Kolliphor SLS and Kolliphor SLS Fine can be stored for at least two years. It is important that they are protected from moisture and stored at less than 30 C. Handling and Disposal Please refer to the individual Material Safety Data Sheet (MSDS) for instruction on safe and proper handling and disposal. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information = Registered trademark of BASF in many countries.
1. Introduction Historical aspects of polyvinylpyrrolidone The modern acetylene chemistry was developed at BASF in the 1930s by Reppe. One of the many products that emerged from this work are the soluble polyvinyl- pyrrolidone grades, obtained by radical polymerization of the monomer unit N-vinyl pyrrolidone. The polymerization can be performed either in water or in organic solutions. Triggered by organic or inorganic radical starters, the polymers span a wide range of molecular weights. Because of its solubility in water and in many organic solvents, its high binding power and its ability to form complexes, soluble polyvinylpyrrolidones are very valuable synthetic polymers for the pharmaceutical industry. Separate Technical Information Sheets are available for the Povidones with low molecular weights, for the insoluble Kollidon grades (Crospovidone) and for Kollidon VA 64, the copolymer consisting of N-vinylpyrrolidone and vinyl acetate (Copovidone). More information on Kollidon grades may be found in the book, Kollidon, Poly- vinylpyrrolidone for the Pharmaceutical Industry. 2. Technical properties Description The range of medium and high molecular weight Povidones comprises of the grades Kollidon 25, Kollidon 30, Kollidon 30 LP, which are of medium molecular weight and are polymerized in aqueous solution and spray dried. In addition, the high mole- cular weight grade Kollidon 90 F, after being polymerized in water achieving a very highly viscous polymer solution, is finally dried using a drum dryer. The product range comes as white powders with faint, characteristic odor. Structural formula Trivial names Soluble polyvinylpyrrolidone is also known as povidon(e), povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone) and PVP. CAS number 9003-39-8
Product range and molecular weights The product range of the medium and high molecular weight Povidones comprises of 4 different products which are, product dependent, manufactured in the production sites in Ludwigshafen, Geismar and/or Shanghai. The molecular weight of polymers can be expressed in three different forms, as weight average molecular weight, as number average molecular weight and as viscosity average molecular weight. The molecular weight of povidone is usually expressed as the K-value, from whict it is possible to calculate the viscosity average molecular weight (M,). However, the weight average molecular weight (M,,) is found more frequently in the literature. The following M,, values were determined for different grades of Kollidon in recent measurements. In contrast to former determinations SEC was performed using a detection system not requiring reference standards anymore. Nominal Compendial range M,, K-Value for K-value [g/mol] Kollidon 25 25 24-27 28000 - 34000 Kollidon 30 30 28 - 32 44000 - 54000 Kollidon 30 LP 30 28 - 32 44000 - 54000 Kollidon 90 F 90 85 - 95 900000 1200000 Table1 Solubility The solubility of Kollidon varies considerably from one solvent to another. In Table 2 below, soluble signifies that a solution of at least 10% can be prepared, and insoluble signifies that the solubility is less than 1%. Soluble in: chloroform n-butanol cyclohexanol n-propanol ethanol abs. polyethylene glycol 300 glycerol polyethylene glycol 400 isopropanol propylene glycol methanol triethanolamine methylene chloride water Insoluble in: cyclohexane pentane diethyl ether carbon tetrachloride ethyl acetate toluene liquid paraffin xylene Table 2: Solubility of Kollidon Grades
Particle size When analyzed the particle size distribution using a sieving method, particle size distributions of the various polymers can be described with the following ranges. Product <50 um >250 um Kollidon 25 max. 40% max. 5% Kollidon 30 max. 40% max. 5% Kollidon 30 LP max. 20% max. 5% Kollidon 90 F max. 10% max. 15% Table 3 Bulk density Bulk density of Kollidon is determined according to Ph. Eur. current edition, method 2.9.34. Product Bulk density Kollidon 25/30/30 LP 400 600 g/L Kollidon 90 F 400 550 g/L Table 4: Bulk density of the Kollidon grades Particle size distribution and bulk density are considered characteristic values. They are not part of any specifications. Particle size distribution and bulk density are considered characteristic values. They are not part of any specifications. Glass transition temperature Tg, Product Tg, [C] Kollidon 25 165 Kollidon 30 171 Kollidon 30 LP 171 Kollidon 90 F 177 The glass transition temperature was determined by DSC as Tg,, after having eliminated water by heating and finally cooling the dried polymer to room temperature for a second cycle.
Viscosity Fig. 1 shows the relationship between the viscosity of aqueous solutions of the different grades of Kollidon and their concentration. Fig. 1: Viscosity of Kollidon solutions (Ubbelohde viscometer, 25 C) Complexation, chemical interactions Povidone can form fairly stable association compounds or complexes with a number of active substances. The best known example is PVP-iodine which is the subject of a separate leaflet. The ability of Kollidon to form a water-soluble complex with insoluble active substances can be used in pharmaceuticals to improve the release rate and solubility of drugs. There are a few substances such as the polyphenols that form stronger complexes that can precipitate in neutral or acidic media. It must be noted that if povidone is combined with strongly alkaline substances such as lithium carbonate or sodium hydroxide it can crosslink and become insoluble, particularly at elevated temperatures. In extreme cases, this can increase the viscosity of liquid presentation forms and delay bioavailability in solid presentation forms.
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application The main applications of the soluble Kollidon grades are summarized in Table 6. Binder Tablets, capsules, granules Bioavailability enhancement Tablets, capsules, granules, pellets, suppositories, transdermal systems Film formation Opthalmic solutions, tablets, medical plastics Solubilization Oral, parenteral and topical solutions Lyophilising agent Injection preparations, oral lyophilisates Stabilisation of suspensions Oral and parenteral suspensions Oral instant beverage powders and granules for redispersion Viscosity modifier Ophthalmic formulations Adhesives Transdermal systems, adhesive gels Drug stabilisation Enzymes in diagnostics Table 6: Main applications of the soluble Kollidon grades of medium and high molecular weight The adhesive, film-forming, dispersing and thickening properties of the soluble Kollidon grades are used in the various modifications of granulation technologies for tablet production, film coating and in the preparation of other dosage forms. The improvement in the solubility of active ingredients brought about by complexatior or association, and the thickening effect find use mainly in the manufacture of liquid presentation forms. The grade of Kollidon that is selected depends mainly on its molecular weight, as this dictates the viscosity, binding effect, the complexation capacity and how readily it is eliminated from the body. A detailed description of the applications is to be found in the book, Kollidon, poly- vinylpyrrolidone for the Pharmaceutical Industry. Tablet binding Kollidon 25, Kollidon 30, Kollidon 30 LP and Kollidon 90 F When applied for granulation in high shear mixers or fluid-bed granulators the resultinc granules with Kollidon 25, Kollidon 30 and Kollidon 90 F are hard, free flowing with a low proportion of fines. Binding strength is excellent to achieve hard and stable tablets. Kollidon 25 and Kollidon 30 require binder quantities of 2% and 5% related to the tablet weight. As Kollidon 90 F has a higher binding capacity the required quantities are 2% or even less. The high viscosity of binder solutions of Kollidon 90 F sometimes requires precautions to ensure the granules to be evenly wetted. Kollidon 25, 30 and 90 F are also suitable for the direct compression of tablets without granulation. This technique requires a certain relative humidity, as the powder mixture must have a certain moisture content to bind properly. If Kollidon is used in addition to microcrystalline cellulose, it not only makes the tablets harder but also gives them stronger edges. For best results in direct compression, all the excipients should have acertain moisture content. This applies to starch, micro- crystalline cellulose and lactose monohydrate as fillers. It can be seen from Fig. 2 that there is hardly any difference in the hardness of lactose placebo tablets made with Kollidon 25 and Kollidon 30. However, the same quantity (3% of the tablet weight) of Kollidon 90 F almost doubles the hardness, compared with Kollidon 25.
Fig. 2: Lactose monohyarate tablets with 3% Kollidon (wet granulation) Kollidon is also suitable as a binder in fluidized-bed granulation processes. Thanks to their relatively low viscosity, solutions of Kollidon 25 and Kollidon 30 can be prepared relatively quickly, and sprayed easily, to quickly give stable granules. Co-precipitation, co-milling Kollidon 25, 30 The dissolution rate and therefore the absorption rate of drugs that do not dissolve readily in water can be greatly improved by co-milling or coprecipitation with Kollidon 25 or Kollidon 30, as the complex formed is, in effect, a solid solution of the drug in the Kollidon. This requires an excess of Kollidon to maintain the (partially) amorphous form of the active substance. Suitable processes include mixing, co-milling or melt extrusion of the Kollidon-drug mixture, or coprecipitation, granulation onto a carrier or spray-drying a solution containing the drug and Kollidon. The literature contains hundreds of publications on this application. The most frequently tested active substance mentioned is probably nifedipine. Stabilizers of suspensions Kollidon 25, 30, 90 F These grades can be used to stabilize oral and topical suspensions with a wide range of active ingredients, e.g. acyclovir, ibuprofen, magaldrate, nystatin, phenytoin, trimethoprim, sulfonamides and antibiotics, as well as sugar-coating suspensions. Combinations of Kollidon 90 F with Kollidon CL-M have often given very good results. Thickener Kollidon 90 F Because of its good solubility in water and alcohol, Kollidon 90 F can be used as a thickener for aqueous or aqueous-alcoholic solutions for oral application (viscosity curve, see Figure 1).
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage condition: 6. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technica representative. Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data For information on toxicological issues please refer to the tox abstract which can be supplied on request. More/detailed toxicological information for Kollidon grades is available on request under Secrecy Agreement.
10. PRD and Article numbers 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30034967 _ Kollidon 25 57254799 25 kg Cardboard boxes 50348143 0.5 kg Plastic pail 30697299 Kollidon 25 50574244 50 kg Plastic drums 50574245 0.5 kg Plastic pail 30034974 Kollidon 30 Origin Germany 57254693 25 kg Cardboard boxes 50347950 0.5 kg Plastic pail 30525451 Kollidon 30 Origin Germany 50022331 50 kg Plastic drums 50347978 0.5 kg Plastic pail 30403404 Kollidon 30 Origin USA 55238758 1 kg PE-Bottle 55087337 50 kg PE-Drum, removable head 30660388 Kollidon 30 Origin China 50486018 50 kg Plastic drums 50498559 0.5 kg Plastic pail 30255812 Kollidon 30 LP 50347979 0.5 kg Plastic pail 50796353 25 kg Cardboard boxes 30034978 Kollidon 90 F 50347976 0.5 kg Plastic pail 51031936 25 kg Cardboard boxes BASFs commercial product number. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Omega-3-acid ethyl esters 90 (Ph.Eur) Omega-3-Acid Ethyl Esters (USP) September 2022
1. Introduction In general, Omega-3 fatty acids are naturally occurring nutrients that are important for human health. They cannot be synthesized by the human body but are vital for normal metabolism. Omega-3 fatty acids are poly unsaturated fatty acids with a double bond from the 3rd carbon atom from the end (omega). The most abundant omega- 3 fatty acids are EPA, DHA and alfa-linoleic acid (ALA). EPA and DHA are long-chain fatty acids found in algal oil and fish. EPA and DHA have been widely studied for medical and nutritional applications. K85EE is produced from the body oil of certain species of wild, fatty fish. The manufacturing process includes a transesterification step from a triglyceride to an ethyl ester compound and several concentration and purification steps, including molecular distillation. the human body but are vital for normal metabolism. Omega-3 fatty acids are poly unsaturated fatty acids with a double bond from the DHA have been widely studied for medical and nutritional applications. K85EE is produced from the body oil of certain species of wild, fatty fish. The manufacturing process includes < transesterification step from a triglyceride to an ethyl ester compound and several concentration and purification steps, including molecular distillation. Due to the high amount of unsaturated fatty acids, the product will easily oxidize in contact with air, and needs to be protected from contact with oxygen. The container is therefore flushed with nitrogen prior to, during and after filling. Due to the high amount of unsaturated fatty acids, the product will easily oxidize in contact with air, and needs to be protected nitrogen prior to, during and after filling. 2. Technical properties Composition Omega-3 acid ethyl esters (K85EE) is an oil containing a minimum of 90% of omega-3 acid ethyl esters, comprised of 85% of two unsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in ethyl ester (EE) form. The only ingredient added to K85EE is the antioxidant alpha tocopherol. The remaining part of the composition is comprised of other, naturally occurring fatty acids. Omega-3 acid ethyl esters (K85EE) is an oil containing a minimum of 90% comprised of other, naturally occurring fatty acids. K85EE fully complies to the monographs of the European Pharmacopeia and the US Pharmacopeia. Description Name K85EE United States Adopted Names (USAN) Omega-3-acid ethyl esters Pharmacopeia name Omega-3-acid ethyl esters 90 (Ph.Eur) Omega-3-Acid Ethyl Esters (USP) Nomenclature of the EPA ethyl ester DHA ethyl ester two main components Pharmacopeia name Ethyl Icosapentate (JP) Docosahexaenoic acid ethyl Eicoapentaenoic acid ethyl ester ester (USP) (USP) International Icosapent ethyl ester Doconexent ethyl ester nonproprietary United States Adopted Icosapent ethyl N/A Names (USAN)
Eicosapentaenoate Docosahexaenoate Trivial names Timnodonic acid ethyl Cervonic acid ethyl ester ester Synonyms Eicosapentaenoic acid Docosahexaenoic acid ethyl ethyl ester, Ethyl-EPA, ester, Ethyl-DHA, C22:6n-3 ethyl C20:5n-3 ethyl ester, EPA ester, DHA EE EE CAS-No 86227-47-6 81926-94-5 Molecular formula Cz2H34O2 CoaHs6O2 Relative Molecular 330.50 356.54 mass Secondary USP UPAC Nomeric CAS- components Notation number Octadecatrienoi Alpha-lonoleic acid Ethyl all cis-9, 12, 15- C18:3n- 1191-41-9 cacid EE ethyl ester Octadecatrienoate 3 Octadecatetrae Moroctic acid ethyl Ethyl all cis-6, 9, 12, C18:4n- 119798-44-6 noic acid EE ester 15- 3 Octadecatetraenoate Eicosatetraenoi Eicosatetraenoic Ethyl all cis-8, 11, 14, C20:4 n- 123940-93-2 cacid EE acid ethyl ester 17-Eicosatetraenoate 3 Heneicospenta Heneicospentaenoic Ethyl all cis-6, 9, 12, C21:5 n- 131775-86-5 enoic acid EE acid ethyl ester 15, 18- 3 Heneicospentaenoate Docosapentaen Docosapentaenoic Ethyl all cis-7, 10, 13, C22:5 n- 119818-40-5 oic acid EE acid ethyl ester 16, 19- 3 (Clupanopdonic Docosapentaenoate acid ethyl ester) Eicosapentaenoate Docosahexaenoate Trivial names Timnodonic acid ethyl ester Cervonic acid ethyl ester Synonyms Eicosapentaenoic acid Docosahexaenoic acid ethyl ethyl ester, Ethyl-EPA, ester, Ethyl-DHA, C22:6n-3 ethyl C20:5n-3 ethyl ester, EPA ester, DHA EE EE CAS-No 86227-47-6 81926-94-5 Molecular formula Cz2H34O2 CoaHs6O2 Relative Molecular 330.50 356.54 mass Secondary USP UPAC Nomeric CAS- components Notation number Octadecatrienoi Alpha-lonoleic acid Ethyl all cis-9, 12, 15- C18:3n- 1191-41-9 cacid EE ethyl ester Octadecatrienoate 3 Octadecatetrae Moroctic acid ethyl Ethyl all cis-6, 9, 12, C18:4n- 119798-44-6 noic acid EE ester 15- 3 Octadecatetraenoate Eicosatetraenoi Eicosatetraenoic Ethyl all cis-8, 11, 14, C20:4 n- 123940-93-2 cacid EE acid ethyl ester 17-Eicosatetraenoate 3 Heneicospenta Heneicospentaenoic Ethyl all cis-6, 9, 12, C21:5 n- 131775-86-5 enoic acid EE acid ethyl ester 15, 18- 3 Heneicospentaenoate Docosapentaen Docosapentaenoic Ethyl all cis-7, 10, 13, C22:5 n- 119818-40-5 oic acid EE acid ethyl ester 16, 19- 3 (Clupanopdonic acid ethyl ester) Docosapentaenoate
Structural formula 3. Physical and chemical properties 3. Physical and chemical properties Omega-3 acid ethyl esters (K85EE) is a clear, light yellow liquid oil. Appearance Omega-3 acid ethyl esters (K85EE) is practically insoluble in water, very soluble in organic solvents such as acetone, ethanol (96%), methanol and heptane. Omega-3 acid ethyl esters (K85EE) is practically insoluble in water, very soluble in organic solvents such as acetone, ethanol Freezing point <- 20C Boiling point > 400 C Flash point > 95C Vapour pressure Negligible Density 0.9 g/ml (20C)
4. Medical information Applications K85EE is an active pharmaceutical ingredient oil. It is well suited for soft gelatin capsules and can be used as the sole fill ingredient. This dosage form has proven suitable for K85EE. K85EE is not suitable for liquid multidose formulations as it will readily oxidize in contact with atmospheric oxygen, and also has an unpleasant taste and odour. K85EE is an active pharmaceutical ingredient oil. It is well suited for soft gelatin capsules and can be used as the sole fill ingredient. This dosage form has proven suitable for K85EE. K85EE is not suitable for liquid multidose formulations as it will readily oxidize in contact with atmospheric oxygen, and also has an unpleasant taste and Therapeutic indication K85EE is used as an active ingredient in pharmaceutical drug products after approval of the documented indication by the competent authority. The approved indications may be different in Clinical Pharmacology Mechanism of Action The mechanisms of action of K85EE are not completely understoc The mechanisms are likely multi-factorial. Please refer to the approved Summary of Product Characteristics (SmPC) / Full Prescribing Information for finished drug products containing Omega-3 acid ethyl esters. The mechanisms of action of K85EE are not completely understood. Prescribing Information for finished drug products containing Please refer to the approved Summary of Product Characteristics (SmPC) / Full Prescribing Information for finished drug products containing Omega-3 acid ethyl esters. Please refer to the approved Summary of Product Characteristics
5. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment or can be requested from your BASF sales representative Please refer to the individual material safety data sheet (MSDS) ERSTE TA SES STE ORNs, RENE Nceseea TF Material safety data sheets are sent with every consignment can be requested from your BASF sales representative can be requested from your BASF sales representative The current version of the product specifications is available at ReagXcellance (Home (force com)) or from vour BASE cale RegXcellence (Home (force.com)) or from your BASF sales representative. Please refer to the document Quality & Regulatory Product Information which is available in RegXcellence@ (Home (force.com)). 8. PRD and Article numbers PRD-No. Product name Article Packaging Sales region 30593625 K85EE 50355167 190kg steel Europe and those drum accepting CEP 30593626 Omega 3 fatty acid 50355168 190kg steel Only for ethyl ester drum Italy 30593627 K85EE Omega-3- 50355169 190kg steel USA acid ethylesters drum 30593631 K85EE Omega-3- 50355400 190kg steel Only for acid ethylesters drum Japan 30593633 K85EE Omega-3- 50355403 190kg steel Global, acid ethylesters drum except US and Japan Certification of Suitability of the monograph of the European Pharmacopeia
This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NC WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. BASF Nutrition & Health - www.pharma-ingredients.basf.com
Kolliphor Grades - Emulsifier for topical pharmaceutical application: January 2014 ) = Registered trademark of BASF in many countries.
Rebranding As a result of the integration of former Cognis excipients in the BASF portfolio a rebranding was conducted. The rebranding should increase the reliability and compliance for the supply of pharmaceutical excipients. The following table shows a comparison of old versus new trade names. Tradename Former Tradename Kolliphor CS 12 Eumulgin B1 PH Kolliphor CS 20 Eumulgin B2 PH Kolliphor CSS Lanette E PH Kolliphor CS A Lanette N PH Kolliphor CSL Lanette SX PH Tradename Table 1: New Tradenames Old Tradenames PRD-No., Article-No. and CAS.-No. Tradename PRD-No. Article-No. CAS.-No. Kolliphor CS 12 30554458 50253256 68439-49-6 Kolliphor CS 20 30554459 50253257 68439-49-6 Kolliphor CSS 30554486 50253269 68955-20-4 Kolliphor CS A 30554487 50253281 67762-27-0 68955-20-4 Kolliphor CSL 30554435 50253856 67762-27-0 161-21-3 68955-20-4 Table 2: PRD and Article and CAS number of the Kolliphor Grades See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Regulatory Status In table 3 you can find all the monographs for the Kolliphor Grades. New Name Monograph Tests Kolliphor CS 12 Ph. Eur. : Macrogol Cetostearyl Ether 12 Kolliphor CS 20 Ph. Eur. : Macrogol Cetostearyl Ether 20 USP/NF: Polyoxyl 20 Cetostearyl Ether Kolliphor CSS Ph. Eur. : Sodium Cetostearyl Sulphate Kolliphor CS A Ph. Eur. : Cetostearyl Alcohol (Type A), Emulsifying Kolliphor CSL not monographed Table 3: Compendial names
An emulsion is a dispersion of droplets of a non-miscible liquid in a continuous phase. The polar (hydrophilic) aqueous phase and the non-polar (lipophilic) oil phase of an emulsion cannot be combined in a stable and homogenous way without a surface-active additive. Product groups Emulsifiers are interfacial active substances that reduce the interfacial tension between the oil and the water phase. The emulsifier is adsorbed at the interface, giving a film between both phases, which prevents coalescence of droplets. Due to its amphiphilic structure, the polar part of the emulsifier has an affinity to the water phase and the non-polar part of the emulsifier to the oil phase. Emulsifiers can be defined according to their hydrophilic/lipophilic characteristics In 1949 W.C. Griffin proposed the HLB (Hydrophilic- Lipophilic Balance) system in which non-ionic surfactants have been classified on a scale from 0 to 20. Emulsifiers with a strong lipophilic character have low HLB values between 3 to 8 and tend to form W/O emulsions. Emulsifiers of the HLB range of 8 to 18 are hydrophilic and form O/W emulsions. HLB values from 12 to 18 are most favorable for solubilization to enhance bio- availability of active ingredients. Emulsifiers can be classified according the chemical structure in non-ionic and ionic emulsifiers or emulsifying waxes. Non-lonic Emulsifier Ethoxylates Chemical structure Figure 1: Chemical structure Kolliphor CS 12 and Kolliphor CS 20 Typical Properties Product R-Lipo- N-Hydro- Appearance HLB Usage pH phil phil value concen- working tration range Kolliphor CS 12 C,,,C,, 12xEO White or 13 05-5% 2-12 yellowish white waxy powder Kolliphor CS 20 C,,,C,, 20xEO White or 15 05-5% 2-12 yellowish white waxy powder Table 4: Typical properties Kolliphor CS 12 and Kolliphor CS 20
lonic Emulsifier Kolliphor CSS Chemical Structure Figure 4: Chemical structure Kolliphor CSS (n=15 or 17) Typical properties olliphor CSS_ White or pale yellow amorphous >40 0.5-2% 7- or crystalline powder Emulsifying Waxes (Cream-bases) are a combination of a consistency factor (eg. Fatty alcohols) and an emulsifier. They are especially designed to enable an effective and short development time of a topical pharmaceutical formulation. Cream-bases/Emulsifying Waxes Typical properties Typical properties Product Ingredients Appearance HLB Usage pH value concen- working tration range Kolliphor CS A Cetostearyl Alcohol White or pale 7.0 0.5-5% 6-12 Sodium Cetostearyl vet waxy Sulphate pellets Kolliphor CSL Cetostearyl Alcohol Pellets 75 0.5-5% 6-12 Sodium Lauryl with a faint Sulfate characteristic odor Sodium Ceteary Sulfate Table 6: Typical property of the creambases/emulsifying waxes
Application The choice of emulsifiers for specific applications depends on the desired pro- perties of the formulation (e.g. stability, viscosity, skin feel and API), or on the desired processing technology (e.g. PIT, Hot or cold processing). The traditional processing technology for emulsion is the so called hot process, where you combine both water and oil phase at a temperature of 70 85 C. With this technology you are very flexible in the ingredients you can choose in your emulsion. Beside the well-known hot process of emulsification, there is also the possibility to formulate an emulsion with a processing temperature at room temperature. The processing of O/W emulsions at room temperature has several significant benefits. For example, it is no longer necessary to heat the water and oil phase to 70 80 C. This saves considerable amounts of energy and reduces the production time as the cooling step is eliminated. Another very important advantage is that heat-sensitive APIs can be added t the emulsions at any point. On the other hand the possible ingredients are limited as there is not melting step of the oil phase. In the BASF portfolio of emulsifier for topical pharmaceutical applications only Kolliphor PS 60 is suitable for this kind of processing technology. Another very interesting processing technology is the Phase Inversion Technology (PIT) as it leads to water thin emulsions with a very small droplet sizes and thus these emulsions are very stable. This processing technology uses the temperature dependency of the HLB value of non-ionic emulsifiers as this kind of emulsifier change solubility behavior with elevated temperature. This can be used for pharma- ceutical applications where a very thin emulsion is needed, which is easy to distribute over the skin (e.g. sorayable wound sprays etc.). = a\e >. 8\8 ee 5 B/2/E = F/JE o el fete! S] She a 2s 5 o 2) dD) 33), 5/2 9 S\5\5 3/8 E)E R ele] S/S) 0/5] 8] Pia Wy} 2) OE) 19) a) s 2i0 QS/Z\ S/S 3 ss 8 4/85 Product Ph. Eur. S\SIGISIESEAAZIGA Kolliphor CS 12} Marcrogol Cetosteary x x x x x]x x Ether 12 Kolliphor CS 20} Marcrogol Cetosteary x x x x x]x x Ether 20 Kollliphor CS A Cetostearylalcohol x bay xX x x (Type A), Emulsifying i _ Kollliphor CSS__ Sodium Cetosteary! x ba x x Sulphate Kollliphor CSL x Ba X x x Table 7: Application fields in topical pharmaceutical formulations of the Kolliphor grades
Skin Tolerance All Kolliphor grades are based on vegetable and synthetic raw materials. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreemen In originally sealed containers all Kolliphor types can be stored for at least two years. It is important that they are protected from moisture and stored at less than 30 C. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal Handling and Disposal This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. January 2014
Supersedes issue dated November 2010 Methacrylic acid/ethyl acrylate copolymer dispersion for enteric coating Methacrylic acid/ethyl acrylate copolymer dispersion for enteric coating
Contents 1. Introduction 1:2 1.3 1.4 Se ee ae AE General Structural formula Trivial names Commercial form 2. Specifications and properties 2.1 Description 2.2 Specifications 2.3 Regulatory status 3. Application and examples of formulations 4. Storage 5. Stability 6. PRD-Nos. 7. Packaging
1. Introduction 1.1 General Kollicoat MAE 30 DP is a copolymer derived from methacrylic acid/ethyl acrylate. The copolymer is used as film-former in the pharmaceutical industry for the production of enteric coated solid oral dosage forms. 1.2 Structural formula The ratio of the components in the copolymer is roughly 1:1. The Kollicoat MAE 30 DP has a anionic character. The average molecular weight M,, is of the order of 250,000 AMU. Methacrylic Acid Copolymer Type C (USP), Methacrylic Acid Copolymer LD (JPE) and Methacrylic Acid-Ethyl Acrylate Copolymer (Ph. Eur.), Methacrylsaure Copolymer. Kollicoat MAE 30 DP is an aqueous dispersion with a solids content of 30%. The milky white, low-viscosity product has a faint, characteristic odour. 1.4 Product form 2. Specifications and properties Kollicoat MAE 30 DP contains 0.7% sodium lauryl sulfate and 2.3% Polysorbate 80 as emulsifying agents. (The percentage refers to the solid substances.) The fatty acids used in the manufacture of Polysorbate 80 are of vegetable origin. 2.1 Description Kollicoat MAE 30 DP is a weakly acidic copolymer that dissolves at a pH above 5.5. See separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). 2.2 Specifications Kollicoat MAE 30 DP meets the following currentcompendial requirements 2.3 Regulatory status 1. Methacrylic Acid Ethyl Acrylate Copolymer (1:1) Dispersion 30% (Ph. Eur. 2. Methacrylic Acid Copolymer Dispersion (USP) 3. Methacrylic Acid Copolymer LD (JPE ) The name of this monograph will be modified as of May 1 , 201 7 as follows: The name of this monograph will be modified as of May 1, 2017 as follows: Methacrylic acid and Ethyl acrylate Copolymer Dispersion
3. Applications and typical formulations 3.1 Processing instructions Plasticizers are essential to improve the flexibility of the films. UINAVIE PIGSUCIZETS OF YlOSs WILETISIIErS ale 1,2-propylene glycol Triethyl citrate Polyethylene glycols Triacetin e 1,2-propylene glycol e Triethyl citrate e Polyethylene glycols e Triacetin The recommended amount of plasticizer is 10 - 15% relative to the dry matter content of the film former. Kollicoat MAE 30 DP is incompatible with magnesium stearate. However, any magnesium stearate in the tablet core to be coated does not represent problems. 1,2-propylene glycol improves the processability and barrier properties of the film coatings. Anumber of factors may cause aqueous dispersions to coagulate during processing, rendering them unusable: oT Fe ~~ e Addition of finely divided pigments e High shear gradients on stirring and grinding e Addition of emulsifying agents, stabilizers or wetting agents Changes in pH Cationic additives Organic solvents. e Formation of foam Foam formation during processing can be prevented by adding a silicone antifoam such as Pharsil 21046. Flat-plate stirrers have proved suitable for the production of spray suspensions. Spray suspensions with a 15 30% solids content give good results and save time in spraying. To avoid problems in incorporating auxiliaries in the aqueous suspensions, we recommend to: Dilute the dispersion to a solids content of 20% Stir the desired auxiliary into the dispersion in form of a dilute solution. The following excipients can be included in a film-coating formulation: the rollowing excipients can be Inciuded In a Tilm-coating Ttormulation e Talc e Syloid e Aerosil and Kaolin as release and smoothing agents; e Pigments The Kollicoat MAE 30 DP has a high pigment binding capacity: two to three parts of pigments or other auxiliaries may be added for one part of solid polymer. Use the dispersion under stirring within 24 hours after preparation.
3.2 Coloured enteric film coatings for tablets Composition of the spray suspension Polymer suspension Alternative Kollicoat MAE 30 DP 495.00 50.00 Propylene glycol 22.25 2.25 Water 319.30 32.25 Pigment suspension Titanum dioxide 4.95 0.50 Sicovit Red 30 4.95 0.50 Talc 39.60 4.00 Water 103.95 10.50 990.00 100.00 Solids content of the spray 22.25% suspension Content of polymer dry substance 15.0% Polymer applied (as solids) 4.0 mg/cm? Total solids applied 5.9 mg/cm? Polymer suspension Polymer suspension Preparation of the spray suspension Polymer Suspension Kollicoat MAE 30 DP: Propylene glycol is first stirred into the specified amount of water. Kollicoat MAE 30 DP is then stirred in. Pigment suspension Sicovit Red 30, titanium dioxide and talc are intensively stirred into the specified amount of water and homogenized in a corundum disk mill. Spray suspension The pigment suspension is stirred into the coating suspension. The spray suspensio must be stirred during spraying to prevent the solid substances settling out. Coating pan: Size of batch: Air supply temperature: Product temperature: Spraying pressure: Spraying rate: Spraying time: Coating pan: Size of batch: Air supply temperature: Product temperature: Spraying pressure: Spraying rate: Spraying time: Accela Cota 24 (Manest 5 kg 60 C 32 - 35 C 2 bar 40 g/m OF _QaAnNmn Coating equipment and parameters
Release rates of diclofenac Na and acetylsalicylic acid tablets The tablets were made with the following formulations: a) Diclofenac Na Diclofenac Na 49.7 mg, Ludipress 201.4 mg, Kollidon VA 64 14.9 mg, Kollidon CL 5.0 mg, Aerosil 200 1.2 mg, magnesium stearate 2.8 mg b) Acetylsalicylic acid Acetylsalicylic acid 100 mg, Ludipress 148.5 mg, Avicel PH 102 50.0 m magnesium stearate 1.5 mg
3.3 Coloured enteric film coatings for pellets and crystals Composition of the spray suspension Polymer suspension Alternative Kollicoat MAE 30 DP 495.00 50.00 Propylene glycol 22.28 2.25 Water 319.27 32.25 Pigment suspension Titanium dioxide 4.95 0.5 Sicovit Red 30 4.95 0.5 Talc 39.60 4.0 Water 103.95 10.5 990.00 100,0 Solids content of the spray 22.25% suspension Solid polymer in the spray 15.0% suspension Solid polymer applied 4.0 mg/cm? Total solids applied 5.9 mg/cm? The formulation has been calculated for 500 g of crystals (diameter 0.3 1.0 mm) Polymer suspension Preparation of the spray suspension See the processing notes under 3.2 Coating pan: Size of batch: Air supply temperature: Exhaust air temperature: Spraying pressure: Spraying time: WSG Aerome 500 g 60 C 35 C 1 bar 100 min Coating equipment and parameters WSG Aeromatic Strea 1
Release rates of diclofenac Na pellets and acetylsalicylic acid crystals 3.4 White enteric film coatings for pellets Composition of the spray suspension Polymer suspension Alternative Kollicoat MAE 30 DP 2250.0 50.0 Propylene glycol 67.5 1.5 Water 1435.0 31.9 Pigment suspension Kollidon 30 22.5 0.5 Titanium dioxide 45.0 1.0 Talc 180.0 4.0 Water 500.0 144 4500.0 100.0 Solids content of the spray 22.0% suspension Dry polymer content 15.0% Solid polymer applied 2.0 mg/cm? Total solids applied 2.9 mg/cm? The formulation below is calculated for 5 kg of pellets (diameter 0.8 1.2 mm) Duarte hu Wainht a CAmnRAGIHAN. 0.
Preparation of the spray suspension Polymer suspension See the processing notes under 3.2. Pigment suspension Dissolve Kollidon 30 in the specified amount of water. Proceed as usual. Spray suspension See suggested method under 3.2. Soating equipment and parameters 3.5 Colourless enteric coatings for soft gelatin capsules Composition of the spray The formulation below is intended for 5 kg of soft gelatin capsules Polymer suspension Alternative Kollicoat MAE 30 DP 1680.0 70.0 Propylene glycol 100.8 4.2 Water 619.2 25.8 2400.0 100.0 Solids content of the spray 25.2% suspension Content of polymer dry substance 21.0% Polymer applied (as solids) 10.0 mg/cm? Total solids applied 12.0 mg/cm? Preparation of the spray suspension a Kollicoat MAE 30 DP: polypropylene glycol is first dissolved in the specified amount of water. Then Kollicoat MAE 30 DP is stirred in. Coating pan: Size of batch: Inlet air temperature: Product temperature: Spraying pressure: Spraying rate: Spraying time: Coating pan: Size of batch: Inlet air temperature: Product temperature: Spraying pressure: Spraying rate: Spraying time: Coating equipment and parameters Accela Cota 24 (Manesty 5 kg 50 C 30 - 32 C 2 bar 30 - 35 g/m
3.6 Subcoating of tablet cores Some tablet cores contain either a water-sensitive drug or a highly effective tablet disintegrant, e. g. Kollidon CL. To prevent interactions with an aqueous coating formulation a polymeric water barrier must be applied first. The same applies if the cores are too soft, or if an aqueous coating will not adhere on their surface. In such cases, heating the cores to about 35 C and spraying them with a 10% solution of Kollidon VA 64, e.g. in isopropanol has given good results. Experience indicates that an adequate subcoating film is built up when small amounts of Kollidon VA 64 or Kollidon IR are applied, i. e. approx. 0.5 mg/cm. 3.7 Further applications Fine coatings of 0.5 2.0 mg/cm? (solids), can be applied for the following purposes: FIN NAR LI eh NE SEL ESN gy: SC 1 A IE I I a e Masking unpleasant tastes and odours, e As a barrier between incompatible active substances, Protection against atmospheric humidity. EP 152 038 and EP 208 213 concerning aqueous dispersions for coating pharma- ceutical products containing dispersed latex particles (A) of a polymer that contains carboxyl groups soluble in water between pH 5.0 and 8.0 and (B) a film-forming polymer (of great elasticity) that is insoluble in water, in which the weight ratio of the total amount of latex particles A and B lies between 60:40 and 5:95. 4. Storage Kollicoat MAE 30 DP should be protected from frost and kept below 30 C. Kollicoat MAE 30 DP (aqueous dispersion) is stable for at least 18 months in the unopened original containers and storage conditions below 30 C. The dispersion must be protected from heat or frost. Once a drum has been opened, care must be taken to avoid contamination and the content must be used within a few weeks. 7. Packaging This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
PronovaPure 400:200 TC Valid for batches produced from January 2014 Chemical names of active ingredient CAS-No. Description eg ee erat PronovaPure 400:200 TG is a pale yellow fish oil concentrate. The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Scombridae and Carangidae). The product is a triglyceride (TG), rich in omega-3 fatty acids. The content of EPA (Eicosapentaenoic acid expressed as TG) and DHA (Docosahexaenocic acid expressed as TG) is min. 600 mg/g. Articles Country of origin
Composition Stability, Storage and Handling Ingredients in descending order of weight: Fish oil concentrate, tocopherol-rich extract (E 306). mainly derived from soybean (from identity preserved, not genetically modified origin) Ingredients in descending order of weight: Fish oil concentrate, tocopherol-rich extract (E 306). mninh; darned fram envhaan [fram idantihy nroecansat Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 36 months. Solubility - Practically insoluble in water, very soluble in acetone and heptane, slightly soluble in anhydrous ethanol. Applications  Specification PronovaPure 400:200 TG is intended for use in dietary supplements such as in soft gel capsules. as triglycerides Ph. Eur. 1352/2.4.29 EPA (Eicosapentaenocic acid) min. 400 mg/g DHA (Docosahexaenoic acid) min. 200 mg/g EPA & DHA (Eicosapentaenoic 600-700 mg/g & Docosahexaenoic acid) Total Omega-3 fatty acids min. 650 mg/g Note PronovaPure 400:200 TG must be handled in accordance with the Material Safety Data Sheet. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR ee ae ee Re RE Tete TO Or oe Wee See eR Races NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Standards Produced under cGMP and HACPP principles. Monographs and Regulations PronovaPure 400:200 TG meets the requirements for an omega-3 fatty acid source in most countries. The product complies with the USP monograph for Omega-s acid triglycerides and the Ph. Eur. monograph on Omega-3-acid triglycerides (1352). Further, the product conforms to the voluntary GOED monograph in the current version. Fish oil concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have kA KA Ahearn pA Fish oil concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed.
Kolliphor Grades - Emulsifier for topical pharmaceutical application: January 2014 ) = Registered trademark of BASF in many countries.
Rebranding As a result of the integration of former Cognis excipients in the BASF portfolio a rebranding was conducted. The rebranding should increase the reliability and compliance for the supply of pharmaceutical excipients. The following table shows a comparison of old versus new trade names. Tradename Former Tradename Kolliphor CS 12 Eumulgin B1 PH Kolliphor CS 20 Eumulgin B2 PH Kolliphor CSS Lanette E PH Kolliphor CS A Lanette N PH Kolliphor CSL Lanette SX PH Tradename Table 1: New Tradenames Old Tradenames PRD-No., Article-No. and CAS.-No. Tradename PRD-No. Article-No. CAS.-No. Kolliphor CS 12 30554458 50253256 68439-49-6 Kolliphor CS 20 30554459 50253257 68439-49-6 Kolliphor CSS 30554486 50253269 68955-20-4 Kolliphor CS A 30554487 50253281 67762-27-0 68955-20-4 Kolliphor CSL 30554435 50253856 67762-27-0 161-21-3 68955-20-4 Table 2: PRD and Article and CAS number of the Kolliphor Grades See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Regulatory Status In table 3 you can find all the monographs for the Kolliphor Grades. New Name Monograph Tests Kolliphor CS 12 Ph. Eur. : Macrogol Cetostearyl Ether 12 Kolliphor CS 20 Ph. Eur. : Macrogol Cetostearyl Ether 20 USP/NF: Polyoxyl 20 Cetostearyl Ether Kolliphor CSS Ph. Eur. : Sodium Cetostearyl Sulphate Kolliphor CS A Ph. Eur. : Cetostearyl Alcohol (Type A), Emulsifying Kolliphor CSL not monographed Table 3: Compendial names
An emulsion is a dispersion of droplets of a non-miscible liquid in a continuous phase. The polar (hydrophilic) aqueous phase and the non-polar (lipophilic) oil phase of an emulsion cannot be combined in a stable and homogenous way without a surface-active additive. Product groups Emulsifiers are interfacial active substances that reduce the interfacial tension between the oil and the water phase. The emulsifier is adsorbed at the interface, giving a film between both phases, which prevents coalescence of droplets. Due to its amphiphilic structure, the polar part of the emulsifier has an affinity to the water phase and the non-polar part of the emulsifier to the oil phase. Emulsifiers can be defined according to their hydrophilic/lipophilic characteristics In 1949 W.C. Griffin proposed the HLB (Hydrophilic- Lipophilic Balance) system in which non-ionic surfactants have been classified on a scale from 0 to 20. Emulsifiers with a strong lipophilic character have low HLB values between 3 to 8 and tend to form W/O emulsions. Emulsifiers of the HLB range of 8 to 18 are hydrophilic and form O/W emulsions. HLB values from 12 to 18 are most favorable for solubilization to enhance bio- availability of active ingredients. Emulsifiers can be classified according the chemical structure in non-ionic and ionic emulsifiers or emulsifying waxes. Non-lonic Emulsifier Ethoxylates Chemical structure Figure 1: Chemical structure Kolliphor CS 12 and Kolliphor CS 20 Typical Properties Product R-Lipo- N-Hydro- Appearance HLB Usage pH phil phil value concen- working tration range Kolliphor CS 12 C,,,C,, 12xEO White or 13 05-5% 2-12 yellowish white waxy powder Kolliphor CS 20 C,,,C,, 20xEO White or 15 05-5% 2-12 yellowish white waxy powder Table 4: Typical properties Kolliphor CS 12 and Kolliphor CS 20
lonic Emulsifier Kolliphor CSS Chemical Structure Figure 4: Chemical structure Kolliphor CSS (n=15 or 17) Typical properties olliphor CSS_ White or pale yellow amorphous >40 0.5-2% 7- or crystalline powder Emulsifying Waxes (Cream-bases) are a combination of a consistency factor (eg. Fatty alcohols) and an emulsifier. They are especially designed to enable an effective and short development time of a topical pharmaceutical formulation. Cream-bases/Emulsifying Waxes Typical properties Typical properties Product Ingredients Appearance HLB Usage pH value concen- working tration range Kolliphor CS A Cetostearyl Alcohol White or pale 7.0 0.5-5% 6-12 Sodium Cetostearyl vet waxy Sulphate pellets Kolliphor CSL Cetostearyl Alcohol Pellets 75 0.5-5% 6-12 Sodium Lauryl with a faint Sulfate characteristic odor Sodium Ceteary Sulfate Table 6: Typical property of the creambases/emulsifying waxes
Application The choice of emulsifiers for specific applications depends on the desired pro- perties of the formulation (e.g. stability, viscosity, skin feel and API), or on the desired processing technology (e.g. PIT, Hot or cold processing). The traditional processing technology for emulsion is the so called hot process, where you combine both water and oil phase at a temperature of 70 85 C. With this technology you are very flexible in the ingredients you can choose in your emulsion. Beside the well-known hot process of emulsification, there is also the possibility to formulate an emulsion with a processing temperature at room temperature. The processing of O/W emulsions at room temperature has several significant benefits. For example, it is no longer necessary to heat the water and oil phase to 70 80 C. This saves considerable amounts of energy and reduces the production time as the cooling step is eliminated. Another very important advantage is that heat-sensitive APIs can be added t the emulsions at any point. On the other hand the possible ingredients are limited as there is not melting step of the oil phase. In the BASF portfolio of emulsifier for topical pharmaceutical applications only Kolliphor PS 60 is suitable for this kind of processing technology. Another very interesting processing technology is the Phase Inversion Technology (PIT) as it leads to water thin emulsions with a very small droplet sizes and thus these emulsions are very stable. This processing technology uses the temperature dependency of the HLB value of non-ionic emulsifiers as this kind of emulsifier change solubility behavior with elevated temperature. This can be used for pharma- ceutical applications where a very thin emulsion is needed, which is easy to distribute over the skin (e.g. sorayable wound sprays etc.). = a\e >. 8\8 ee 5 B/2/E = F/JE o el fete! S] She a 2s 5 o 2) dD) 33), 5/2 9 S\5\5 3/8 E)E R ele] S/S) 0/5] 8] Pia Wy} 2) OE) 19) a) s 2i0 QS/Z\ S/S 3 ss 8 4/85 Product Ph. Eur. S\SIGISIESEAAZIGA Kolliphor CS 12} Marcrogol Cetosteary x x x x x]x x Ether 12 Kolliphor CS 20} Marcrogol Cetosteary x x x x x]x x Ether 20 Kollliphor CS A Cetostearylalcohol x bay xX x x (Type A), Emulsifying i _ Kollliphor CSS__ Sodium Cetosteary! x ba x x Sulphate Kollliphor CSL x Ba X x x Table 7: Application fields in topical pharmaceutical formulations of the Kolliphor grades
Skin Tolerance All Kolliphor grades are based on vegetable and synthetic raw materials. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreemen In originally sealed containers all Kolliphor types can be stored for at least two years. It is important that they are protected from moisture and stored at less than 30 C. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal Handling and Disposal This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. January 2014

Table of contents Introduction Polyethylene glycol portfolio 5 Typical chemical and physical properties 6 Applications 8 Tablets, liquids, and suspensions 9 Softgels 10 Ensuring softgel performance with low aldehyde Kollisolv? PEGs 13 Topicals 20 Hydrophilic ointment formulation 20 Emulgel formulation 21 Suppository formulation 22 Product details and key benefits 24 Product and sample article numbers 25 ZoomLab, RegXcellence, & MyProductWorld 26 Introduction Polyethylene glycol portfolio
Polyethylene glycol portfolio Kollisolv PEGs are colorless, almost odorless, and tasteless liquids or white solids at room temperature. These products are manufactured by alkali-catalyzed polymerization of ethylene oxide with subsequent neutralization of the catalyst. The number in the name of the product indicates its average molecular weight. Chemical name CAS number Our portfolio of Kollisolv PEGs offers assurance of high-quality production in cGMP manufacturing conditions that meet the compendial requirements of USP-NF and Ph. Eur. At low molecular weights, our Kollisolv? PEGs are present as colorless liquids, and at higher molecular weights these products exist as white semi-solids and solids.
Unlike standard grade PEGs with a total aldehyde content of 50 ppm, our low aldehyde Kollisolv PEGs are restricted to an aldehyde content maximum of 10 ppm and offer assurance of control. With a restricted total aldehyde content to a maximum of 10 ppm, these excipients are especially suited for sensitive APIs and applications, including softgel shells and fills. Colorless, almost odorless, and tasteless liquid at room temperature Average molecular weight (g/mol) 285 to 315 380 to 420 380 to 420 570 to 630 570 to 630 Melting point (C) -15 to -8 4to8 4to8 15 to 25 15 to 25 Hydroxyl value (ng KOH/g) 340 to 394 264 to 300 264 to 300 178 to 197 178 to 197 Viscosity at 25 C (mPa:s) 80 to 105 105 to 130 105 to 130 Solid Solid Viscosity at 99 C (mm?/s) 5.4 to 6.4 6.8 to 8.0 6.8 to 8.0 9.9 to 11.3 9.9 to 11.3 fery soluble in water and alcohol, practically insoluble in oils and fa
Tablets, liquids, and suspensions Kollisolv PEGs can be used in tablet applications as a component of the core or coating. They can also serve as lubricants in the processing of a tablet. In tablet core applications, solic Kollisolv PEGs can be used as a binder or additive. Solid and semi-solid Kollisolv? PEGs can be used in coating applications as a plasticizer and film former. Polyethylene glycols, or macrogols, are mainly used as solubilizers, surfactants, and solvents. As multifunctional ingredients, these excipients play an essential role in various oral and topical formulations. Low-molecular-weight liquid polyethylene glycols are excellent solvents for numerous substances that do not readily dissolve in water. They are widely used as solvents and solubilizing agents for active substances and excipients in liquid and semi-solid preparations. They can also be used as plasticizers in tablets, capsule shells, and film coatings.
Softgels Figure 1. Solubility of Kollidon VA 64 in Kollisolv PEG 300, 400, and 600 at room temperature. BASF offers a range of liquid Kollisolv? PEGs and other complementary products for softgel applications. From solubility enhancement to crystallization inhibition, these products make for easier softgel formulation with greater predictability and reliability. BASF solubilizers such as Kolliphor RH 40 (Ph. Eur.: macrogolglycerol hydroxystearate; USP-NF: polyoxyl 40 hydrogenated castor oil), Kolliphor EL (Ph. Eur.: macrogolglycerol ricinoleate, USP-NF: polyoxyl 35 castor oil), or Kolliphor HS 15 (Ph. Eur.: macrogol 15 hydroxystearate; USP-NF: polyoxyl 15 hydroxystearate) can be used in combination with liquid Kollisolv PEGs to increase the solubilization capacity, allowing for the enhanced dissolution of challenging APIs. Crystallization inhibitors such as Kollidon VA 64 (Ph. Eur., USP-NF: copovidone), Kollidon 30 (Ph. Eur., USP-NF: povidone), and Kollidon 12 PF (Ph. Eur., USP-NF: povidone) can be used with liquid Kollisolv PEGs to prevent drug recrystallization. These crystallization inhibitors form homogenous blends at common processing and filling temperatures, and provide an additional benefit of increasing fill viscosity. This increased fill viscosity allows for more consistent filling and lower weight variance between softgels capsules. Blends of Kollisolv PEGs with Kollidon crystallization inhibitors are stable at room temperature up to 40% concentration by weight. Figure 2. Solubility of Kollidon 30 in Kollisolv PEG 300, 400, and 600 at room temperature. Figure 3. Solubility of Kollidon 12 PF in Kollisolv PEG 300, 400, and 600 at room temperature.
Advancements in increased temperature control for softgel encapsulation machines provide opportunities to use fills with greater crystallization inhibitor concentration. Use of common processing temperatures of 40 or 60 C leads to as much as 80% reduction in fill viscosity. This gives significant advantages by increasing processing speed with lower flow resistance of fills and increasing softgel shelf stability with greater crystallization inhibitor content when using liquid Kollisolv? PEGs with Kollidon crystallization inhibitors. Softgels are oral formulations that are composed of a pharmaceutical grade shell which encapsulates the liquid fill. Shell-fill compatibility requires the strategic selection of excipients to minimize degradation byproducts known to be harmful for softgel stability. To ensure capsu integrity and dissolution reproducibility, the fill must be compatible with the shell, and neither prematurely rupture the shell nor restrict release of the active post-delivery. Aldehydes are a common concern in softgels, especially soft gelatin capsules, where chemical crosslinking of the gelatin peptide backbone will cause insoluble films or pellicles that disrupt dissolution testing. The consequence of crosslinking is often an altered dissolution behavior of the capsule, one that will fail dissolution testing in vitro. While this crosslinking does not always translate to failure in vivo, where enzymes can cleave the peptide backbone, the USP <711> recommends a two-tiered dissolution investigation when in vitro dissolution failure arises from crosslinking. The complicated testing protocol includes pH-dependent enzyme selection and, as elaborated in USP <1094>, additional testing on the compatibility of any surfactants includec in the medium. These additional tests require cumbersome method development and validation, lengthening the time and complexity of going to market. Figure 4. Viscosity vs. concentration of Kollidon VA 64 in Kollisolv PEG 300 at 25, 40 and 60 C.
To study the effect of degradation byproducts, particularly aldehydes, on softgel performance, five lots of polyethylene glycol 400 (PEG 400) of varying grades and storage conditions were selected for testing (Table 1). Two fresh lots of Kollisolv? PEG 400 LA were evaluated, as well as one Kollisolv PEG 400 LA at the 2-year retest. A compendial grade of PEG 400 that met Ph. Eur. and USP monographs was included, as well as a standard, non-pharmacopoeia PEG 400. The standard grade PEG 400 was a forced-aged compendial PEG 400 sample, stressed through aging at 60 C for 9 days and 80 C for 7 days. The starting aldehyde levels for each sample was determined by an in-house R&D method (Figure 7). Kollisolv PEG 400 LA had the lowest aldehyde concentration, under 10 ppm, with nc difference between fresh and at 2-year retest. The compendial PEG 400 sample had an aldehyde concentration almost two-fold higher than Kollisolv PEG 400 LA. Standard PEG 400 was nearl six-fold higher. Figure 7. Starting aldehyde levels for each grade of PEG 400. Table 1. PEG 400 samples for softgel formulations. Sample # Material Age to retest Grade 1 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 2 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 3 Kollisolv PEG 400 LA At 2-year retest Low aldehyde (Ph. Eur., USP) 4 Compendial PEG 400 Compendial (Ph. Eur., USP) 5 PEG 400 Standard Samples 1 and 2 represented two different freshly opened lots.
Brilliant Blue, serving as a model active pharmaceutical ingredient (API), was formulated at eque parts in the five PEG 400 samples. After the formulations were filled into softgel capsules using lab-scale filling equipment, the capsules were then stored at ambient (25 C, 60% RH) and accelerated (40 C, 75% RH) conditions for a 12-month period. In vitro dissolution of the softgel capsules was performed to evaluate the effect of aldehyde content on dissolution. The dissolution time to release 80% of the loaded Brilliant Blue was captured for each sample (Fig. 9). Softgels containing Kollisolv PEG 400 LA demonstrated an equivalent dissolution time over the full 12 months under ambient conditions; while even the compendial grade PEG 400 containing softgels exhibited delayed dissolution within 6 months. When stored at ambient conditions, the softgel capsules composed of Kollisolv? PEG 400 LA demonstrated superior stability over compendial and standard PEG 400 (Fig. 8). Over the course of 12 months, the softgels filled with fresh and 2-year Kollisolv? PEG 400 LA showed a stable release profile with no evidence of crosslinking or change in dissolution. The equivalence of performance with product age, fresh and at two years, demonstrates the stability of Kollisolv PEG 400 LA and reliability of performance. Figure 9. Dissolution time (until 80% release) of softgels stored at ambient (25 C, 60% RH) conditions taken as the time in minutes. In contrast, the softgel consisting of compendial PEG 400 increasingly delayed dissolution, with significant changes in dissolution evident by month 6. To an exaggerated degree, the softgel containing standard PEG 400 showed retarded dissolution and evidence of near-immediate crosslinking within the first month. Figure 8. Dissolution of softgels stored at ambient (25 C, 60% RH) conditions over a 12-month period. In accordance with USP<711>, formulations made with the compendial PEG 400 would require proof of gelatin crosslinking via spectroscopic methods and complicated dissolution tests. Comparatively, formulations that consisted of Kollisolv? PEG 400 LA would not require further investigation regarding crosslinking or dissolution. Even under stressed aging in accelerated storage conditions, softgels consisting of Kollisolv PEG 400 LA within the full 2-year retest period exhibited equivalent performance, demonstrating stability of the product within its shelf-life. Under accelerated storage, dissolution of capsules of fresh and retest-aged Kollisolv PEG 400 LA remained equivalent through 3 months (Fig. 10). In contrast, compendial PEG 400 mirrored the failure of standard, non- pharmacopoeia PEG 400, and both products showed immediately delayed dissolution within the first month, failing due to crosslinking of soft gelatin capsules. In this case, even meeting Ph. Eur. and USP standards for a pharmaceutical excipient did not impart stability over a non- pharmaceutical grade of PEG 400.
Figure 10. Dissolution of softgels stored at accelerated (40 C, 75% RH) conditions over a 6-month period. Under accelerated conditions, Kollisolv? PEG 400 LA offered improved stability of the dissolutior profile. Regardless of age, the three Kollisolv? PEG LA samples demonstrated an equivalent dissolution time over 3 months, suggesting stability studies under these conditions is feasible through 3 months (Fig. 11). In contrast, both compendial and standard, non-pharmacopoeia grades of PEG 400 exhibited delayed dissolution immediately, failing accelerated stability studies under these conditions. Aldehyde content within the softgels was determined at time points within both storage conditions. As softgel fills, Kollisolv? PEG 400 LA samples demonstrated minimal changes in the aldehyde content over a 2-year retest period. Evaluation of the aldehyde content showed that storage condition did not significantly impact the total aldehyde amount present in the softgel fill. Ultimately, Kollisolv PEG 400 LA did not develop aldehyde content over time when formulated in softgels, whether fresh or at retest, under ambient or accelerated storage (Fig. 12). Figure 12. Aldehyde development of Kollisolv PEG 400 LA in softgels, over 12 months at under ambien and accelerated storage. Figure 11. Dissolution time (until 80% release) of softgels stored at ambient (40 C, 75% RH) conditions taken as the time in minutes. In summary, Kollisolv? PEG 400 LA outperformed compendial PEG 400. The dissolution profiles from softgels at both ambient and accelerated storage conditions reflected a pre dilection towards Kollisolv PEG 400 LA, with stable release seen for longer than from compendial PEG 400. When using Kollisolv PEG 400 LA as the softgel fill, aldehydes did not develop over time at either ambient or accelerated storage conditions. Rather, the source and quality of the products had the greatest effect on the aldehyde levels. Fresh and at-retest Kollisolv PEG 400 LA samples offered a 50% reduction in starting average aldehyde content in comparison to compendial grade PEG 400. The repeatable and stable dissolution profiles seen for Kollisolv PEG 400 LA bring the advantages of rapid development and ease of qualification.
Topicals Emulgel formulation When used for topical applications, solid and liquid Kollisolv PEGs be combined to form water-soluble bases for ointments, suppositor and ovula. Low-molecular-weight Kollisolv? PEGs can be used as solvents, conditioners, adhesion promoters, and humectants. These products, like Kollisolv PEG 300, Kollisolv PEG 400, and Kollisolv PEG 1000, promote ease of application, softening on contact with skin, and localization of active delivery. High-molecular-weight Kollisolv PEGs can be used as structuring agents and thickeners to increase the viscosity of formulations. These include Kollisolv PEG 1450, Kollisolv PEG 3350, and Kollisolv PEG 8000. Hydrophilic ointment formulation Kollisolv PEG ointments can be used as an alternative to traditional petrolatum-based ointmen formulations. By pairing different amounts of high- and low-molecular-weight chains, PEG ointments can be tuned for desirable rheological profiles and sensory. Procedure 1. Prepare phase A by weighing ingredients into an appropriately sized beaker. 2. Heat the mixture to 60 C and continue heating until the mixture has completely melted. Try to minimize the heating time as much as possible. 3. Once all the components have melted, place phase A underneath an overhead mixer. Stir at a low shear rate until cooled to room temperature. Kollisolv PEG 3350 is commercially available only in the USA and Canada as an excipient.
Suppositories allow formulators to accurately deliver active ingredients through an alternative route. Kollisolv PEG suppositories are ideal for the formulation of suppository matrices, offering a melting temperature range within physiologically relevant conditions and compatibility with hydrophilic druas.
Product details and key benefits Product details Regulatory Manufacturing site Manufacturing process Re-test period Certified Handling Safety data sheet Retest date and storage conditions Specification Regulatory status Key benefits Supply reliability & consistent quality Sustainability Technical service BASF Virtual Pharma Assistants Kollisolv? PEGs USP-NF, Ph. Eur. Geismar, Louisiana (USA) Synthetic 24 months Kosher, Halal Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRPI). For current specification, please speak to your local BASF sales or technical representative. Please refer to Quality & Regulatory Product Information (QRPI). Kollisolv PEGs are manufactured in a GMP compliant facility in the U.S. ensuring: Consistent quality and safety @ Reliable, vertically integrated supply BASF is a proud member of the Pharmaceutical Supply Chain Initiative (PSCl), whose vision is to establish and promote responsible practices that will continuously improve human rights, health, safety, and environ- mentally sustainable outcomes for supply chains worldwide. @ World class expertise in excipient chemistry Formulation guidance with ZoomLab @ Regulatory documentation available in RegXcellence Product details available via MyProductWorld @ Full pharma regulatory documentation and submission support Product details and key benefits

For sample requests contact us at pharma-solutions@basf.com This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to th extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matte in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2022 BASF Corporation. All Rights Reserved.
Technical Information Fatty acids and alcohols: Consistency factors for topical formulations, and excipients for solid oral dosage forms. Oktober 2021 WF-No. 137189 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes fatty acids and alcohols that can be used as (co-) emulsifiers and consistency factors in topical pharmaceutical applications, but may also function as excipients in solid oral dosage forms, e.g., as matrix formers and lubricants. This document focuses on fatty acids and alcohols of the Kolliwax family. Please refer to the individual technical information sheet for specific information on our two glyceride based grades Kolliwax GMS II and Kolliwax HCO (Glycerol Monostearate, and Hydrogenated Castor Oil, respectively). Trade name Compendial Name Kolliwax CA Ph.Eur.: Cetyl Alcohol USP/NF: Cetyl Alcohol Kolliwax CSA 50 Ph.Eur.: Cetostearyl Alcohol USP/NF: Cetostearyl Alcohol JP: Cetostearyl Alcohol Kolliwax CSA 70 Ph.Eur.: Cetostearyl Alcohol Kolliwax MA USP/NF: Myristyl Alcohol Kolliwax SA Ph.Eur.: Stearyl Alcohol Kolliwax SA Fine USP/NF: Stearyl Alcohol JP: Stearyl Alcohol Kolliwax S Ph.Eur.: Stearic Acid 50 Kolliwax S Fine USP/NF: Stearic Acid 50 llPe Stearic Acid 50 Table 1: Compendial names for fatty alcohols and acids of the Kolliwax family. Description 2. Technical properties Kolliwax grades are white to slightly yellowish, waxy substances derived from natural ressources, namely coconut oil, palm kernel oil, and/or palm stearine. With melting points above room temperature, these products are either supplied as powder, pearls, or pelletts (see table1 and table 2 for details). The numeric part of the name of the two grades of Kolliwax CSA represents the approximate weight percentage of stearyl alcohol. es ene Trade name Chemical nature CAS-No. Melting ranges [cy Kolliwax CA Cetyl Alcohol (C,,) 36653-82-4 46-52 Koliwax CSA S0_ Cety/Stearyl Alcohol 7769 97.9 1666 Kolliwax CSA70_ (Cie/Cra) Kolliwax MA Myristyl Alcohol (C,,) 112-72-1 36-42 Kolliwax SA Stearyl Alcohol (C,,) 112-92-5 57-60 Kolliwax SA Fine Koliwax?S Stearic/Palmitio Acid g 7754 93.05 308 Kolliwax S Fine (Cil/Cy6) Values given for guidance only, see specification sheets for detailed information on melting and/or freezing temperatures. Table 2: Properties of fatty alcohols and acids of the Kolliwax family.
Figure 1: Typical appearance of the Kolliwax grades. The scale in the back is metric, with 1 mm per mark. For detailed information on particle size distributions, please refer to the individual product specification sheets. Scanning electron mircroscopy (SEM) igure 2: SEM images of Kolliwax S, and Kolliwax S Fine. Please refer to the individu: specification sheets for detailed information on particle size distributions.
3. Application Overview The following table 3 gives an overview on the most important applications and functions of the Kolliwax fatty alcohols and acids: while fatty acids and alcohols are generally used as consistency factors, our fine grades of stearic acid and stearyl alcoho (Kolliwax S Fine and Kolliwax SA Fine, respectively) allow to use these substances in the preparation of solid dosage forms, where they can aid as lubricants or matrix formers. Table 3: Application of the Kolliwax grades. Emulsions Exhibiting excellent skin tolerance, the Kolliwax grades can be used for all kinds of topical pharmaceutical applications, such as creams, gels, lotions, and ointments. The typical usage concentration in emulsions is about 1- 5%. All Kolliwax grades will act as consistency factors and co-emulsifiers at the same time. With their amphiphilic structure, they will stabilize the interface between oil and water and will help to enhance the viscosity by building up a liquid crystalline network (lamellar sheet structure). Stabilizing w/o and 0/w emulsions, they also aid in bringing a unique softness and creaminess to the targeted formulation. Lubricants In tableting processes for solid oral dosage forms, lubricants are used to prevent ingredients from clumping to undesired aggregates and from sticking to the tablet punches or capsule filling machine. In addition, lubricants hamper the friction that would hinder tablet formation and ejection. Among inorganic materials (e.g. talc or silica), fat based substances like vegetable stearin, magnesium stearate or stearic acid are commonly used as lubricants in tablets or hard gelatin capsules. Lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. Formulation examples Guideline for the preparation of the model formulations: MaYIGenne 1Or UWle PrepalrauviOrl OF WIE MIOQE! fOMTIUlAvOrls. 1. Heat components of phase A to 80 - 85 C and stir until transformed into a homo- geneous melt. 2. Heat components of phase B to 80 85 C. Under constant stirring, slowly add phase A to phase B, homogenize for 5 min at 5000 rpm. Let cream cool to 35 C while mixing at 200 rpm, and add preservative.
Model formulation Rich Cream: This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as emulsifiers to create avery stiff cream that offers a slow spread and a cushioned feeling when rubbing into the skin. Its high immediate smoothness results from the utilization of Kollicream IPM, a fast spreading oil with broad penetration enhancement properties that can aid as a solubilizer for lipophilic drugs. Ingredient Phase Ph. Eur. name Role Amount [wt.-%] A __ Kolliwax CSA 70 Cetostearyl Alcohol Consistency Factor, 7.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 25 40-55 (Type Il) Co-Emulsifier Kolliphor PS 60 Polysorbate 60 Emulsifier 4.2 Kollisolv@ MCT 70 Medium Chain Emollient 11.5 Triglycerides Kollicream IPM Isopropyl Myristate Emollient 1.3 B Deionized Water 69.2 Solvent _____. Glycerol 3.3 C_ Euxyl PE 9010 Preservative 1.0 Table 4: Model formulation for a rich Cream. Model formulation Light Cream: This formulation is a smooth cream with easy distribution, medium viscosity, and a glossy finish. Due to the difference in HLB values, the blending ratio of Kolliphor CS 12 and Kolliphor CS 20 can be used as a factor to maximize emulsion stability. Phase Ingredient Ph. Eur. name Role Amount [wt.-%] A_ Kolliwax CSA 50 Cetostearyl Alcohol Consistency Factor, 4.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 5.0 40-55 (Type Il) Co-Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Emulsifier 2.0 Ether 20 Kolliphor CS 12 Macrogol Cetostearyl Emollient 0.8 Ether 12 Kollicream CP 15 Cetyl Palmitate 15 Emollient 0.8 Kollicream IPM Isopropyl Myristate Emollient TA B__ Deionized Water 74.0 Solvent Glyerol 5.0) C_ Euxyl PE 9010 Preservative 1.0 in Si Pe Table 5: Model formulation for a light cream. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment.
5. Product specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554718 olliwax CA 50253459 25 kg Plastic film bag 50259499 0.5 kg Plastic bottle 30554719 olliwax CSA 50. 50253501 25 kg Plastic film bag 50259500 0.5 kg Plastic bottle 30554721 olliwax CSA 70 50253504 25 kg Plastic film bag 50259502 0.5 kg Plastic bottle 30554492 olliwax MA 50375472 20 kg Corrugated fiberboard box with PE liner 50259498 0.5 kg Plastic bottle 30554720 olliwax SA 50253503 25 kg Plastic film bag 50259501 0.5 kg Plastic bottle 30563963 olliwax SA Fine 50284249 25 kg Plastic film bag 50372378 0.5 kg Plastic bottle 30554752 olliwax S 50253532 25 kg Plastic film bag 50259521 0.5 kg Plastic bottle 30554750 olliwax S Fine 50253810 25 kg Plastic film bag 50259508 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
PronovaPure 400:200 EI Valid for batches produced from January 2014 Chemical names of active ingredient CAS-No. Description PronovaPure 400:200 EE is a light yellow fish oil ethyl ester concentrate. ee ES, eS Ee The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Scombridae and Carangidae). The product is an ethyl ester (EE), rich in omega-3 fatty acids. The content of EPA (Eicosapentaenoic acid expressed as EE) and DHA (Docosahexaenoic acid expressed as EE) is min. 600 mg/g. Articles Country of origin
Monographs and Regulations Composition A RE Oe, Ree Ee ee eS PronovaPure 400:200 EE meets the requirements for an omega-3 fatty acid source in most countries. The product complies with the Ph. Eur. monograph on Omega-3-acid ethyl esters 60 (2063). Further, the product conforms to the voluntary GOED monograph in the current version. Fish oil ethyl ester concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed. TT a ey ee eR PronovaPure 400:200 EE meets the requirements for an omega-3 fatty acid source in most countries. The product complies with the Ph. Eur. monograph on Omega-3-acid ethyl esters 60 (2063). Further, the product conforms to the voluntary GOED monograph in the current version. Fish oil ethyl ester concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed. Ingredients in descending order of weight: Fish oil ethyl ester concentrate, tocopherol-rich extract (E 306). mainly derived from soybean (from identity preserved, not genetically modified origin) Ingredients in descending order of weight: Fish oil ethyl ester concentrate, tocopherol-rich extract (E 306). mainly derived from soybean (from identity preserved, not genetically modified origin) Solubility Practically insoluble in water, very soluble in acetone, in ethanol (96 per cent), in heptane and in methanol. Practically insoluble in water, very soluble in acetone, in ethanol (96 per cent), in heptane and in methanol. Specification Stability, Storage and Handling Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 36 months. as ethyl ester Ph. Eur. 2063/2.4.29 EPA (Eicosapentaenocic acid) min. 400 mg/g DHA (Docosahexaenoic acid) min. 200 mg/g EPA & DHA (Eicosapentaenoic 600-700 mg/g & Docosahexaenocic acid) Total Omega-3 content min. 650 mg/g as ethyl ester Ph. Eur. 2063/2.4.29 EPA (Eicosapentaenocic acid) min. 400 mg/ DHA (Docosahexaenoic acid) min. 200 mg/< EPA & DHA (Eicosapentaenoic 600-700 mg/c & Docosahexaenoic acid) Total Omega-3 content min. 650 mg/c AL IGdol VV INUIT TO. The product is sensitive to oxygen, light and heat. It should therefore be stored in the tightly sealed, lightproof packaging in a cool place. Once opened, it is recommended to use the remaining contents as quickly as possible. Applications   PronovaPure 400:200 EE is intended for use in dietary supplements such as in soft gel capsules. For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Note PronovaPure 400:200 EE must be handled in accordance with the Material Safety Data Sheet. PronovaPure 400:200 EE must be handled in accordance with the Material Safety Data Sheet. This document, or any answers or information provided herein b\ BASF, does not constitute a legally binding obligation of BASF. Whik the descriptions, designs, data and information contained herein ar presented in good faith and believed to be accurate, it is provided fo your guidance only. Because many factors may affect processing o application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It doe: not relieve our customers from the obligation to perform a full inspectior of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOF A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OF THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUF TERMS AND CONDITIONS OF SALE. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation ie Cerne gare! cee Ray Caen cat ace cet ee: eaten. Standards Produced under cGMP and HACCP principles. OL ING PIOGUCTS UPON Gerivery OF any OIner ODEGADON. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS: DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Kollicoat MAE 100-55 Kollicoat MAE 100 P Methacrylic acid/ethyl acrylate copolymers in powder form for enteric coating Methacrylic acid/ethyl acrylate copolymers in powder form for enteric coating
Contents 1. Introduction 1.1 General remarks 1.2 Structural formula 1.3 Commercial form 4A Pharmarnnnaia) citiia 1.2 Structural formula 1.4 Pharmacopoeial situation 2. Specification and properties 2.1 Description 2.2 Specifications 2.3 Solubility 2.1 Description 3. Processsing Notes 3.1 Use of plasticizer 3.1 Use of plasticizer 3.2 Re-dispersion of Kollicoat MAE 100-55 3.3 Re-dispersion of Kollicoat MAE 100 P 4. Applications and typical formulations using Kollicoat MAE 100-55 4.1 Enteric coating of ASS-crystals 4.3 Enteric coating of diclofenac-Na tablets 4.5 Enteric coating of propranolol tablets 5. Applications and typical formulations using Kollicoat MAE 100 P 5.1 Coloured enteric film coatings for tablets 5.1 Coloured enteric film coatings for tablets 5.2 Coloured enteric film coatings for pellets and crystals 5.3 White enteric film coatings for pellets 5.4 Colourless enteric coatings for soft gelatine capsules 5.5 Seal-coating of cores 5.6 Further applications 6. Equipment cleaning recommendations 7. Storage 8. Shelf life 8. Shelf life 9. Product Numbers 10. Packaging
1. Introduction 1.1 General remarks Kollicoat MAE100-55 and Kollicoat MAE 100 P are spray-dried copolymers consisting of methacrylic acid and ethyl acrylate. They are used as film-formers for enteric coatings of solid dosage forms like crystals, multi-particulates, mini-tablets, tablets soft-gel capsules and others. 1.2 Structural formula The monomer ratio in the copolymers is 1:1. The average molecular weight M,, is of the order of 250,000 AMU. Both copolymers have an anionic character. In contrast to Kollicoat MAE 100-55 the copolymer in Kollicoat MAE 100 P is partially neutralized before spray drying. 1.3 Commercial form Both Kollicoat MAE 100-55 and Kollicoat MAE 100 P are white powders with a faint characteristic odour. In order to apply Kollicoat MAE 100-55 the powder has to be re-dispersed in water with the addition of a caustic excipient, preferably sodium hydroxide solution. The pre-neutralized carboxyl groups in the Kollicoat MAE 100 P powder make it easy to re-disperse in water without further excipients added for partial neutralization. 1.4 Pharmacopoeial situation The polymers are listed in the three major pharmacopoeias as follows: Kollicoat MAE 100-55: h.Eur.: = Methacrylic Acid Ethyl Acrylate Copolymer (1:1) Type A ISP/NF: Methacrylic Acid and Ethyl Acrylate Copolymer NF PE: Dried Methacrylic Acid Copolymer LD Kollicoat MAE 100 P: Ph. Eur.: Methacrylic Acid Ethyl Acrylate copolymer (1:1), Type B USP-NF: _ Partially-Neutralized Methacrylic Acid and Ethyl Acrylate copolymer
2. Specifications and properties The Kollicoat MAE grades contain 0.7% sodium lauryl sulfate (USP) and 2.3% Polysorbate 80 (Ph.Eur.) as emulsifying agents. (The percentages refer to the solid substances.) 2.1 Description Polysorbate 80 is manufactured using oil of vegetable origin. The Kollicoat MAE grades are weakly acidic copolymers that dissolve at a pH-value above 5.5. See separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). 2.2 Specification The Kollicoat MAE grades are re-dispersible in water. The achieved dispersions regain their milky white appearance either when using a neutralization medium (Kollicoat MAE 100-55) such as 1 mol/L NaOH or just when mixing it with water (Kollicoat MAE 100 P). When treated with higher quantities of dilute alkalis the Kollicoat MAE powder grades (like the Kollicoat MAE 30 DP dispersion) become soluble and form clear to slightly cloudy solutions of moderate viscosity. Kollicoat MAE 100-55 powder dissolves in alcohols such as methanol, ethanol or i-propanol to yield clear to slightly cloudy solutions Mixing of the re-dispersed aqueous formulations of Kollicoat MAE 100-55 or Kollicoat MAE 100 P with acetone, ethanol or isopropanol in a ratio of 1:5 a faint opalescent or clear, moderately viscous solution is obtained. Upon addition of the organic solvent to the dispersion, the polymer initially precipitates, then re-dissolves as more solvent is added. 3. Processing notes 3.1 Use of plasticizer Plasticizers are essential to improve the flexibility of the films formed. Suitable plasticizers or gloss intensifiers are aN a MI ac oR ce e 1,2-propylene glycol e Triethyl citrate e Polyethylene glycols such as PEG 400 e 1,2-propylene glycol e Triethyl citrate e Polvethviene alvcols such as PEG 4 The recommended amounts of plasticizers range from 10% to 25% relative to the amount of polymer dry matter. The Kollicoat MAE grades are incompatible with magnesium stearate as part of the coating formulation. However, any magnesium stearate present in the cores to be coated does not present problems. 1.2-propylene glycol improves the processibility and barrier properties of the film coatings. A number of factors may cause aqueous dispersions to coagulate during processing, rendering them unusable: SAL PARE ES RENAE Ea AN Addition of finely divided pigments High shear gradients on stirring and grinding Addition of emulsifying agents, stabilizers or wetting agents Changes in pH Cationic additives Organic solvents. Foam formation Foam formation during processing can be prevented by adding a silicone antifoan such as Pharsil 21046. Flat-plate stirrers have proved suitable for the production of spray suspensions.
Spray suspensions with a 15 30% solids content give good results and save time in spraying. recommend to: Dilute the dispersion to a solids content of 15% to 20% Stir the desired auxiliary into the dispersion in the form of a diluted solution. The following excipients can be included in a film-coating formulation: ENS REN Ne RRO ARO EER REE LE OTE Te SUSE Se REA. Fee Re ae OM TGR REE MON NR IR e Talc Syloid Aerosil and Kaolin as release and smoothing agents; e Pigments The Kollicoat MAE grades have a high pigment binding capacity: two to three parts of pigments or other auxiliaries may be added for one part of solid polymer. The proper use of Kollicoat MAE 100-55 comprises of two steps: 1.Re-dispersion of Kollicoat MAE 100-55 powder to form an aqueous latex dispersion 2.Addition of plasticizer To achieve a proper re-dispersion the polymer powder has to be incorporated in water in combination with a caustic compound to achieve the requested degree of neutralization of around 6 mol-percent of the methyacrylic acid moieties in the polymer. This neutralized polymer dispersion can be further processed by adding the required additives such as plasticizer, colorants etc. to generate a coating dispersion of an appropriate concentration. For the re-dispersion step a number of caustic excipients can be used for neutrali- zation. The compounds proposed in the following list are applied in a 1 mol/L aqueous solution if not otherwise stated. Sodium hydroxide (NaOH) is the most recommended compound. Others are SADIE SE FEE LRAR NARONee ET SNA NAS RNS: Nee INES EAS Se Potassium hydroxide (KOH) Ammonia (NH, in water) Ammonium bicarbonate (NH,)HCO, Ammonium carbonate (NH,),CO, (to be applied in a concentration of 0.5 mol/L The following graph shows the viscosity determination for a 20% dispersion of Kollicoat MAE 100 P and the situation for Kollicoat MAE 100-55 after its re- dispersion using a 1 mol/L solution of sodium hydroxide and ammonia, respectively to achieve a 6 mol-% neutralization of the methacrylic acid moiety.
Shortly after the addition of the caustic compound the viscosity of the re-dispersed enteric polymer reaches already its minimum level. Different neutralization media have only little influence on the finally achievable viscosity. The following graph shows the resulting viscosities for the 6 mol-% neutralization of Kolllicoat MAE 100-55 using either a solution of 1 mol/L NaOH, of 1 mol/L ammonia, of 1 mol/L ammonium hydrogen carbonate or of 0.5 mol/L ammonium carbonate solution, respectively. To manufacture 1 kg of a Kollicoat MAE-enteric coating dispersion the following procedure has to be followed: Processing recommendations Instead of adding 100 ml of a 1 mol/L NaOH solution the alternative neutralizing agents mentioned above can be applied. The dry matter content has to be adjusted accordingly. When stirring the powder into water an aqueous dispersion is achieved with pro- cessing properties similar to those of Kollicoat MAE 100-55 or Kollicoat MAE 30 DP-dispersions. Procedure: Add the powder to the specified quantity of water with stirring. During stirring ensure that ensure that e the powder does not form lumps e the powder is immediately wetted e the speed of the stirrer always matches the viscosity not too much foam is being formed. To avoid lump formation and deposits on the stirrer, a stirrer with no horizontal surfaces, e.g. a bar or gate-type should be used. When the powder has been incorporated, the viscosity initially rises and then decreases on further stirring. The dispersion should be stirred for 2 - 4 hours to ensure complete re-dispersion. It must be ensured that not too much air is entrained in the dispersion when it thickens. Acconcentration of 20% has been found to be the optimum. The further steps in the preparation of a suitable dispersion are essentially the same as for Kollicoat MAE 30 DP. It is not necessary to add any other auxiliaries such as alkali to re-disperse Kollicoat MAE 100 P. The powder contains already the necessary percentage of neutralized methacrylic acid groups for easy re-dispersion.
4. Applications and typical formulations using Kollicoat MAE 100-55 For the proper handling of Kollicoat MAE 100-55 it is recommended to follow the instructions given for the re-dispersion of the polymer in section 3.2. Thorough calculation of the dry matter content of the polymer dispersion after addition of the selected neutralisation compound is essential. Formulations with Kollicoat MAE 100-5 The crystals were enteric coated using a Kollicoat MAE 100-55-formulation without pigments. The ASS-crystals were coated in a Glatt WSG fluid-bed coater with a 7 Wurster insert. 4.1 Enteric coated acetyl salicylic acid crystals Acetyl salicylic acid crystals with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendation: in chapter 3.2. An aqueous polymer dispersion containing 600 g of Kollicoat MAE 100-55 with the appropriate amount of triethyl citrate as plasticizer are prepared as follows: Ingredients Parts by weight Composition Ig] [%] Kollicoat MAE 100-55 600.0 18.00 Triethyl citrate 60.0 1.80 (10% relative to polymer weight) NaOH (1 mol/L) 204.0 0.25 Demineralized Water 2460.0 = Total 3224.0 20.10 The polymer powder is stirred into 2200 g of water. The required quantity of NaOH-solution is added and the re-dispersion is performed for 30 minutes under stirring while the triethyl citrate is dispersed in the remaining volume of water in a separate beaker. The plasticizer dispersion is combined with the polymer dispersion and stirred for 2 hours. Coating equipment Glatt GPCG 3.1 with Wurster insert (7 ) Batch size Number of nozzles Nozzle diameter Total applied quantity (for 50% weight gain) Spraying rate Spraying pressure Spraying time Air supply Inlet air temperature Drying time Weight gain kg mm g g/min bar min ms/h C min % 1.0 1 0.8 2750 20.0 1.0 ~ 140 90 ...130 60 8 20 to 50 Coating equipment and process parameters Coating equipment and process parameters
Release testing Kollicoat MAE 100-99 coating eee 20% weight gain === 40% weight gain === 50% weight gain At the recommended minimum coating level of 20% weight gain the release level of acetyl salicylic acid crystals of less than 10% within the 2 h residence time in 0.08N HCl can be achieved. 4.2 Enteric coated acetyl salicylic acid tablets (100 mg/tablet) Composition of the tableting mixture Ingredients Parts by weight Composition Ig] [%] Acetyl salicylic acid 285.7 28.6 Ludipress 704.3 70.4 Stearyl fumarate-Na (Pruv) 10.0 1.0 Total 1000.0 100.0 Processing of the tableting mixture The ingredients except the sodium stearyl fumarate are blended in a Turbula blender for 10 minutes and passed through an 800 ~m-sieve. The lubricant is added and the resulting blend is additionally mixed for 1 minute. Rotary press Tablet shape Tablet weight Tablet diameter Compression force Korsch XL 100 concave 350 mg 9mm 6 kN Tableting equipment
Enteric coating with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Prepare around 1200 g of a dispersion containing around 220 g of Kollicoat MAE 100-55 Ingredients Parts by weight Composition Dry matter Ig] [%] [%] Kollicoat MAE 100-55 218.0 18.2 18.2 Triethyl citrate 21.8 1.8 1.8 (10% relative to polymer weight) NaOH (1 mol/L) 75.2 6.3 0.3 Demineralized Water 887.0 73.7 - Total 1200.0 100.0 20.2 Composition of the coating formulation Around 200 g of the water is used to disperse the triethyl citrate. Kollicoat MAE 100-55 is added to the remaining quantity of water and dispersec after the addition of the required quantity of 1 mol/L NaOH-solution. After 30 minutes of permanent stirring the plasticizer dispersion is added. The resulting coating suspension is stirred for 2 h prior to use. The recommended conditions are shown in the following. The cores were heated to 50 C for 30 minutes before applying the coating formulation. Release testing Kollicoat MAE 100-55 coating levels: Hicoat MAE 1QQ-99 Coating levels: == 3 mg/cm? === 4 mg/cm? === 6 mg/cm? == allowance limit == buffer change
4.3 Enteric coated Diclofenac-Na tablets (50 mg/tablet) Composition of the tableting mixtur Ingredients Parts by weight Composition Ig] [%] Diclofenac-Na 181.8 18.2 Ludipress 738.2 73.8 Kollidon VA 64 Fine 50.9 5.1 Kollidon CL 18.2 1.8 Aerosil 200 3.6 0.4 Magnesium stearate 7.3 0.7 Total 1000.0 100.0 Processing of the tableting mixture The ingredients except the Mg-stearate are blended in a Turbula T2C blender for 10 minutes and passed through an 800 um-sieve. Finally the magnesium stearate is added and the resulting blend is mixed for 1 minute. Rotary press Tablet shape Tablet weight Tablet diameter Compression force Korsch XL 100 concave 275 mg 9mm 15 kN Enteric coating with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Ingredients Parts by weight} Composition Dry matter Ig] [%] [%] Kollicoat MAE 100-55 451.5 18.1 18.1 Triethyl citrate 45.0 1.8 1.8 (10% relative to polymer weight) NaOH (1 mol/L) 153.5 61 2.5 Demineralized Water 1850.0 74.0 - Total 2500.0 100.0 22.3 Composition of the coating formulation Around 200 g of the water is used to disperse the triethyl citrate. Kollicoat MAE 100-55 is added to the remaining quantity and dispersed after the addition of the 1 mol/L NaOH-solution. After 30 minutes of permanent stirring the plasticizer-dispersion is added. The resulting coating suspension is stirred for 2 h prior to use. Coating equipment Manesty Coater XL Lab 01 Batch size kg 4.0 Number of nozzles 1 Nozzle diameter mm 0.8 Spraying rate g/min 20 Application quantity mg/cm? 3-4 Spraying time min 40 Air supply ms/h 400 Inlet air temperature C 55 Drying time min 5 Coating equipment and process parameters
Release testing Kollicoat MAE 100-55 coating levels 4.4 Enteric coated pantoprazol-Na mini-tablets (6.4 mg tablet weight) The mini-tablets were coated using an aqueous solutions of Kollicoat MAE 100-55 in a fluid bed coater. A a sub-coat is applied to prevent the API from degradation caused by interacting with water. Composition of the tableting mixture Ingredients Parts by weight Composition Ig] [%] Pantoprazole Na hydrate 242.4 12.12 Ludipress LCE 1547.6 77.38 Kollidon VA 64 fine 100.0 5.00 Kollidon CL-F 100.0 5.00 Mg-stearate 10.0 0.50 Total 2000.0 100.00 Processing of the tableting mixture Prior to use all ingredients were sieved through an 800um-sieve. After sieving the ingredients with the exception of Mg-stearate were blended in a Turbula T2C blender for 8 minutes. Finally the magnesium stearate was added and the tableting mixture is achieved after 2 minutes additional blending. Korsch XL 100 4 micro punches, no engravings Coating equipment and process parameters ee eee Son an ee in eee Tee ey eR ee ie ee es Tablet diameter Tablet shape Tableting speed Agitator filling shoe Compression force Tablet weight 2mm concave 30 rpm 5 rom 1,5 KN 6.4 mg Around 312,000 mini-tablets were achieved. At a tablet weight of 6.4 mg one tablet contains 0.78 mg of pantoprazole Na.
Enteric coating with Kollicoat MAE 100-55 To prevent the API in the mini-tablets to interact with the aqueous coating formulation a sub-coat consisting either of Kollicoat IR White Il, Kollicoat IR or Kollidon VA 64 can be applied. The latter one has the advantage that the polymer can be applied using an organic solvent e.g. i-propanol. Ingredients Parts by weight Composition Ig] [%] Kollicoat IR White II 199.3 19.9 FD&C Blue No.1 0.7 0.1 Water 800.0 80.0 Total 1000.0 100.0 Glatt GPCG 3.1, Granu 51, Nozzle position 1: top spray Nozzle Mini tablet load Sub-coat dispersion Spray rate Atomization air Air volume rate Inlet air temperature Product temperature mm 9 g g/min bar ms/h C C 0.8 1500 825 20 2.0 206 60 48 Ingredients Parts by weight Composition Ig] [%] Kollicoat IR White II 199.3 19.9 FD&C Blue No.1 0.7 04 Water 800.0 80.0 Total 1000.0 100.0 Ingredients and composition Glatt GPCG 3.1, Granu 51, Nozzle position 1: top spray Coating equipment anc process parameters MIAN APU VT, ATAU Ul, INULEIC PUOIIVUIT I. LUN OMIay Nozzle mm 0.8 Mini tablet load g 1500 Sub-coat dispersion g 825 Spray rate g/min 20 Atomization air bar 2.0 Air volume rate ms/h 206 Inlet air temperature C 60 Product temperature C 48 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Ingredients Parts by weight Composition Ig] [%] Kollicoat MAE 100-55 600.0 18.0 Triethy! citrate 60.0 1.8 (10% relative to polymer weight) NaOH (1 mol/L) 207.0 0.2 Water 2470.0 Total 3337.0 20.0 Ingredients and composition Around 1800 ml of water is used to re-disperse the Kollicoat MAE 100-55 while the 1 mol/L NaOH-solution is added. The mixture is stirred for 30 minutes. In parallel the plasticizer is dispersed in the remaining quantity of water. After adding the dispersed plasticizer to the polymer dispersion this is stirred fo 2 hours. Enteric coating formulation is applied until a coating level of 4.5 mg/cm? was achieved. Coating equipment and process parameters Glatt GPCG 3.1, Granu 51, nozzle position 1: top spray Batch size kg 1.37 Number of nozzles 1 Nozzle diameter mm 0.8 Spraying rate g/min 20 Atomization air bar 2.0 Air supply ms/h 206 Inlet air temperature C 50 Product temperature C 39 Drying time min 5
The coated mini-tablets are filled in hard-gel capsules. To achieve the claimed API concentration of 40 mg per capsule 52 mini-tablets are required. Finished dosage form Release testing Due to the sensitivity of the API release testing with a buffer change is not opportune. The tests at pH 1.2 and pH 6.8 have to be performed separately.
4.5 Enteric Coated Propranolol tablets (30 mg/tablet) Composition of the tableting mixture Ingredients Parts by weight Composition Ig] [%] Propranolol 300.0 16.7 Ludipress LCE 1383.0 76.8 Kollidon VA 64 Fine 54.0 3.0 Kollidon CL-F 54.0 3.0 Magnesium stearate 9.0 0.5 Total 1800.0 100.00 Processing of the tableting mixture The ingredients except the Mg-stearate are blended in a Turbula blender for 10 minutes and passed through an 800 um-sieve. Finally the magnesium stearate is added and the resulting blend is mixed for 1 minute. Coating equipment and process parameters Rotary press Korsch XL 100 Rotary press Korsch XL 100 Tablet shape 7 mm concave, engraved Tableting speed S rpm Tablet weight 180 mg Tablet diameter 7mm Compression force 5 kN Tablet hardness 85-110N Friability 0.02% Enteric coating with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Ingredients Parts by weight Composition Percentage [gl [%] Kollicoat MAE 100-55 172.0 172.0 17.9 Triethyl citrate TH2 17.2 1.8 NaOH-solution; (1 mol/L) 59.4 2.5 0.3 Water 710.0 - - Total 958.4 191.7 20.0 Coating equipment Manesty XL Lab01 Batch size kg 4.0 Number of nozzles 1 Nozzle diameter mm 0.8 Pan speed rpm 25 Spraying rate g/min 20 Spraying pressure bar 1.8 Air supply ms/h 400 Inlet air temperature C 55 Drying time min. 55 C 5 Composition of the coating formulation Coating equipment and process parameters Coating equipment Manesty XL Lab01 Batch size Number of nozzles Nozzle diameter Pan speed Spraying rate Spraying pressure Air supply Inlet air temperature Drying time kg mm rpm g/min bar ms/h C min. 55 C 4.0 0.8 25 20 1.8 400 55
Release testing Kollicoat MAE 100-55 coating levels: wee 5 mg/cm? === 6 mg/cm? ==== allowance limit ==== buffer change Kollicoat MAE 100-55 coating levels: MCOal WIA 1UU-00 C m= 5 mg/cm? == 6 mg/cm? == allowance limit == buffer change
5. Applications and typical formulations using Kollicoat MAE 100 P 5.1 Coloured enteric film coatings for tablets The formulation below is for 5 kg of propranolol cores coatings for tablets (diameter 9 mm;weight 330 mg) See 3.3 Processing notes Re-dispersion of coating polymer Composition of the spray suspension Polymer suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 148.50 15.00 1,2-propylene glycol 22.28 2.26 Water 665.77 67.25 Pigment suspension Titanium dioxide 4.95 0.5 Sicovit Red 30 4.95 0.5 Talc 36.60 4.0 Water 103.95 10.5 Total 990.00 100.0 Solids content of the spray suspension 22.25% Content of polymer dry substance 15.0% Polymer applied (as solids) 4.0 mg/cm? Total solids applied 5.9 mg/cm? Preparation of the spray suspension Polymer suspension Kollicoat MAE 100 P is dispersed in the specified amount of water. When completely dispersed, the plasticizer is incorporated. Pigment suspension Sicovit Red 30, titanium dioxide and talc are intensively stirred into the specified amount of water and homogenized in a corundum disk mill. Spray suspension The pigment suspension is stirred into the coating suspension. The spray suspension must be stirred during spraying to prevent the solid substances settling out. Coating pan: Size of batch: Air supply temperature: Product temperature: Spraying pressure: Spraying rate: Spraying time: Accela Cota 24 (Manesty) 5 kg 60 C 32 - 35 C 2 bar 40 g/m 25 - 30 min Coating equipment and process parameters
5.2 Coloured enteric film coatings for pellets and crystals Re-dispersion of coating polymer Composition of the spray suspension The following formulation is calculated for 500 g of ASS-crystals spray suspension (diameter 0.3 1.0 mm) Polymer suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 148.5 14.9 1,2-propylene glycol 22.3 2.2 Water 675.8 67.6 Pigment suspension Titanium dioxide 5.0 0.5 Sicovit Red 30 5.0 0.5 Talc 39.6 4.0 Water 104.0 10.4 Total 1000.0 100.0 Solids content of the spray suspension Solid polymer in the spray suspension Solid polymer applied Total solids applied Coating pan: Size of batch: Air supply temperature: Exhaust air temperature: Spraying pressure: Spraying time: WSG Aeromatic Strea 1 500 g 60C 35 C 1 bar 100 min Coating equipment and process parameters Release rates of diclofenac Na and acetylsalicylic acid tablets
5.3 White enteric film coatings for pellets Re-dispersion of coating polymer See 3.3 Processing notes Composition of the spray suspension The following formulation is calculated for 5 kg of pellets (diameter 0.8 1.2 mm) Polymer suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 675.0 15.0 1,2-propylene glycol 67.5 1,5 Water 3.010.0 66.9 Pigment suspension Kollidon 22.5 0.5 Titanium dioxide 45.0 1.0 Talc 180.0 4.0 Water 500.0 1144 Total 4500.0 100.0 Polymer (solids) applied Total solids applied Solids content of the spray suspension 22.0% Polymer (solids) in the spray suspension 15.0% mg/cm? mg/cm? Preparation of the spray suspension Polymer suspension Dissolve Kollidon 100 P in the specified amount of water. Proceed as usual. Pigment suspension Spray suspension See suggested method under 3.3. Coating pan: Size of batch: Air supply temperature: Exhaust air temperature: Spraying rate: Spraying time: Hittlin Kugelcoater HKC 5 TJ 5 kg 60 C 32 - 35 C 45 g/m 100 min Coating equipment and process parameters
5.4 Colourless enteric coatings for soft-gel capsules Re-dispersion of coating polymer The following formulation is intended for 5 kg of soft-gel capsules Composition of the spray Total solids applied 12.0 mg/cm? Coating suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 500.0 21.0 1,2-propylene glycol 100.8 4.2 Water 1,795.2 74.8 Total 2400.0 100.0 Solids content of the spray suspension 25.2% Content of polymer dry substance 21.0% Polymer applied (as solids) 10.0 mg/cm? Polymer suspension Preparation of the spray suspension Polypropylene glycol is first dissolved in the specified amount of water. Then Kollicoat MAE 100 P is stirred in until completely redispered. The blend is stirred for 3 hours. Coating pan: Size of batch: Inlet air temperature: Product temperature: Spraying rate: Spraying time: Accela Cota 24 (Manesty) 5 kg 50 C 30-32 C 30 35 g/min 70 min Coating equipment and process parameters
5.5 Seal-coating of tablet cores Some tablet cores contain a water-sensitive drug or a highly effective tablet disintegrant, e.g. Kollidon CL. Before they can be coated with aqueous solutions a seal coat has to be applied. The same applies if the cores are too soft, or if an aqueous coating will not take to theirsurface. In such cases, heating the cores to about 35 C and spraying them with a 10% solution of Kollidon VA 64, e.g. in isopropanol has given good results. Experience indicates that an adequate sub-coating film is built up when small amounts of Kollidon VA 64 are applied, i.e. approx. 0.4 mg/cm?. Alternatively seal-coating can be performed using Kollicoat IR or even Kollicoat IR White Il. When using aqueous seal-coats a hydrophobic plasticizer can be used. In order to prevent interactions with hydrophilic or water-absorbing components present in the core low spray rates have to be used in the initial stage of the seal-coat application. 5.6 Further applications Coatings levels of 0.5 2.0 mg/cm? can be applied for the following purposes: To mask unpleasant tastes and odours To protect the tablet core against atmospheric humidity As a barrier between incompatible active substances
6. Equipment Cleaning Recommendations Kollicoat MAE 100-55 and Kollicoat 100 become water-soluble after neutralizing the majority of the polymers methacrylic acid moiety. To achieve this level cleaning is thus best performed using dilute NaQH-solutions containing small amounts, e.g. 0.5 - 1% of a surfactant such as sodium lauryl sulfate (SLS). 7. Storage The powder products Kollicoat MAE 100-55 and Kollicoat MAE 100 P should be stored at temperatures below 25 C. In contrast to the Kollicoat MAE 30 DP dispersion the powder grades do not require transportation and storage above 0C. Kollicoat MAE 100-55 and Kollicoat MAE 100 P are stable for at least 18 months in the unopened original drums at room temperature. After re-dispersion to aqueous forms the exposure to heat or frost, as well as foam formation have to be avoided. These effects may cause coagulation and turn the products defective. Once a drum has been opened the contents it is recommended to use the content within a few weeks. Kollicoat MAE 100-55 Kollicoat MAE 100 P 10. Packaging 20 kg polyethylene drums with a PE inner liner. 20 kg polyethylene drums with a PE inner liner. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information
1. Introduction BASF offers a broad portfolio of functional excipients including our pharmaceutical grade polysorbate 80, Kolliphor PS 80. With consistent quality and reliable supply, Kolliphor PS 80 is a versatile, multifunctional excipient that acts as a solubilizing agent for a variety of pharmaceutical formulations and as plasticizer for solid dispersions and oral dosage forms. In addition to these robust functionalities, Kolliphor PS 80 is also a non-ionic surfactant and oil-in-water emulsifier that offers broad pH range applicability and good skin tolerance. Kolliphor PS 80 is applicable for the development of oral and topical formulations. 2. Chemical information Chemical name Polysorbate 80, Polyoxyethylene (20) sorbitan monooleate CAS number 9005-65-6 Regulatory status Kolliphor PS 80 meets the current USP-NF, Ph. Eur., and JP monographs under its compendial name Polysorbate 80. Furthermore, it meets the requirements of IPEC-PQG GMP for Excipients. Sustainable sourcing Roundtable on Sustainable Palm Oil (RSPO) certification available Polysorbate 80 is a non-ionic surfactant and emulsifier for pharmaceutical applications, derived from polyethoxylation of sorbitan oleate esters (sorbitan monooleate). Chemical Structure: Chemical Structure:
3. Selected chemical and physical parameters Kolliphor PS 80 typical values Property Kolliphor PS 80 typical values Appearance Colorless or yellow, clear liquid with a faint characteristic odor HLB 15 CMC 35 mg/L Specific gravity 1.06 to 1.09 g/cm Viscosity 300 to 500 cSt Solubility in water Dispersible in water Si ee ER ace the polarity of non-ionic emulsifiers is temperature dependent; the polarity decreases with elevated temperatures, resulting in an increase in the lipophilicity of the emulsifier. 4. Applications Polysorbates are mainly used as solubilizers, emulsifiers, or suspension stabilizers for pharmaceutical applications. Depending on the HLB value and the miscibility in water of the product, polysorbates either act more as a solubilizer or emulsifier. Kolliphor PS 80 is more suitable for use as a solubilizer of poorly water-soluble drug substances in either liquid or solid oral dosage forms. This excipient also functions as a suspension stabilizer in addition to a skin penetration enhancer for topical applications. Solubilization Solubilization performance based on model APIs The formulation of poorly water soluble active pharmaceutical ingredients (APIs) poses a distinct challenge to pharmaceutical formulators. With newly discovered APIs trending towards an increase in lipophilicity and complexity, drug solubilizers such as Kolliphor PS 80 have become essential for the development of stable and efficacious formulations. A high-throughput screening robot was used to study the solubilizing performance of Kolliphor PS 80 based on model APIs with different physicochemical profiles. Kolliphor PS 80 was tested as a drug solubilizer at concentrations of 0, 5, 10, 15, and 20%. The upper-limit concentration of 20% which exceeds typical usage levels in standard pharmaceutical liquid or solid formulations was established to allow for an assessment of a potential saturation effect. The selected model APIs differed in molecular weight, estimated logP values, estimated water solubility, and melting point. The table below shows an overview of these attributes for all selected model compounds. API Molecular logP Water solubility Tm (C) weight (g/mol) (ppm) Carbamazepine 236.27 2.1 154 201 206 Cinnarizine 368.51 5.19 1.72 117-120 Danazol 337.46 3.62 0.71 224 227 Fenofibrate 360.83 4.86 17.6 81 Ketoconazole 531.43 4.3 9.31 146 Piroxicam 331.35 2.2 143 198 200
Solubility enhancement of model APIs by using Kolliphor PS 80 (polysorbate 80). Solubility enhancement of model APIs by using Kolliphor PS 80 (polysorbate 80) Kolliphor PS 80 demonstrated a significant improvement in the solubility. Regardless of the physicochemical attributes of the model API, the solubilization of all APIs was concentration dependent. The solubilization capacity of Kolliphor PS 80 can be attributed to its long C18:1 chain length allowing for interaction with hydrophobic APIs and thus enhanced solubilization performance.
Orals Drug solubilization via hot melt extrusion (HME) The solubilization performance of Kolliphor PS 80 for the API Ritonavir was investigated in formulation obtained by hot melt extrusion (HME) employing Kollidon VA 64 (copovidone) as a matrix. Formulation API Ritonavir Polymer Kollidon VA 64 Solubilizer Kolliphor PS 80 API Polymer Solubilizer 30.0% 70.0% - 30.0% 67.5% 2.5% 30.0% 65.0% 5.0% 30.0% 62.5% 7.5% 16 mm Twin Screw Extruder PTW Thermo Fischer Throughput 1 kg/h Screw speed 200 rpm Extrusion temperature 135 C Pelletization 1.5mm The dissolution curves show the effectiveness of Kolliphor PS 80 on dissolution of Ritonavir from a Kollidon VA 64-based matrix. Even at the low concentration of 2.5%, Kolliphor PS 80 had a significant impact on increasing drug availability, demonstrating approximately 80% drug release within the first 30 minutes. The release was independent of the tested concentrations (i.e., 2.5, 5.0, and 7.5%) of the solubilizer.
An enteric coating that is emulsified by Kolliphor PS 80 to form a sprayable suspension. Step Ingredient Chemical Name Amount (g) Water Water 200 Kolliphor PS 80 Polysorbate 80 3.0 2 Kolliwax GMS II Mono- and di-glycerides 8.0 Triethyl citrate Triethyl citrate 25.0 3 Water Water 208 4 Kollicoat? MAE 30 DP Methacrylic acid copolymer 556 dispersion Procedure Step 1: Surfactant Solution Dissolve Kolliphor PS 80 in approx. half of the total water amount. Heat the solution to a temperature of 70 80 C. Step 2: Emulsification Add Kolliwax GMS II and triethyl citrate while homogenizing with a high-shear mixer. Keep homogenizing the mixture for 10 min. Step 3: GMS Emulsion Let the mixture cool under stirring while slowly adding the remaining half of the water amount. Step 4: Spray Suspension Slowly add the cold GMS emulsion to the coating dispersion. Continue stirring to obtain a homogeneous mixture. Step 1 Kolliphor PS 80 70-80 C Cy (@) Water Step 3 <30C Kolliwax GMS II Step 2 Triethyl citrate ww: @ o e EE (a) GMS emulsion Step 4 ~y Step Ingredient Chemical Name Amount (g) Water Water 200 Kolliphor PS 80 Polysorbate 80 3.0 2 Kolliwax GMS II Mono- and di-glycerides 8.0 Triethyl citrate Triethyl citrate 25.0 3 Water Water 208 4 Kollicoat? MAE 30 DP Methacrylic acid copolymer 556 dispersion Note: Pigments can be dispersed into the remaining water amount and added accordingly in step 3. Before spraying, the suspension should be passed through a 0.5 mm sieve.
Topicals Light cream A light-weight, airy cream that is emulsified by Kolliphor PS 80. Phase Ingredient Chemical name Wt% Kollicream IPM Isopropyl myristate 20 A Kolliwax GMS II Mono- and di-glycerides 1.45 Kolliphor PS 80 Polysorbate 80 3.55 Deionized water Water 73.1 B Carbopol ETD 2020 polymer Acrylates/C10-30 alkyl 0.2 acrylate crosspolymer Cc Triethanolamine Triethanolamine 1 D Phenoxyethanol Phenoxyethanol 0.7 Procedure . Weigh out phase A into an appropriately sized beaker. Place the mixture under an overhead mixer and set to 50 rpm. Heat the mixture to 80 C. . In aseparate beaker, weigh out the water for phase B and heat to 80 C. Sprinkle Carbopol while stirring. . Add phase A to phase B under shear and then neutralize with triethanolamine (phase C). . Homogenize mixture at 5000 rpm for 2 minutes. 5. Place the mixture under an overhead mixer and allow to cool under mild shear. . When the formulation has cooled to 45 C, add in phenoxyethanol (phase D). Rich cream A rich, luxurious cream that is stabilized with Kolliphor PS 80. Phase Ingredient Chemical name Wt% Kollicream 3C Cocoyl caprylocaprate 20 A Kolliwax GMS II Mono- and di-glycerides 2.5 Kolliphor PS 80 Polysorbate 80 2.5 Deionized water Water 73.1 B Carbopol ETD 2020 polymer Acrylates/C10-30 alkyl 0.2 acrylate crosspolymer Cc Triethanolamine Triethanolamine 1 D Phenoxyethanol Phenoxyethanol 0.7
Procedure . Weigh out phase A into an appropriately sized beaker. Place the mixture under an overhead mixer and set to 50 rpm. Heat the mixture to 80 C. . In aseparate beaker, weigh out the water for phase B and heat to 80 C. Sprinkle Carbopol while stirring. . Add phase A to phase B under shear and then neutralize with triethanolamine (phase C). . Homogenize mixture at 5000 rpm for 2 minutes. 5. Place the mixture under an overhead mixer and allow to cool under mild shear. . When the formulation has cooled to 45 C, add in phenoxyethanol (phase D).
5. Product details Product details PRD number 30776819 Packaging and article numbers 190 kg lacquered steel drum (ART 50729133) 25 kg lacquered steel drum (ART 50740519) Sample and article number 0.5 kg amber glass bottle (ART 50729134) Regulatory and Quality Refer to the individual document quality and regulatory product information (QRPI), available on RegXcellence and from your local BASF sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. Certification EXCiPACT GMP, Kosher, Halal, RSPO Handling and Safety Refer to the safety data sheet (SDS) for instructions on safe and proper handling and disposal. SDS are available on request and are sent with every consignment. Product Specification The current version of the product specification is available on RegXcellence and MyProductWorld or from your local BASF sales representative. Regulatory and Quality Refer to the individual document quality and regulatory product information (QRPI), available on RegXcellence and from your local BASF sales representative. The QRPI document covers all relevant information including retest periods and storage conditions.
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Table of contents Introduction Polyethylene glycol portfolio 5 Typical chemical and physical properties 6 Applications 8 Tablets, liquids, and suspensions 9 Softgels 10 Ensuring softgel performance with low aldehyde Kollisolv? PEGs 13 Topicals 20 Hydrophilic ointment formulation 20 Emulgel formulation 21 Suppository formulation 22 Product details and key benefits 24 Product and sample article numbers 25 ZoomLab, RegXcellence, & MyProductWorld 26 Introduction Polyethylene glycol portfolio
Polyethylene glycol portfolio Kollisolv PEGs are colorless, almost odorless, and tasteless liquids or white solids at room temperature. These products are manufactured by alkali-catalyzed polymerization of ethylene oxide with subsequent neutralization of the catalyst. The number in the name of the product indicates its average molecular weight. Chemical name CAS number Our portfolio of Kollisolv PEGs offers assurance of high-quality production in cGMP manufacturing conditions that meet the compendial requirements of USP-NF and Ph. Eur. At low molecular weights, our Kollisolv? PEGs are present as colorless liquids, and at higher molecular weights these products exist as white semi-solids and solids.
Unlike standard grade PEGs with a total aldehyde content of 50 ppm, our low aldehyde Kollisolv PEGs are restricted to an aldehyde content maximum of 10 ppm and offer assurance of control. With a restricted total aldehyde content to a maximum of 10 ppm, these excipients are especially suited for sensitive APIs and applications, including softgel shells and fills. Colorless, almost odorless, and tasteless liquid at room temperature Average molecular weight (g/mol) 285 to 315 380 to 420 380 to 420 570 to 630 570 to 630 Melting point (C) -15 to -8 4to8 4to8 15 to 25 15 to 25 Hydroxyl value (ng KOH/g) 340 to 394 264 to 300 264 to 300 178 to 197 178 to 197 Viscosity at 25 C (mPa:s) 80 to 105 105 to 130 105 to 130 Solid Solid Viscosity at 99 C (mm?/s) 5.4 to 6.4 6.8 to 8.0 6.8 to 8.0 9.9 to 11.3 9.9 to 11.3 fery soluble in water and alcohol, practically insoluble in oils and fa
Tablets, liquids, and suspensions Kollisolv PEGs can be used in tablet applications as a component of the core or coating. They can also serve as lubricants in the processing of a tablet. In tablet core applications, solic Kollisolv PEGs can be used as a binder or additive. Solid and semi-solid Kollisolv? PEGs can be used in coating applications as a plasticizer and film former. Polyethylene glycols, or macrogols, are mainly used as solubilizers, surfactants, and solvents. As multifunctional ingredients, these excipients play an essential role in various oral and topical formulations. Low-molecular-weight liquid polyethylene glycols are excellent solvents for numerous substances that do not readily dissolve in water. They are widely used as solvents and solubilizing agents for active substances and excipients in liquid and semi-solid preparations. They can also be used as plasticizers in tablets, capsule shells, and film coatings.
Softgels Figure 1. Solubility of Kollidon VA 64 in Kollisolv PEG 300, 400, and 600 at room temperature. BASF offers a range of liquid Kollisolv? PEGs and other complementary products for softgel applications. From solubility enhancement to crystallization inhibition, these products make for easier softgel formulation with greater predictability and reliability. BASF solubilizers such as Kolliphor RH 40 (Ph. Eur.: macrogolglycerol hydroxystearate; USP-NF: polyoxyl 40 hydrogenated castor oil), Kolliphor EL (Ph. Eur.: macrogolglycerol ricinoleate, USP-NF: polyoxyl 35 castor oil), or Kolliphor HS 15 (Ph. Eur.: macrogol 15 hydroxystearate; USP-NF: polyoxyl 15 hydroxystearate) can be used in combination with liquid Kollisolv PEGs to increase the solubilization capacity, allowing for the enhanced dissolution of challenging APIs. Crystallization inhibitors such as Kollidon VA 64 (Ph. Eur., USP-NF: copovidone), Kollidon 30 (Ph. Eur., USP-NF: povidone), and Kollidon 12 PF (Ph. Eur., USP-NF: povidone) can be used with liquid Kollisolv PEGs to prevent drug recrystallization. These crystallization inhibitors form homogenous blends at common processing and filling temperatures, and provide an additional benefit of increasing fill viscosity. This increased fill viscosity allows for more consistent filling and lower weight variance between softgels capsules. Blends of Kollisolv PEGs with Kollidon crystallization inhibitors are stable at room temperature up to 40% concentration by weight. Figure 2. Solubility of Kollidon 30 in Kollisolv PEG 300, 400, and 600 at room temperature. Figure 3. Solubility of Kollidon 12 PF in Kollisolv PEG 300, 400, and 600 at room temperature.
Advancements in increased temperature control for softgel encapsulation machines provide opportunities to use fills with greater crystallization inhibitor concentration. Use of common processing temperatures of 40 or 60 C leads to as much as 80% reduction in fill viscosity. This gives significant advantages by increasing processing speed with lower flow resistance of fills and increasing softgel shelf stability with greater crystallization inhibitor content when using liquid Kollisolv? PEGs with Kollidon crystallization inhibitors. Softgels are oral formulations that are composed of a pharmaceutical grade shell which encapsulates the liquid fill. Shell-fill compatibility requires the strategic selection of excipients to minimize degradation byproducts known to be harmful for softgel stability. To ensure capsu integrity and dissolution reproducibility, the fill must be compatible with the shell, and neither prematurely rupture the shell nor restrict release of the active post-delivery. Aldehydes are a common concern in softgels, especially soft gelatin capsules, where chemical crosslinking of the gelatin peptide backbone will cause insoluble films or pellicles that disrupt dissolution testing. The consequence of crosslinking is often an altered dissolution behavior of the capsule, one that will fail dissolution testing in vitro. While this crosslinking does not always translate to failure in vivo, where enzymes can cleave the peptide backbone, the USP <711> recommends a two-tiered dissolution investigation when in vitro dissolution failure arises from crosslinking. The complicated testing protocol includes pH-dependent enzyme selection and, as elaborated in USP <1094>, additional testing on the compatibility of any surfactants includec in the medium. These additional tests require cumbersome method development and validation, lengthening the time and complexity of going to market. Figure 4. Viscosity vs. concentration of Kollidon VA 64 in Kollisolv PEG 300 at 25, 40 and 60 C.
To study the effect of degradation byproducts, particularly aldehydes, on softgel performance, five lots of polyethylene glycol 400 (PEG 400) of varying grades and storage conditions were selected for testing (Table 1). Two fresh lots of Kollisolv? PEG 400 LA were evaluated, as well as one Kollisolv PEG 400 LA at the 2-year retest. A compendial grade of PEG 400 that met Ph. Eur. and USP monographs was included, as well as a standard, non-pharmacopoeia PEG 400. The standard grade PEG 400 was a forced-aged compendial PEG 400 sample, stressed through aging at 60 C for 9 days and 80 C for 7 days. The starting aldehyde levels for each sample was determined by an in-house R&D method (Figure 7). Kollisolv PEG 400 LA had the lowest aldehyde concentration, under 10 ppm, with nc difference between fresh and at 2-year retest. The compendial PEG 400 sample had an aldehyde concentration almost two-fold higher than Kollisolv PEG 400 LA. Standard PEG 400 was nearl six-fold higher. Figure 7. Starting aldehyde levels for each grade of PEG 400. Table 1. PEG 400 samples for softgel formulations. Sample # Material Age to retest Grade 1 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 2 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 3 Kollisolv PEG 400 LA At 2-year retest Low aldehyde (Ph. Eur., USP) 4 Compendial PEG 400 Compendial (Ph. Eur., USP) 5 PEG 400 Standard Samples 1 and 2 represented two different freshly opened lots.
Brilliant Blue, serving as a model active pharmaceutical ingredient (API), was formulated at eque parts in the five PEG 400 samples. After the formulations were filled into softgel capsules using lab-scale filling equipment, the capsules were then stored at ambient (25 C, 60% RH) and accelerated (40 C, 75% RH) conditions for a 12-month period. In vitro dissolution of the softgel capsules was performed to evaluate the effect of aldehyde content on dissolution. The dissolution time to release 80% of the loaded Brilliant Blue was captured for each sample (Fig. 9). Softgels containing Kollisolv PEG 400 LA demonstrated an equivalent dissolution time over the full 12 months under ambient conditions; while even the compendial grade PEG 400 containing softgels exhibited delayed dissolution within 6 months. When stored at ambient conditions, the softgel capsules composed of Kollisolv? PEG 400 LA demonstrated superior stability over compendial and standard PEG 400 (Fig. 8). Over the course of 12 months, the softgels filled with fresh and 2-year Kollisolv? PEG 400 LA showed a stable release profile with no evidence of crosslinking or change in dissolution. The equivalence of performance with product age, fresh and at two years, demonstrates the stability of Kollisolv PEG 400 LA and reliability of performance. Figure 9. Dissolution time (until 80% release) of softgels stored at ambient (25 C, 60% RH) conditions taken as the time in minutes. In contrast, the softgel consisting of compendial PEG 400 increasingly delayed dissolution, with significant changes in dissolution evident by month 6. To an exaggerated degree, the softgel containing standard PEG 400 showed retarded dissolution and evidence of near-immediate crosslinking within the first month. Figure 8. Dissolution of softgels stored at ambient (25 C, 60% RH) conditions over a 12-month period. In accordance with USP<711>, formulations made with the compendial PEG 400 would require proof of gelatin crosslinking via spectroscopic methods and complicated dissolution tests. Comparatively, formulations that consisted of Kollisolv? PEG 400 LA would not require further investigation regarding crosslinking or dissolution. Even under stressed aging in accelerated storage conditions, softgels consisting of Kollisolv PEG 400 LA within the full 2-year retest period exhibited equivalent performance, demonstrating stability of the product within its shelf-life. Under accelerated storage, dissolution of capsules of fresh and retest-aged Kollisolv PEG 400 LA remained equivalent through 3 months (Fig. 10). In contrast, compendial PEG 400 mirrored the failure of standard, non- pharmacopoeia PEG 400, and both products showed immediately delayed dissolution within the first month, failing due to crosslinking of soft gelatin capsules. In this case, even meeting Ph. Eur. and USP standards for a pharmaceutical excipient did not impart stability over a non- pharmaceutical grade of PEG 400.
Figure 10. Dissolution of softgels stored at accelerated (40 C, 75% RH) conditions over a 6-month period. Under accelerated conditions, Kollisolv? PEG 400 LA offered improved stability of the dissolutior profile. Regardless of age, the three Kollisolv? PEG LA samples demonstrated an equivalent dissolution time over 3 months, suggesting stability studies under these conditions is feasible through 3 months (Fig. 11). In contrast, both compendial and standard, non-pharmacopoeia grades of PEG 400 exhibited delayed dissolution immediately, failing accelerated stability studies under these conditions. Aldehyde content within the softgels was determined at time points within both storage conditions. As softgel fills, Kollisolv? PEG 400 LA samples demonstrated minimal changes in the aldehyde content over a 2-year retest period. Evaluation of the aldehyde content showed that storage condition did not significantly impact the total aldehyde amount present in the softgel fill. Ultimately, Kollisolv PEG 400 LA did not develop aldehyde content over time when formulated in softgels, whether fresh or at retest, under ambient or accelerated storage (Fig. 12). Figure 12. Aldehyde development of Kollisolv PEG 400 LA in softgels, over 12 months at under ambien and accelerated storage. Figure 11. Dissolution time (until 80% release) of softgels stored at ambient (40 C, 75% RH) conditions taken as the time in minutes. In summary, Kollisolv? PEG 400 LA outperformed compendial PEG 400. The dissolution profiles from softgels at both ambient and accelerated storage conditions reflected a pre dilection towards Kollisolv PEG 400 LA, with stable release seen for longer than from compendial PEG 400. When using Kollisolv PEG 400 LA as the softgel fill, aldehydes did not develop over time at either ambient or accelerated storage conditions. Rather, the source and quality of the products had the greatest effect on the aldehyde levels. Fresh and at-retest Kollisolv PEG 400 LA samples offered a 50% reduction in starting average aldehyde content in comparison to compendial grade PEG 400. The repeatable and stable dissolution profiles seen for Kollisolv PEG 400 LA bring the advantages of rapid development and ease of qualification.
Topicals Emulgel formulation When used for topical applications, solid and liquid Kollisolv PEGs be combined to form water-soluble bases for ointments, suppositor and ovula. Low-molecular-weight Kollisolv? PEGs can be used as solvents, conditioners, adhesion promoters, and humectants. These products, like Kollisolv PEG 300, Kollisolv PEG 400, and Kollisolv PEG 1000, promote ease of application, softening on contact with skin, and localization of active delivery. High-molecular-weight Kollisolv PEGs can be used as structuring agents and thickeners to increase the viscosity of formulations. These include Kollisolv PEG 1450, Kollisolv PEG 3350, and Kollisolv PEG 8000. Hydrophilic ointment formulation Kollisolv PEG ointments can be used as an alternative to traditional petrolatum-based ointmen formulations. By pairing different amounts of high- and low-molecular-weight chains, PEG ointments can be tuned for desirable rheological profiles and sensory. Procedure 1. Prepare phase A by weighing ingredients into an appropriately sized beaker. 2. Heat the mixture to 60 C and continue heating until the mixture has completely melted. Try to minimize the heating time as much as possible. 3. Once all the components have melted, place phase A underneath an overhead mixer. Stir at a low shear rate until cooled to room temperature. Kollisolv PEG 3350 is commercially available only in the USA and Canada as an excipient.
Suppositories allow formulators to accurately deliver active ingredients through an alternative route. Kollisolv PEG suppositories are ideal for the formulation of suppository matrices, offering a melting temperature range within physiologically relevant conditions and compatibility with hydrophilic druas.
Product details and key benefits Product details Regulatory Manufacturing site Manufacturing process Re-test period Certified Handling Safety data sheet Retest date and storage conditions Specification Regulatory status Key benefits Supply reliability & consistent quality Sustainability Technical service BASF Virtual Pharma Assistants Kollisolv? PEGs USP-NF, Ph. Eur. Geismar, Louisiana (USA) Synthetic 24 months Kosher, Halal Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRPI). For current specification, please speak to your local BASF sales or technical representative. Please refer to Quality & Regulatory Product Information (QRPI). Kollisolv PEGs are manufactured in a GMP compliant facility in the U.S. ensuring: Consistent quality and safety @ Reliable, vertically integrated supply BASF is a proud member of the Pharmaceutical Supply Chain Initiative (PSCl), whose vision is to establish and promote responsible practices that will continuously improve human rights, health, safety, and environ- mentally sustainable outcomes for supply chains worldwide. @ World class expertise in excipient chemistry Formulation guidance with ZoomLab @ Regulatory documentation available in RegXcellence Product details available via MyProductWorld @ Full pharma regulatory documentation and submission support Product details and key benefits
For sample requests contact us at pharma-solutions@basf.com This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to th extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matte in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2022 BASF Corporation. All Rights Reserved.
Kolliphor Grades - Emulsifier for topical pharmaceutical application: January 2014 ) = Registered trademark of BASF in many countries.
Rebranding As a result of the integration of former Cognis excipients in the BASF portfolio a rebranding was conducted. The rebranding should increase the reliability and compliance for the supply of pharmaceutical excipients. The following table shows a comparison of old versus new trade names. Tradename Former Tradename Kolliphor CS 12 Eumulgin B1 PH Kolliphor CS 20 Eumulgin B2 PH Kolliphor CSS Lanette E PH Kolliphor CS A Lanette N PH Kolliphor CSL Lanette SX PH Tradename Table 1: New Tradenames Old Tradenames PRD-No., Article-No. and CAS.-No. Tradename PRD-No. Article-No. CAS.-No. Kolliphor CS 12 30554458 50253256 68439-49-6 Kolliphor CS 20 30554459 50253257 68439-49-6 Kolliphor CSS 30554486 50253269 68955-20-4 Kolliphor CS A 30554487 50253281 67762-27-0 68955-20-4 Kolliphor CSL 30554435 50253856 67762-27-0 161-21-3 68955-20-4 Table 2: PRD and Article and CAS number of the Kolliphor Grades See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Regulatory Status In table 3 you can find all the monographs for the Kolliphor Grades. New Name Monograph Tests Kolliphor CS 12 Ph. Eur. : Macrogol Cetostearyl Ether 12 Kolliphor CS 20 Ph. Eur. : Macrogol Cetostearyl Ether 20 USP/NF: Polyoxyl 20 Cetostearyl Ether Kolliphor CSS Ph. Eur. : Sodium Cetostearyl Sulphate Kolliphor CS A Ph. Eur. : Cetostearyl Alcohol (Type A), Emulsifying Kolliphor CSL not monographed Table 3: Compendial names
An emulsion is a dispersion of droplets of a non-miscible liquid in a continuous phase. The polar (hydrophilic) aqueous phase and the non-polar (lipophilic) oil phase of an emulsion cannot be combined in a stable and homogenous way without a surface-active additive. Product groups Emulsifiers are interfacial active substances that reduce the interfacial tension between the oil and the water phase. The emulsifier is adsorbed at the interface, giving a film between both phases, which prevents coalescence of droplets. Due to its amphiphilic structure, the polar part of the emulsifier has an affinity to the water phase and the non-polar part of the emulsifier to the oil phase. Emulsifiers can be defined according to their hydrophilic/lipophilic characteristics In 1949 W.C. Griffin proposed the HLB (Hydrophilic- Lipophilic Balance) system in which non-ionic surfactants have been classified on a scale from 0 to 20. Emulsifiers with a strong lipophilic character have low HLB values between 3 to 8 and tend to form W/O emulsions. Emulsifiers of the HLB range of 8 to 18 are hydrophilic and form O/W emulsions. HLB values from 12 to 18 are most favorable for solubilization to enhance bio- availability of active ingredients. Emulsifiers can be classified according the chemical structure in non-ionic and ionic emulsifiers or emulsifying waxes. Non-lonic Emulsifier Ethoxylates Chemical structure Figure 1: Chemical structure Kolliphor CS 12 and Kolliphor CS 20 Typical Properties Product R-Lipo- N-Hydro- Appearance HLB Usage pH phil phil value concen- working tration range Kolliphor CS 12 C,,,C,, 12xEO White or 13 05-5% 2-12 yellowish white waxy powder Kolliphor CS 20 C,,,C,, 20xEO White or 15 05-5% 2-12 yellowish white waxy powder Table 4: Typical properties Kolliphor CS 12 and Kolliphor CS 20
lonic Emulsifier Kolliphor CSS Chemical Structure Figure 4: Chemical structure Kolliphor CSS (n=15 or 17) Typical properties olliphor CSS_ White or pale yellow amorphous >40 0.5-2% 7- or crystalline powder Emulsifying Waxes (Cream-bases) are a combination of a consistency factor (eg. Fatty alcohols) and an emulsifier. They are especially designed to enable an effective and short development time of a topical pharmaceutical formulation. Cream-bases/Emulsifying Waxes Typical properties Typical properties Product Ingredients Appearance HLB Usage pH value concen- working tration range Kolliphor CS A Cetostearyl Alcohol White or pale 7.0 0.5-5% 6-12 Sodium Cetostearyl vet waxy Sulphate pellets Kolliphor CSL Cetostearyl Alcohol Pellets 75 0.5-5% 6-12 Sodium Lauryl with a faint Sulfate characteristic odor Sodium Ceteary Sulfate Table 6: Typical property of the creambases/emulsifying waxes
Application The choice of emulsifiers for specific applications depends on the desired pro- perties of the formulation (e.g. stability, viscosity, skin feel and API), or on the desired processing technology (e.g. PIT, Hot or cold processing). The traditional processing technology for emulsion is the so called hot process, where you combine both water and oil phase at a temperature of 70 85 C. With this technology you are very flexible in the ingredients you can choose in your emulsion. Beside the well-known hot process of emulsification, there is also the possibility to formulate an emulsion with a processing temperature at room temperature. The processing of O/W emulsions at room temperature has several significant benefits. For example, it is no longer necessary to heat the water and oil phase to 70 80 C. This saves considerable amounts of energy and reduces the production time as the cooling step is eliminated. Another very important advantage is that heat-sensitive APIs can be added t the emulsions at any point. On the other hand the possible ingredients are limited as there is not melting step of the oil phase. In the BASF portfolio of emulsifier for topical pharmaceutical applications only Kolliphor PS 60 is suitable for this kind of processing technology. Another very interesting processing technology is the Phase Inversion Technology (PIT) as it leads to water thin emulsions with a very small droplet sizes and thus these emulsions are very stable. This processing technology uses the temperature dependency of the HLB value of non-ionic emulsifiers as this kind of emulsifier change solubility behavior with elevated temperature. This can be used for pharma- ceutical applications where a very thin emulsion is needed, which is easy to distribute over the skin (e.g. sorayable wound sprays etc.). = a\e >. 8\8 ee 5 B/2/E = F/JE o el fete! S] She a 2s 5 o 2) dD) 33), 5/2 9 S\5\5 3/8 E)E R ele] S/S) 0/5] 8] Pia Wy} 2) OE) 19) a) s 2i0 QS/Z\ S/S 3 ss 8 4/85 Product Ph. Eur. S\SIGISIESEAAZIGA Kolliphor CS 12} Marcrogol Cetosteary x x x x x]x x Ether 12 Kolliphor CS 20} Marcrogol Cetosteary x x x x x]x x Ether 20 Kollliphor CS A Cetostearylalcohol x bay xX x x (Type A), Emulsifying i _ Kollliphor CSS__ Sodium Cetosteary! x ba x x Sulphate Kollliphor CSL x Ba X x x Table 7: Application fields in topical pharmaceutical formulations of the Kolliphor grades
Skin Tolerance All Kolliphor grades are based on vegetable and synthetic raw materials. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreemen In originally sealed containers all Kolliphor types can be stored for at least two years. It is important that they are protected from moisture and stored at less than 30 C. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal Handling and Disposal This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. January 2014
Technical Information Kollidon VA 64 and Kollidon VA 64 Fine are vinylpyrrolidone-vinyl acetate copolymers. They are used in the pharmaceutical industry as dry binder in tablets, as matrix formers for amorphous solic dispersions, as retarding and as film-forming agents. July 2022 Supersedes issue dated March 2019 Last change WF-No. DAWF-2022-0821 = Registered trademark of BASF in many countries.
1. Introduction Kollidon VA 64 and Kollidon VA 64 Fine are vinylpyrrolidone-vinyl acetate copoly- mers which are soluble both in water and in alcohols. They are well-known by thei monographic name Copovidone or Copolyvidone. In the pharmaceutical industry they are widely used as dry and wet binder in tablets, as film forming agent or ir retard formulations. A major application of Kollidon VA 64 is as matrix in amorphous solid dispersions. For further details that are beyond the scope of this leaflet, please consult the book, Kollidon Polyvinylpyrrolidone excipients for the Pharmaceutical Industry (03_030748e). 2. Technical properties Description Kollidon VA 64 and Kollidon VA 64 Fine are spray dried polymer powders of a co- polymer derived from the monomers N-vinylpyrrolidone (NVP) and vinyl acetate (VAc) with a weight ratio of approx. 6:4. The powders are white or slightly yellowish, have a faint characteristic odor and practically no taste. CAS-number 25086-89-9 Structural formula Infrared spectrum The infrared spectrum shown in Fig. 1 was obtained with a tablet of Kollidon VA 64 in potassium bromide. Arrows indicate where the spectrum differs from that of povidone.
Molecular weight The average molecular weight is usually expressed as a K value. The exact weight- average molecular weight, Mw of the product is best determined by measuring the light scatter of a solution. Values in the range of 45,000 - 70,000 have been determined for Kollidon VA 64 and Kollidon VA 64 Fine. Solubility Kollidon VA 64 and Kollidon VA 64 Fine readily dissolve in all hydrophilic solvents. Solutions of more than 10% concentration can be prepared in: water, ethanol, isopropanol, methylene chloride, glycerol and propylene c Viscosity The values shown in Fig. 2 were determined at 25 C in a capillary viscometer. They represent typical values. Fig. 2: Viscosity of Kollidon VA 64 in water and isopropanol. Bulk density The bulk density of Kollidon VA 64 Fine usually lies in the range of 0.08 0.15 g/ml. The bulk density of Kollidon VA 64 is above that one of Kollidon VA 64 Fine and is in the range of about 0.2 0.4 g/ml. Particle size distribution Typical values for the particle size of Kollidon VA 64 and Kollidon VA 64 Fine are as follows: Kollidon VA 64 Kollidon VA 64 Fine >250 um [%] max. 7% max. 2% <50 um [%] max. 35% min. 35%
Hygroscopicity Kollidon VA 64 and Kollidon VA 64 Fine absorb only about one third of the quantity of water absorbed by povidone, e.g. Kollidon 30 (Fig. 3). Fig. 3: Hygroscopicity of Kollidon VA 64 and Kollidon 30. 3. Example application General Copovidone has been used for decades in the pharmaceutical industry. Up to about 1975 it was marketed under the name of Luviskol VA 64, which today is used only for the technical/cosmetic grade of this copolymer. This is why older publications often refer to the use of Luviskol VA 64 in pharmaceuticals. Binder for tablets and granules Kollidon VA 64 and Kollidon VA 64 Fine are excellent binders for tablets and granules. Between 2% and 8%, as a proportion of the final weight of the preparation, is usually used. An important property of Kollidon VA 64 and Kollidon VA 64 Fine in this application is the plasticity, which distinguishes the products from povidone (e.g. Kollidon 30). This property often gives granules and mixtures that are less susceptible to capping during tabletting, and tablets that are less brittle. Dry Binder for direct compression Kollidon VA 64 and Kollidon VA 64 Fine have been found to be excellent dry binders for direct compression. Especially the Kollidon VA 64 Fine gives much better results than any of the Povidone grades or other dry-binders of the group of cellulose derivatives. The hardness, friability, porosity and disintegration time of lactose and starch placebo tablets produced with Kollidon VA 64 are directly related to the compression force used (see Table 1).
Table 1: Tablet properties related to the compression force Compression Hardness Friability Porosity Disintegration force time [kp] IN] [%] [%] [s] 500 23.5 3.07 13.03 17 1000 55.8 0.98 6.87 58 1500 61.7 0.59 6.41 77 2000 65.7 0.49 5.33 90 2500 67.6 0.35 5.07 102 Kollidon VA 64 and Kollidon VA 64 Fine can be added to materials such as sorbitol, mannitol, starch, or direct compression aids, e.g. micro crystalline cellulose, whose own binding strength is inadequate, to give tablets with very good properties. Table 2, for example, is suitable for direct compression. The literature contains a large number of vitamin formulations with Kollidon VA 64 (see Generic Drug Formulations latest edition). Table 2: Ascorbic acid chewable tablets 100 mg Ascorbic acid powder 42.4% Sucrose ground 13.0% Sucrose crystalline 8.0% Microcrystalline cellulose 28.3% Kollidon VA 64 2.4% Polyethylene glycol 6000 powder 2.0% Orange aroma + strawberry aroma (2 + 1) 1.2% Cyclamate sodium 2.4% Saccharin sodium 01% Aerosil 200 0.2% Equipment Rotary press: Korsch PH 100/6 Punch diameter: 8 mm, biplanar Speed: 30 rpm Tablet Properties: Weight 250 mg Hardness 157N Friability <0.1% The following examples show the properties of Kollidon VA 64 Fine in formuations for direct compression.
Table 3: Acetyl salycilic acid tablets 500 mg formulated with Kollidon VA 64 Fine Acetylsalicylic acid 500.0 mg Avicel PH 102 200.0 mg Kollidon VA 64 Fine 60.0 mg Kollidon CL 25.0 mg Magnesium stearate 3.0 mg Total 788.0 mg TNUMIGUOTT VEN OS TIS MYM TYE Kollidon CL 25.0 mg Magnesium stearate 3.0 mg 788.0 mg Total The individual components were sieved through a 0.8 mm sieve. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN respectively. Equipment Rotary press: Korsch PH 100/6 Punch diameter: 12 mm beveled edge Speed: 30 rpm Tablet properties Compression _ Tablet weight Hardness Disintegration _ Friability Force [kN] [mg] [IN] [min:sec] [%] 6.8 772.3 81 04:13 0.4 10.7 777.5 140 08:25 0.2 16.5 768.0 187 15:03 <0.1 788.0 mg The individual components were sieved through a 0.8 mm sieve. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN respectively. Tablet properties Compression _ Tablet weight Hardness Disintegration Friability Feu [mg] [IN] [min:sec] [%] 6.8 772.3 81 04:13 0.4 10.7 777.5 140 08:25 0.2 16.5 768.0 187 15:03 <0.1 Table 4: Indomethacin Tablets 50 mg formulated with Kollidon VA 64 Fine Indomethacin Kollidon VA 64 Fine 20.0 mg Di-tab 212.0 mg Kollidon CL 15.0 mg Magnesium stearate 3.0 mg 300.0 mg Total The individual components were sieved through 0.8 mm. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN, respectively. Equipment Rotary press: Punch diameter: Speed: Equipment Rotary press: Punch diameter: Speed: Korsch PH 100/6 8 mm, beveled edge 30 rpm
Tablet properties Compression Tablet weight Hardness _ Disintegration Friability Force [kN] [mg] [IN] [min:sec] [%] 5.6 301.9 62 00:22 0.16 9.7 304.5 101 00:36 <0.1 15.9 304.0 158 01:12 <0.1 Table 5: Atenolol Tablets 50 mg formulated with Kollidon VA 64 Fine Atenolol 50.0 mg Ludipress 135.7 mg Kollidon VA 64 Fine 15.0 mg Kollidon CL 25.0 mg Aerosil 200 1.3mg Magnesium stearate 3.0 mg Total 230.0 mg Total The individual components were sieved through 0.8 mm. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN, respectively. Korsch PH 100/6 8 mm, beveled ed: 30 rom Tablet properties Compression _ Tablet weight Hardness Disintegration Friability Force [kN] [mg] [IN] [min:sec] [%] 5.8 230.8 94 03:54 <0 9.6 221.4 132 04:14 <0.1 15.8 218.6 147 05:08 <01
Wet granulation Kollidon VA 64 and Kollidon VA 64 Fine can also be used as a binder in wet granulation for the production of tablets and granules, since it is readily soluble in all the usual solvents. It can then be added either as a solution during granulation, or dry to the other ingredients, in which case the solvent is added alone during granulation. Trials so far conducted with both methods, using equal quantities of liquid, produced tablets of much the same hardness. A combination of the two methods, i.e. mixing some of the Kollidon VA 64 with the active ingredient, and dissolving the rest in the solvent, sometimes gives the best results. This is particularly recommended if the active ingredient does not readily absorb the solvent. Since it is less hygroscopic than povidone (e.g. Kollidon 25 or 30), Kollidon VA 64 gives granules that have less tendency to stick to the punches of the tabletting machine, when operating under humid conditions. The binding power of Kollidon VA 64 is comparable to that of Kollidon 25 and Kollidon 30. The formulations in Table 3 are typical of those used for producing tablets by wet granulation (see Generic Drug Formulations, latest edition). Table 6: 500 mg ampicillin tablets and 400 mg cimetidine tablets formulatec with Kollidon VA 64 Ampicillin trinydrate 500 g i Cimetidine = 400 g Corn starch 242 g 170g Il Kollidon VA 64 25g 20g lsopropanol or water q.s. qs. Ill Kollidon CL 15g - Magnesium stearate 10g 3g Aerosil 200 89g = Mixture is granulated with solution Il, dried and sieved. The granules are then mixed with Ill and pressed into tablets at low to medium pressure. Tablets obtained in the laboratory had the following properties: Weight 798 mg 601 mg Diameter 16mm 12mm Hardness 170 N 91N Disintegration in gastric juice 5 min 91 min Friability 0.35% 0.5% Dissolution (USP) 10 min: 62% 20 min: not 91% 30 min: tested 100% Apart from its use in tablets, Kollidon VA 64 can also be used to produce very stable granules, e.g. for instant multivitamin drinks.
Roller compaction Kollidon VA 64 Fine was specifically suitable for the application in roller-compaction and is the material of choice in terms of particle size distribution and particle shape for this application. Due to the particle size it is able to cover a bit surface area and to form numerous bridges in the tablet structure that lead to hard tablets with a reduced friability. The formulations in tables 4 and 5 are typical examples for Kollidon VA 64 Formulation using this technique. Table 7: Allopurinol Tablets 300 mg formulated with Kollidon VA 64 Fine 1. Allopurinol 100.0 mg 2. Ludipress 50.0 mg 3. Kollidon VA 64 Fine 10.0 mg 4. Kollidon CL 6.0 mg 5. Magnesium stearate 1.0 mg 2. Ludipress 50. 3. Kollidon VA 64 Fine 10. 4. Kollidon CL 6. 5. Magnesium stearate 1. The compounds were compacted using a Gerteis compactor under the follc conditions Roller compactor: Gerteis Type Mini-Pactor M1114 Roll width: 25mm Compression force: 2 kN/cm Gap width: 3mm Tamping/feeding ratio: 120% Roll speed: 2 rpm Mesh sizes 1.25 mm Aftar camnartinn the matorial wae hlanded far 10 mini tac in a Thirhiila hlander wy 1e compounds were compacted using a Gerteis compactor ur ditions ler compactor: oll width: ompression force: ap width: imping/feeding ratio: Il speed: esh sizes Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm The compounds were compacted using a Gerteis compactor under the following conditions After compaction the material was blended for 10 minutes in a Turbula blender with the remaining Ludipress and the magnesium stearate and tableted as follows. Allopurinol compacted formulation 167.0 mg Ludipress 133.0 mg Magnesium stearate 1.0 mg Total weight 301.0 mg Equipment Tablet press: Korsch PH 100/6 Compression force: 18kKN Punch diameter: 8 mm, beveled edge Compression speed: 30 rpm Tablet properties: Compression _ Tablet weight Hardness Disintegration _ Friability force time [kN] [mg] [IN] [min:sec] [%] 16.4 280.8 246 09:29 <0 Allopurinol compacted formulation Tablet properties: Compression _ Tablet weight Hardness Disintegration Friability force time [kN] [mg] [IN] [min:sec] [%] 16.4 280.8 246 09:29 < 0.1
Table 8: Paracetamol Tablets 300 mg formulated with Kollidon VA 64 Fine Paracetamol Powder 500.0 mg 2. Avicel PH 102 131.0 mg 3. Kollidon VA 64 Fine 45.0 mg 4. Kollidon CL 21.0 mg 5. Aerosil 200 5.0 mg 6. Magnesium stearate 3.0 mg Se See Se eee The compounds 1 to 6 were compacted using a Gerteis compactor und following conditions. Roller compactor: Roll width: Compression force: Gap width: Tamping/feeding ratio: Roll speed: Mesh size: Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm The compounds 1 to 6 were compacted using a Gerteis comp following conditions. Roller compactor: Roll width: Compression force: Gap width: Tamping/feeding ratio: Roll speed: Mesh size: Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm me COMpounas to 6 Were COMpacted USING a GEItelSs COMPpactor following conditions. Roller compactor: Roll width: Compression force: Gap width: Tamping/feeding ratio: Roll speed: Mesh size: Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm After compaction the material was blended for 10 minutes in a Turbula blender with the remaining Kollidon CL and the magnesium stearate and tableted as follows. Paracetamol compacted formulation 695.0 mg Kollidon CL 7.0 mg Magnesium stearate 3.0 mg Total weight 705.0 mg Equipment Tablet press: Korsch PH 100/6 Compression force: 18 kN Punch diameter: 12 mm, beveled edge Compression speed: 30 rpm Tablet properties: Compression _ Tablet weight Hardness Disintegration _ Friability force [kN] [mg] [N] [min:sec] [%] eR AN:42 I7F7R RQ2Q Tablet properties: Compression _ Tablet weight Hardness Disintegration _ Friability force [kN] [mg] [N] [min:sec] [%] 17.6 683.8 66 00:18
Film-coating Kollidon VA 64 forms films that are soluble at all pH values. They are less hygroscopic and more elastic than those formed by povidone (e.g. Kollidon 30). Nevertheless, Kollidon VA 64 usually still absorbs too much water, so that it can seldom be used as the sole film-forming agent in a formulation. It is therefore recommended to combine it with less hygroscopic substances such as cellulose derivatives, shellac or poly- ethylene glycol. Plasticizers are normally not required. The formulations in Tables 4 and 5 are typical formulations for tablet coatings. They were tested on 9 mm diameter, 3.4 mm thick, 200 mg placebo tablet cores in the laboratory. Kollidon VA 64 significantly improves their brittleness and solubility when it is combined with cellulose derivatives. When it is used in film coatings based on shellac, the properties of the film are more consistent. Table 9: Sugar film coating (Accela Cota 24) Suspension: Sucrose 200 g Kollidon VA 64 50g Macrogol 4000 40g Sicovit color lake 15g Sicovit titanium dioxide 30g Talc 50g Water ad 1,200 g Sontinuously spray 1,200 g of this suspension onto 5 kg of tablet cores. The spray conditions are as follows: Continuously spray 1,200 g of this suspension onto 5 kg of tablet cores. The spray conditions are as follows: BAR SAGEM SE NANA TAN RNR ER, Set sae eta: NAL NE Nea Inlet air temperature 45C Outlet air temperature 36 C Nozzle diameter 0.8 mm Spraying pressure 2.0 bar Coating pan speed 15 rpm Spraying time 50 min Quantity of film former applied 4 mg/cm?
Table 10: Film coating with Hypromellose (Accela Cota 24) Kollidon VA 64 53 g PEG 6000 12 g HPMC 6 mPa:s 79 g Water 732 g Il Sicovit Titanium Dioxide 36 g Sicovit Iron Oxide Red 30 18 g Talc 54 9 Water 216 g Total 1200 g Mix Solution with Suspension II, pass through a disc mill. The spray dispersion is calculated to be suitable for 5 kg of cores. The quantity of film former applied is about 3 mg/cm?. The cores size was 9 mm, biconvex. The coating process is performed using the following conditions: Pan speed 12 rpm Spraying rate [1 nozzle] 50 g/min Spraying time 34 min Quantity of applied film former 3.1. mg/cm? 5 min Final drying at 60 C Subcoating If it is intended to coat tablet cores with aqueous solutions or suspensions, it is recommended to provide them with a barrier if they contain a watersensitive active ingredient or a highly effective disintegrant (e.g. Kollidon CL) that is activated by water. This also applies if the cores are too soft or if their adhesive properties are inadequate for aqueous coatings. The cores are warmed to about 35 C and sprayed with a 10% solution of Kollidon VA 64 dissolved in an organic solvent, e.g. isopropanol, ethanol, ethyl acetate or acetone. As soon as a barrier film of adequate thickness has been built up, the aqueous coating can be applied. It has been found that 0.4 mg Kollidon VA 64/cm? is adequate. Sugar-coating Kollidon VA 64 is used in sugar-coating to improve the adhesion of the coating to the surface of the tablet core and to increase the capacity of the coating solution for pigments and improve their dispersibility. However, Kollidon VA 64 helps not only in the application of sugar coatings but also in the automation of the sugar-coating process.
Sprays Because of its good film-forming properties, Kollidon VA 64 can also be used in topical sprays. The formulation in Table 6 provides a typical example of a spray bandage. Table 11: Polidocanol wound spray SERA Gira SNE Mee ee Polidocanol 5g Lutrol E 400 20g Kollidon VA 64 50g Ethocel 20 (Dow) 50g Ethyl acetate 675 g lsopropanol 200 g Fill this solution into spray cans together with the necessary quantity of propellant. Amorphous Solid Dispersions Poorly water-soluble drugs are a constant and growing challenge within the pharmaceutical industry. One proven and viable technology to overcome this challenge is the production of amorphous solid dispersions or ASDs. ASDs are prepared by dissolving the poorly soluble drug within a polymeric matrix, which then releases the drug upon contact with aqueous media, and results in an overall increase of drug solubility and dissolution rate. ASDs may be prepared using well proven methods such as hot melt extrusion, or for temperature sensitive drugs, spray drying. For both technologies, Kollidon VA 64 has proven its suitability to generate thermodynamically and kinetically stable forms of solid API dispersions in a polymer matrix. Amorphous Solid Dispersions by melt extrusion The formulation of stable amorphous solid dispersion by melt extrusion based on Kollidon VA 64 has been established for more than two decades. This polymer has proved its suitability for this application because of its low glass transition temperature (101 C), high temperature resistance (up to 220 C) and optimum thermorheological properties. A number of product parameters have been optimized to minimize degradation of the API during melt extrusion and to ease powder handling. First, the LOD/water content of Kollidon VA 64 was adjusted to a level below the compendial upper limit to reduce the concentration of AP! degradation products during processing. Secondly, the particle size and morphology were optimized to reduce dust formation during powder dispensing, mixing operations and extruder feeding. The resulting intermediate extrusion products can be processed downstream by either filling them directly into hard gelatin capsules or by subsequently milling the extrudates and processing tablet cores or coated tablets.
Amorphous Solid Dispersions by spray drying For the manufacturing of solid dispersions using spray drying, it is essential that both API and matrix polymer are soluble in a suitable volatile organic solvent. Kollidon VA 64 is soluble in a number of organic solvents (see section 2.5) at levels greatly exceeding 10 % [w/w] while simultaneously retaining a low viscosity, which is crucial for successful spray drying. An example of spray dried Kollidon VA 64 from methanol as a model solvent is shown in Figure 4. Figure 4: Spray dried Kollidon VA 64 from methanol from a 10% solution. The high solubility, when combined with the low viscosity of the achieved polymer/ API-solutions, as well as the strong thermodynamic and kinetic interactions with poorly soluble drugs, make this polymer an outstanding matrix polymer for this application. Inhibition of the crystallization of APIs in liquid soft gel formulations Another aspect to the challenge of poorly water-soluble drugs is the ability to retain them in solution once dissolved, thereby maximizing absorption during the transit time of the gastrointestinal tract. Compounds that expand this absorption window are often called crystallization inhibitors as they retain drugs in a supersaturated state for a prolonged time through what is known as the parachute effect. This is in contrast with the spring effect, where drugs immediately recrystallize once in contact with gastrointestinal media. Kollidon VA 64 exhibits these effects when utilized with poorly water-soluble compounds. In this case, the oral dose primarily includes a hard or softgel capsule where Kollidon VA 64 is dissolved in hydrophilic fill formulations such as low molecular weight polyethylene glycols (PEGs), such as Kollisolv PEG 400. With Kollidon VA 64, it is possible to prevent recrystallisation and to achieve a Parachute Effect in both low pH stomach conditions and high pH intestinal conditions. Under stomach conditions, this is shown in Figure 5 for the model poorly soluble drug Danazol with Kollidon VA 64 used at 5% w/w in a PEG 400 liquid fill. The effect is compared with known crystallization inhibitor Kollidon 12 PF and solubilizer Kolliphor RH 40, which exhibits a spring effect. Drug dissolution was determined using a Pion Inform system with 50 ml buffer system of pH 2.0 and pH 6,8, respectively, and 0.5 ml of liquid formulation representing the filling volume of a soft gel capsule.
Figure 5: Parachute effect of Kollidon VA 64 under stomach conditions (pH = 2). Under gastric, acidic conditions, the effect is self-evident, showing Kollidon VA 64 with a significantly improved absorption window. Under intestinal conditions, the same effect is achieved, as shown in Figure 6. Figure 6: Parachute effect at pH 6.8 under intestinal conditions. Under intestinal conditions, a classic spring model for Kolliphor RH 40 is observed, while very little effect of Kollidon 12 PF is noted. However, Kollidon VA 64 shows a significantly improved absorption window.
4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on BASF RegXcellence or from your local BASF sales representative. 5. Product specification The current version of the product specification is available on BASF RegXcellence or from your local BASF sales representative. 5. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI) which is available on BASF WorldAccount, RegXcellence , and from your local sales representative The QRPI covers all relevant information including retest dates, and storage conditions. 7. Toxicology The safety of the polymer in Kollidon grades as pharmaceutical excipient in film coating of solid oral dosage forms is supported by a comprehensive non-clinical study. A summary of the study is available on BASF WorldAccount, RegXcellence or from your local sales representative. A detailed report can be shared as part of a non-disclosure agreement. https://worldaccount.basf.com, RegXxcellence (https://mypharma.basf.com/) 8. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30499395 Kollidon VA 64 60131775 35 kg PE drum with PE liner 30499398 Kollidon VA 64 50131776 35 kg PE drum with PE liner 30239644 Kollidon VA 64 Fine 57071976 15 kg Cardboard box with PE liner aluminium laminated BASFs commercial product number. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Fatty acids and alcohols: Consistency factors for topical formulations, and excipients for solid oral dosage forms. Oktober 2021 WF-No. 137189 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes fatty acids and alcohols that can be used as (co-) emulsifiers and consistency factors in topical pharmaceutical applications, but may also function as excipients in solid oral dosage forms, e.g., as matrix formers and lubricants. This document focuses on fatty acids and alcohols of the Kolliwax family. Please refer to the individual technical information sheet for specific information on our two glyceride based grades Kolliwax GMS II and Kolliwax HCO (Glycerol Monostearate, and Hydrogenated Castor Oil, respectively). Trade name Compendial Name Kolliwax CA Ph.Eur.: Cetyl Alcohol USP/NF: Cetyl Alcohol Kolliwax CSA 50 Ph.Eur.: Cetostearyl Alcohol USP/NF: Cetostearyl Alcohol JP: Cetostearyl Alcohol Kolliwax CSA 70 Ph.Eur.: Cetostearyl Alcohol Kolliwax MA USP/NF: Myristyl Alcohol Kolliwax SA Ph.Eur.: Stearyl Alcohol Kolliwax SA Fine USP/NF: Stearyl Alcohol JP: Stearyl Alcohol Kolliwax S Ph.Eur.: Stearic Acid 50 Kolliwax S Fine USP/NF: Stearic Acid 50 llPe Stearic Acid 50 Table 1: Compendial names for fatty alcohols and acids of the Kolliwax family. Description 2. Technical properties Kolliwax grades are white to slightly yellowish, waxy substances derived from natural ressources, namely coconut oil, palm kernel oil, and/or palm stearine. With melting points above room temperature, these products are either supplied as powder, pearls, or pelletts (see table1 and table 2 for details). The numeric part of the name of the two grades of Kolliwax CSA represents the approximate weight percentage of stearyl alcohol. es ene Trade name Chemical nature CAS-No. Melting ranges [cy Kolliwax CA Cetyl Alcohol (C,,) 36653-82-4 46-52 Koliwax CSA S0_ Cety/Stearyl Alcohol 7769 97.9 1666 Kolliwax CSA70_ (Cie/Cra) Kolliwax MA Myristyl Alcohol (C,,) 112-72-1 36-42 Kolliwax SA Stearyl Alcohol (C,,) 112-92-5 57-60 Kolliwax SA Fine Koliwax?S Stearic/Palmitio Acid g 7754 93.05 308 Kolliwax S Fine (Cil/Cy6) Values given for guidance only, see specification sheets for detailed information on melting and/or freezing temperatures. Table 2: Properties of fatty alcohols and acids of the Kolliwax family.
Figure 1: Typical appearance of the Kolliwax grades. The scale in the back is metric, with 1 mm per mark. For detailed information on particle size distributions, please refer to the individual product specification sheets. Scanning electron mircroscopy (SEM) igure 2: SEM images of Kolliwax S, and Kolliwax S Fine. Please refer to the individu: specification sheets for detailed information on particle size distributions.
3. Application Overview The following table 3 gives an overview on the most important applications and functions of the Kolliwax fatty alcohols and acids: while fatty acids and alcohols are generally used as consistency factors, our fine grades of stearic acid and stearyl alcoho (Kolliwax S Fine and Kolliwax SA Fine, respectively) allow to use these substances in the preparation of solid dosage forms, where they can aid as lubricants or matrix formers. Table 3: Application of the Kolliwax grades. Emulsions Exhibiting excellent skin tolerance, the Kolliwax grades can be used for all kinds of topical pharmaceutical applications, such as creams, gels, lotions, and ointments. The typical usage concentration in emulsions is about 1- 5%. All Kolliwax grades will act as consistency factors and co-emulsifiers at the same time. With their amphiphilic structure, they will stabilize the interface between oil and water and will help to enhance the viscosity by building up a liquid crystalline network (lamellar sheet structure). Stabilizing w/o and 0/w emulsions, they also aid in bringing a unique softness and creaminess to the targeted formulation. Lubricants In tableting processes for solid oral dosage forms, lubricants are used to prevent ingredients from clumping to undesired aggregates and from sticking to the tablet punches or capsule filling machine. In addition, lubricants hamper the friction that would hinder tablet formation and ejection. Among inorganic materials (e.g. talc or silica), fat based substances like vegetable stearin, magnesium stearate or stearic acid are commonly used as lubricants in tablets or hard gelatin capsules. Lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. Formulation examples Guideline for the preparation of the model formulations: MaYIGenne 1Or UWle PrepalrauviOrl OF WIE MIOQE! fOMTIUlAvOrls. 1. Heat components of phase A to 80 - 85 C and stir until transformed into a homo- geneous melt. 2. Heat components of phase B to 80 85 C. Under constant stirring, slowly add phase A to phase B, homogenize for 5 min at 5000 rpm. Let cream cool to 35 C while mixing at 200 rpm, and add preservative.
Model formulation Rich Cream: This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as emulsifiers to create avery stiff cream that offers a slow spread and a cushioned feeling when rubbing into the skin. Its high immediate smoothness results from the utilization of Kollicream IPM, a fast spreading oil with broad penetration enhancement properties that can aid as a solubilizer for lipophilic drugs. Ingredient Phase Ph. Eur. name Role Amount [wt.-%] A __ Kolliwax CSA 70 Cetostearyl Alcohol Consistency Factor, 7.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 25 40-55 (Type Il) Co-Emulsifier Kolliphor PS 60 Polysorbate 60 Emulsifier 4.2 Kollisolv@ MCT 70 Medium Chain Emollient 11.5 Triglycerides Kollicream IPM Isopropyl Myristate Emollient 1.3 B Deionized Water 69.2 Solvent _____. Glycerol 3.3 C_ Euxyl PE 9010 Preservative 1.0 Table 4: Model formulation for a rich Cream. Model formulation Light Cream: This formulation is a smooth cream with easy distribution, medium viscosity, and a glossy finish. Due to the difference in HLB values, the blending ratio of Kolliphor CS 12 and Kolliphor CS 20 can be used as a factor to maximize emulsion stability. Phase Ingredient Ph. Eur. name Role Amount [wt.-%] A_ Kolliwax CSA 50 Cetostearyl Alcohol Consistency Factor, 4.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 5.0 40-55 (Type Il) Co-Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Emulsifier 2.0 Ether 20 Kolliphor CS 12 Macrogol Cetostearyl Emollient 0.8 Ether 12 Kollicream CP 15 Cetyl Palmitate 15 Emollient 0.8 Kollicream IPM Isopropyl Myristate Emollient TA B__ Deionized Water 74.0 Solvent Glyerol 5.0) C_ Euxyl PE 9010 Preservative 1.0 in Si Pe Table 5: Model formulation for a light cream. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment.
5. Product specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554718 olliwax CA 50253459 25 kg Plastic film bag 50259499 0.5 kg Plastic bottle 30554719 olliwax CSA 50. 50253501 25 kg Plastic film bag 50259500 0.5 kg Plastic bottle 30554721 olliwax CSA 70 50253504 25 kg Plastic film bag 50259502 0.5 kg Plastic bottle 30554492 olliwax MA 50375472 20 kg Corrugated fiberboard box with PE liner 50259498 0.5 kg Plastic bottle 30554720 olliwax SA 50253503 25 kg Plastic film bag 50259501 0.5 kg Plastic bottle 30563963 olliwax SA Fine 50284249 25 kg Plastic film bag 50372378 0.5 kg Plastic bottle 30554752 olliwax S 50253532 25 kg Plastic film bag 50259521 0.5 kg Plastic bottle 30554750 olliwax S Fine 50253810 25 kg Plastic film bag 50259508 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.

Table of contents Introduction Polyethylene glycol portfolio 5 Typical chemical and physical properties 6 Applications 8 Tablets, liquids, and suspensions 9 Softgels 10 Ensuring softgel performance with low aldehyde Kollisolv? PEGs 13 Topicals 20 Hydrophilic ointment formulation 20 Emulgel formulation 21 Suppository formulation 22 Product details and key benefits 24 Product and sample article numbers 25 ZoomLab, RegXcellence, & MyProductWorld 26 Introduction Polyethylene glycol portfolio
Polyethylene glycol portfolio Kollisolv PEGs are colorless, almost odorless, and tasteless liquids or white solids at room temperature. These products are manufactured by alkali-catalyzed polymerization of ethylene oxide with subsequent neutralization of the catalyst. The number in the name of the product indicates its average molecular weight. Chemical name CAS number Our portfolio of Kollisolv PEGs offers assurance of high-quality production in cGMP manufacturing conditions that meet the compendial requirements of USP-NF and Ph. Eur. At low molecular weights, our Kollisolv? PEGs are present as colorless liquids, and at higher molecular weights these products exist as white semi-solids and solids.
Unlike standard grade PEGs with a total aldehyde content of 50 ppm, our low aldehyde Kollisolv PEGs are restricted to an aldehyde content maximum of 10 ppm and offer assurance of control. With a restricted total aldehyde content to a maximum of 10 ppm, these excipients are especially suited for sensitive APIs and applications, including softgel shells and fills. Colorless, almost odorless, and tasteless liquid at room temperature Average molecular weight (g/mol) 285 to 315 380 to 420 380 to 420 570 to 630 570 to 630 Melting point (C) -15 to -8 4to8 4to8 15 to 25 15 to 25 Hydroxyl value (ng KOH/g) 340 to 394 264 to 300 264 to 300 178 to 197 178 to 197 Viscosity at 25 C (mPa:s) 80 to 105 105 to 130 105 to 130 Solid Solid Viscosity at 99 C (mm?/s) 5.4 to 6.4 6.8 to 8.0 6.8 to 8.0 9.9 to 11.3 9.9 to 11.3 fery soluble in water and alcohol, practically insoluble in oils and fa
Tablets, liquids, and suspensions Kollisolv PEGs can be used in tablet applications as a component of the core or coating. They can also serve as lubricants in the processing of a tablet. In tablet core applications, solic Kollisolv PEGs can be used as a binder or additive. Solid and semi-solid Kollisolv? PEGs can be used in coating applications as a plasticizer and film former. Polyethylene glycols, or macrogols, are mainly used as solubilizers, surfactants, and solvents. As multifunctional ingredients, these excipients play an essential role in various oral and topical formulations. Low-molecular-weight liquid polyethylene glycols are excellent solvents for numerous substances that do not readily dissolve in water. They are widely used as solvents and solubilizing agents for active substances and excipients in liquid and semi-solid preparations. They can also be used as plasticizers in tablets, capsule shells, and film coatings.
Softgels Figure 1. Solubility of Kollidon VA 64 in Kollisolv PEG 300, 400, and 600 at room temperature. BASF offers a range of liquid Kollisolv? PEGs and other complementary products for softgel applications. From solubility enhancement to crystallization inhibition, these products make for easier softgel formulation with greater predictability and reliability. BASF solubilizers such as Kolliphor RH 40 (Ph. Eur.: macrogolglycerol hydroxystearate; USP-NF: polyoxyl 40 hydrogenated castor oil), Kolliphor EL (Ph. Eur.: macrogolglycerol ricinoleate, USP-NF: polyoxyl 35 castor oil), or Kolliphor HS 15 (Ph. Eur.: macrogol 15 hydroxystearate; USP-NF: polyoxyl 15 hydroxystearate) can be used in combination with liquid Kollisolv PEGs to increase the solubilization capacity, allowing for the enhanced dissolution of challenging APIs. Crystallization inhibitors such as Kollidon VA 64 (Ph. Eur., USP-NF: copovidone), Kollidon 30 (Ph. Eur., USP-NF: povidone), and Kollidon 12 PF (Ph. Eur., USP-NF: povidone) can be used with liquid Kollisolv PEGs to prevent drug recrystallization. These crystallization inhibitors form homogenous blends at common processing and filling temperatures, and provide an additional benefit of increasing fill viscosity. This increased fill viscosity allows for more consistent filling and lower weight variance between softgels capsules. Blends of Kollisolv PEGs with Kollidon crystallization inhibitors are stable at room temperature up to 40% concentration by weight. Figure 2. Solubility of Kollidon 30 in Kollisolv PEG 300, 400, and 600 at room temperature. Figure 3. Solubility of Kollidon 12 PF in Kollisolv PEG 300, 400, and 600 at room temperature.
Advancements in increased temperature control for softgel encapsulation machines provide opportunities to use fills with greater crystallization inhibitor concentration. Use of common processing temperatures of 40 or 60 C leads to as much as 80% reduction in fill viscosity. This gives significant advantages by increasing processing speed with lower flow resistance of fills and increasing softgel shelf stability with greater crystallization inhibitor content when using liquid Kollisolv? PEGs with Kollidon crystallization inhibitors. Softgels are oral formulations that are composed of a pharmaceutical grade shell which encapsulates the liquid fill. Shell-fill compatibility requires the strategic selection of excipients to minimize degradation byproducts known to be harmful for softgel stability. To ensure capsu integrity and dissolution reproducibility, the fill must be compatible with the shell, and neither prematurely rupture the shell nor restrict release of the active post-delivery. Aldehydes are a common concern in softgels, especially soft gelatin capsules, where chemical crosslinking of the gelatin peptide backbone will cause insoluble films or pellicles that disrupt dissolution testing. The consequence of crosslinking is often an altered dissolution behavior of the capsule, one that will fail dissolution testing in vitro. While this crosslinking does not always translate to failure in vivo, where enzymes can cleave the peptide backbone, the USP <711> recommends a two-tiered dissolution investigation when in vitro dissolution failure arises from crosslinking. The complicated testing protocol includes pH-dependent enzyme selection and, as elaborated in USP <1094>, additional testing on the compatibility of any surfactants includec in the medium. These additional tests require cumbersome method development and validation, lengthening the time and complexity of going to market. Figure 4. Viscosity vs. concentration of Kollidon VA 64 in Kollisolv PEG 300 at 25, 40 and 60 C.
To study the effect of degradation byproducts, particularly aldehydes, on softgel performance, five lots of polyethylene glycol 400 (PEG 400) of varying grades and storage conditions were selected for testing (Table 1). Two fresh lots of Kollisolv? PEG 400 LA were evaluated, as well as one Kollisolv PEG 400 LA at the 2-year retest. A compendial grade of PEG 400 that met Ph. Eur. and USP monographs was included, as well as a standard, non-pharmacopoeia PEG 400. The standard grade PEG 400 was a forced-aged compendial PEG 400 sample, stressed through aging at 60 C for 9 days and 80 C for 7 days. The starting aldehyde levels for each sample was determined by an in-house R&D method (Figure 7). Kollisolv PEG 400 LA had the lowest aldehyde concentration, under 10 ppm, with nc difference between fresh and at 2-year retest. The compendial PEG 400 sample had an aldehyde concentration almost two-fold higher than Kollisolv PEG 400 LA. Standard PEG 400 was nearl six-fold higher. Figure 7. Starting aldehyde levels for each grade of PEG 400. Table 1. PEG 400 samples for softgel formulations. Sample # Material Age to retest Grade 1 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 2 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 3 Kollisolv PEG 400 LA At 2-year retest Low aldehyde (Ph. Eur., USP) 4 Compendial PEG 400 Compendial (Ph. Eur., USP) 5 PEG 400 Standard Samples 1 and 2 represented two different freshly opened lots.
Brilliant Blue, serving as a model active pharmaceutical ingredient (API), was formulated at eque parts in the five PEG 400 samples. After the formulations were filled into softgel capsules using lab-scale filling equipment, the capsules were then stored at ambient (25 C, 60% RH) and accelerated (40 C, 75% RH) conditions for a 12-month period. In vitro dissolution of the softgel capsules was performed to evaluate the effect of aldehyde content on dissolution. The dissolution time to release 80% of the loaded Brilliant Blue was captured for each sample (Fig. 9). Softgels containing Kollisolv PEG 400 LA demonstrated an equivalent dissolution time over the full 12 months under ambient conditions; while even the compendial grade PEG 400 containing softgels exhibited delayed dissolution within 6 months. When stored at ambient conditions, the softgel capsules composed of Kollisolv? PEG 400 LA demonstrated superior stability over compendial and standard PEG 400 (Fig. 8). Over the course of 12 months, the softgels filled with fresh and 2-year Kollisolv? PEG 400 LA showed a stable release profile with no evidence of crosslinking or change in dissolution. The equivalence of performance with product age, fresh and at two years, demonstrates the stability of Kollisolv PEG 400 LA and reliability of performance. Figure 9. Dissolution time (until 80% release) of softgels stored at ambient (25 C, 60% RH) conditions taken as the time in minutes. In contrast, the softgel consisting of compendial PEG 400 increasingly delayed dissolution, with significant changes in dissolution evident by month 6. To an exaggerated degree, the softgel containing standard PEG 400 showed retarded dissolution and evidence of near-immediate crosslinking within the first month. Figure 8. Dissolution of softgels stored at ambient (25 C, 60% RH) conditions over a 12-month period. In accordance with USP<711>, formulations made with the compendial PEG 400 would require proof of gelatin crosslinking via spectroscopic methods and complicated dissolution tests. Comparatively, formulations that consisted of Kollisolv? PEG 400 LA would not require further investigation regarding crosslinking or dissolution. Even under stressed aging in accelerated storage conditions, softgels consisting of Kollisolv PEG 400 LA within the full 2-year retest period exhibited equivalent performance, demonstrating stability of the product within its shelf-life. Under accelerated storage, dissolution of capsules of fresh and retest-aged Kollisolv PEG 400 LA remained equivalent through 3 months (Fig. 10). In contrast, compendial PEG 400 mirrored the failure of standard, non- pharmacopoeia PEG 400, and both products showed immediately delayed dissolution within the first month, failing due to crosslinking of soft gelatin capsules. In this case, even meeting Ph. Eur. and USP standards for a pharmaceutical excipient did not impart stability over a non- pharmaceutical grade of PEG 400.
Figure 10. Dissolution of softgels stored at accelerated (40 C, 75% RH) conditions over a 6-month period. Under accelerated conditions, Kollisolv? PEG 400 LA offered improved stability of the dissolutior profile. Regardless of age, the three Kollisolv? PEG LA samples demonstrated an equivalent dissolution time over 3 months, suggesting stability studies under these conditions is feasible through 3 months (Fig. 11). In contrast, both compendial and standard, non-pharmacopoeia grades of PEG 400 exhibited delayed dissolution immediately, failing accelerated stability studies under these conditions. Aldehyde content within the softgels was determined at time points within both storage conditions. As softgel fills, Kollisolv? PEG 400 LA samples demonstrated minimal changes in the aldehyde content over a 2-year retest period. Evaluation of the aldehyde content showed that storage condition did not significantly impact the total aldehyde amount present in the softgel fill. Ultimately, Kollisolv PEG 400 LA did not develop aldehyde content over time when formulated in softgels, whether fresh or at retest, under ambient or accelerated storage (Fig. 12). Figure 12. Aldehyde development of Kollisolv PEG 400 LA in softgels, over 12 months at under ambien and accelerated storage. Figure 11. Dissolution time (until 80% release) of softgels stored at ambient (40 C, 75% RH) conditions taken as the time in minutes. In summary, Kollisolv? PEG 400 LA outperformed compendial PEG 400. The dissolution profiles from softgels at both ambient and accelerated storage conditions reflected a pre dilection towards Kollisolv PEG 400 LA, with stable release seen for longer than from compendial PEG 400. When using Kollisolv PEG 400 LA as the softgel fill, aldehydes did not develop over time at either ambient or accelerated storage conditions. Rather, the source and quality of the products had the greatest effect on the aldehyde levels. Fresh and at-retest Kollisolv PEG 400 LA samples offered a 50% reduction in starting average aldehyde content in comparison to compendial grade PEG 400. The repeatable and stable dissolution profiles seen for Kollisolv PEG 400 LA bring the advantages of rapid development and ease of qualification.
Topicals Emulgel formulation When used for topical applications, solid and liquid Kollisolv PEGs be combined to form water-soluble bases for ointments, suppositor and ovula. Low-molecular-weight Kollisolv? PEGs can be used as solvents, conditioners, adhesion promoters, and humectants. These products, like Kollisolv PEG 300, Kollisolv PEG 400, and Kollisolv PEG 1000, promote ease of application, softening on contact with skin, and localization of active delivery. High-molecular-weight Kollisolv PEGs can be used as structuring agents and thickeners to increase the viscosity of formulations. These include Kollisolv PEG 1450, Kollisolv PEG 3350, and Kollisolv PEG 8000. Hydrophilic ointment formulation Kollisolv PEG ointments can be used as an alternative to traditional petrolatum-based ointmen formulations. By pairing different amounts of high- and low-molecular-weight chains, PEG ointments can be tuned for desirable rheological profiles and sensory. Procedure 1. Prepare phase A by weighing ingredients into an appropriately sized beaker. 2. Heat the mixture to 60 C and continue heating until the mixture has completely melted. Try to minimize the heating time as much as possible. 3. Once all the components have melted, place phase A underneath an overhead mixer. Stir at a low shear rate until cooled to room temperature. Kollisolv PEG 3350 is commercially available only in the USA and Canada as an excipient.
Suppositories allow formulators to accurately deliver active ingredients through an alternative route. Kollisolv PEG suppositories are ideal for the formulation of suppository matrices, offering a melting temperature range within physiologically relevant conditions and compatibility with hydrophilic druas.
Product details and key benefits Product details Regulatory Manufacturing site Manufacturing process Re-test period Certified Handling Safety data sheet Retest date and storage conditions Specification Regulatory status Key benefits Supply reliability & consistent quality Sustainability Technical service BASF Virtual Pharma Assistants Kollisolv? PEGs USP-NF, Ph. Eur. Geismar, Louisiana (USA) Synthetic 24 months Kosher, Halal Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRPI). For current specification, please speak to your local BASF sales or technical representative. Please refer to Quality & Regulatory Product Information (QRPI). Kollisolv PEGs are manufactured in a GMP compliant facility in the U.S. ensuring: Consistent quality and safety @ Reliable, vertically integrated supply BASF is a proud member of the Pharmaceutical Supply Chain Initiative (PSCl), whose vision is to establish and promote responsible practices that will continuously improve human rights, health, safety, and environ- mentally sustainable outcomes for supply chains worldwide. @ World class expertise in excipient chemistry Formulation guidance with ZoomLab @ Regulatory documentation available in RegXcellence Product details available via MyProductWorld @ Full pharma regulatory documentation and submission support Product details and key benefits

For sample requests contact us at pharma-solutions@basf.com This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to th extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matte in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2022 BASF Corporation. All Rights Reserved.
PronovaPure 360:240 TG Chemical names of active ingredient CAS-No. Description PronovaPure 360:240 TG is a pale yellow fish oil concentrate. PronovaPure 360:240 TG is a pale yellow fish oi concentrate. The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Scombridae and Carangidae). The product is a triglyceride (TG), rich in omega-3 fatty acids. The content of EPA (Eicosapentaenoic acid expressed as TG) and DHA (Docosahexaenocic acid expressed as TG) is min. 600 mg/g. Articles Country of origin
Composition Stability, Storage and Handling eee tte ie ees ent ee Ingredients in descending order of weight: Fish oil concentrate, tocopherol-rich extract (E 30 Ingre ients in descending order of weight: Fish oil concentrate, tocopherol-rich extract (E 306). Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 36 months. mainly derived from soybean (from identity preserved, not genetically modified origin) Solubility Practically insoluble in water, very soluble in acetone and heptane, slightly soluble in anhydrous ethanol. Applications Specification Specification  PronovaPure 360:240 TG is intended for use in dietary supplements such as in soft gel capsules. as triglycerides Ph. Eur. 1352/2.4.29 EPA (Eicosapentaenoic acid) min. 360 mg/g DHA (Docosahexaenoic acid) min. 240 mg/g EPA & DHA (Eicosapentaenoic 600-700 mg/g & Docosahexaenocic acid) Total Omega-3 fatty acids min. 650 mg/g Note PronovaPure 360:240 TG must be handled in accordance with the Material Safety Data Sheet. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon deliv ihis agocument, of any answers or information provided herein Dy BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access) Bnei: OMe aOR LR les CNIS LOE, Ginny ee ha NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. Standards Produced under cGMP and HACCP principles. Monographs and Regulations PronovaPure 360:240 TG meets the require- ments for an omega-3 fatty acid source in most countries. The product complies with the USP monograph for Omega-3 acid triglycerides and the Ph. Eur. monograph on Omega-3-acid tri- glycerides (1352). Further, the product conforms to the voluntary GOED monograph in the current version. Fish oil concentrates are accepted for use in dietary Fish oil concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed.
Technical Information Docosahexaenoic acid ethyl ester Docosahexaenoic acid ethyl ester
1. Introduction Maxomega DHA 95 EE AS is an oil containing minimum 95% of the primary omega-3 acid, docosahexaenoic acid (DHA) in ethyl ester (EE) form. Omega-3 fatty acids in general are naturally occurring nutrients that are of high importance for human health. They cannot be synthesized by the human body but are vital for normal metabolism. Omega-3 fatty acids are polyunsaturated fatty acids with < double bound from the 3rd carbon atom from the end (omega). The most abundant omega-3 fatty acids are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alfa-linoleic acid (ALA). EPA and DHA are long-chain fatty acids found in algal oil and fish. EPA and DHA have been widely studied for medical and nutritional applications. Maxomega DHA 95 EE AS is produced from algal oil by several concentration and purification steps including liquid chromatography and silica refining. The algal oil is sourced from the micro organism Schizochytrium sp. The only additional ingredient to DHA EE is the antioxidant dl-alpha tocopherol which is added in a concentration of approximately 0,2%. The minor part (4-5%) that is not DHA EE, consists of other naturally occurring fatty acid in ethyl ester form, including other omega-3 fatty acids. Due to the high amount of unsaturated fatty acids, the product will easily oxidize in contact with air, and needs to be protected from contact with oxygen. The container is therefore flushed with nitrogen prior to, during and after filling with DHA 95 EE. Maxomega DHA 95 EE AS or the genric substance Docosahexaenoic acid ethyl ester has no approved medical indication, but is under development and testing whithin pharmaceutical applications. DHA at lower concentrations sourced from fish or algae are used in nutritional products, either in ethyl ester or triglycerides form. Omega-3 fatty acids in general are naturally occurring nutrients that are of high importance for human health. They cannot be synthesized by the human body but are vital for normal metabolism. Omega-3 fatty acids are polyunsaturated fatty acids with a double bound from the 3rd carbon atom from the end (omega). The most abundant omega-3 fatty acids are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alfa-linoleic acid (ALA). EPA and DHA are long-chain fatty acids found in algal oil and fish. EPA and DHA have been widely studied for medical and nutritional applications. Maxomega DHA 95 EE AS is produced from algal oil by several concentration and omega-3 fatty acids are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alfa-linoleic acid (ALA). EPA and DHA are long-chain fatty acids found in algal oil Maxomega DHA 95 EE AS is produced from algal oil by several concentration and purification steps including liquid chromatography and silica refining. The algal oil is sourced from the micro organism Schizochytrium sp. The only additional ingredient to DHA EE is the antioxidant dl-alpha tocopherol which is added in a concentration of approximately 0,2%. The minor part (4-5%) that is not DHA EE, consists of other naturally occurring fatty acid in ethyl ester form, including other omega-3 fatty acids. Due to the high amount of unsaturated fatty acids, the product will easily oxidize in contact with air, and needs to be protected from contact with oxygen. The container is therefore flushed with nitrogen prior to, during and after filling with DHA 95 EE. Maxomega DHA 95 EE AS or the genric substance Docosahexaenoic acid ethyl ester has no approved medical indication, but is under development and testing whithin pharmaceutical applications. DHA at lower concentrations sourced from fish or alaae are used in nutritional is added in a concentration of approximately 0,2%. The minor part (4-5%) that is not Maxomega DHA 95 EE AS or the genric substance Docosahexaenoic acid ethyl ester has no approved medical indication, but is under development and testing whithin JHA at lower concentrations sourced from fish or algae are used in nutritional
2. Description Name United States Adopted Names (USAN) NA International nonproprietary name (INN) Doconexent ethy! Pharmacopeia name Chemical names Ethyl all cis-4, 7,10,13,16, 19-Docosahexaenoate, Docosahexaenoic acid ethyl ester Cervonic acid ethyl ester, Ethyl-[DHA, DHA EE, C22:6n-3 ethyl ester Molecular formula C,H 6 Oo Relative Molecular mass
3. Physical and chemical properties Appearance Maxomega DHA 96 EE AS is a colourless-to-yellow, clear mobile liquid. Solubility Maxomega DHA 95 EE AS is practically insoluble in water, very soluble in organic solvents such as hexane, acetone, ethanol, and methanol. Boiling point > 400C at 1.013hPa Flash point >100C Vapour pressure Negliable Density 0.914 g/cm (20C) Partioning coefficient in octanol/water (logPow) 9.4 4. Medical information Applications Maxomega DHA 95 EE AS is a highly concentated omega-3 oil containing mainly only one of the omega-3 fatty acids, DHA in ethyl ester form. For application, Maxomega DHA 95 EE AS is typically filled into soft gelatin capsules as the sole fill ingredient. These soft gelatin capsules are suitable for Maxomega DHA EE AS because it protects the active substance from oxygen and masks taste and odour. In consequence, Maxomega DHA EE AS is not suitable for liquid multidose formulations as it will readily oxidize in contact with atmospheric oxygen, and also has an unpleasant taste and odour. Therapeutic indication Maxomega DHA 95 EE AS is not used in any licenced pharmaceutical drug products, and there are no approved therapeutic indications for the generic substance Docosahexaenoic acid ethyl ester.
5. Handling & Safety Please refer to the individual safety data sheet (SDS) for instructions on safe and proper handling and disposal. Safety data sheets are sent with every consignment or can be requested from your BASF sales representative. Re-test period & Storage Conditions Please refer to the document Quality & Regulatory Product Information which is available in RegXcellence, RegXcellence (force.com). Packaging The commercial product is filled in epoxy phenolic lined mild steel drums. The lining is a golden brown colour. The drum closure is made of the same materials. The product is stored under nitrogen atmosphere to prevent oxidation. The external drum surface is blue. 6. Product specifications The current version of the product specifications are available at RegXellence, RegXcellence (force.com) or from your BASF sales representative. Please refer to the document Quality & Regulatory Product Information which is available in RegXcellence,, RegXcellence (force.com) PRD and Article numbers PRD-No. Product name Article numbers Packaging 30635624 Maxomega DHA 95 EE AS 50461831 190kg steel drum 50430534 (sample) 0,1 kg aluminum bottle PRD-No. Product name This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. June 2021
Technical Information = Registered trademark of BASF in many countries.
1. Introduction Historical aspects of polyvinylpyrrolidone The modern acetylene chemistry was developed at BASF in the 1930s by Reppe. One of the many products that emerged from this work are the soluble polyvinyl- pyrrolidone grades, obtained by radical polymerization of the monomer unit N-vinyl pyrrolidone. The polymerization can be performed either in water or in organic solutions. Triggered by organic or inorganic radical starters, the polymers span a wide range of molecular weights. Because of its solubility in water and in many organic solvents, its high binding power and its ability to form complexes, soluble polyvinylpyrrolidones are very valuable synthetic polymers for the pharmaceutical industry. Separate Technical Information Sheets are available for the Povidones with low molecular weights, for the insoluble Kollidon grades (Crospovidone) and for Kollidon VA 64, the copolymer consisting of N-vinylpyrrolidone and vinyl acetate (Copovidone). More information on Kollidon grades may be found in the book, Kollidon, Poly- vinylpyrrolidone for the Pharmaceutical Industry. 2. Technical properties Description The range of medium and high molecular weight Povidones comprises of the grades Kollidon 25, Kollidon 30, Kollidon 30 LP, which are of medium molecular weight and are polymerized in aqueous solution and spray dried. In addition, the high mole- cular weight grade Kollidon 90 F, after being polymerized in water achieving a very highly viscous polymer solution, is finally dried using a drum dryer. The product range comes as white powders with faint, characteristic odor. Structural formula Trivial names Soluble polyvinylpyrrolidone is also known as povidon(e), povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone) and PVP. CAS number 9003-39-8
Product range and molecular weights The product range of the medium and high molecular weight Povidones comprises of 4 different products which are, product dependent, manufactured in the production sites in Ludwigshafen, Geismar and/or Shanghai. The molecular weight of polymers can be expressed in three different forms, as weight average molecular weight, as number average molecular weight and as viscosity average molecular weight. The molecular weight of povidone is usually expressed as the K-value, from whict it is possible to calculate the viscosity average molecular weight (M,). However, the weight average molecular weight (M,,) is found more frequently in the literature. The following M,, values were determined for different grades of Kollidon in recent measurements. In contrast to former determinations SEC was performed using a detection system not requiring reference standards anymore. Nominal Compendial range M,, K-Value for K-value [g/mol] Kollidon 25 25 24-27 28000 - 34000 Kollidon 30 30 28 - 32 44000 - 54000 Kollidon 30 LP 30 28 - 32 44000 - 54000 Kollidon 90 F 90 85 - 95 900000 1200000 Table1 Solubility The solubility of Kollidon varies considerably from one solvent to another. In Table 2 below, soluble signifies that a solution of at least 10% can be prepared, and insoluble signifies that the solubility is less than 1%. Soluble in: chloroform n-butanol cyclohexanol n-propanol ethanol abs. polyethylene glycol 300 glycerol polyethylene glycol 400 isopropanol propylene glycol methanol triethanolamine methylene chloride water Insoluble in: cyclohexane pentane diethyl ether carbon tetrachloride ethyl acetate toluene liquid paraffin xylene Table 2: Solubility of Kollidon Grades
Particle size When analyzed the particle size distribution using a sieving method, particle size distributions of the various polymers can be described with the following ranges. Product <50 um >250 um Kollidon 25 max. 40% max. 5% Kollidon 30 max. 40% max. 5% Kollidon 30 LP max. 20% max. 5% Kollidon 90 F max. 10% max. 15% Table 3 Bulk density Bulk density of Kollidon is determined according to Ph. Eur. current edition, method 2.9.34. Product Bulk density Kollidon 25/30/30 LP 400 600 g/L Kollidon 90 F 400 550 g/L Table 4: Bulk density of the Kollidon grades Particle size distribution and bulk density are considered characteristic values. They are not part of any specifications. Particle size distribution and bulk density are considered characteristic values. They are not part of any specifications. Glass transition temperature Tg, Product Tg, [C] Kollidon 25 165 Kollidon 30 171 Kollidon 30 LP 171 Kollidon 90 F 177 The glass transition temperature was determined by DSC as Tg,, after having eliminated water by heating and finally cooling the dried polymer to room temperature for a second cycle.
Viscosity Fig. 1 shows the relationship between the viscosity of aqueous solutions of the different grades of Kollidon and their concentration. Fig. 1: Viscosity of Kollidon solutions (Ubbelohde viscometer, 25 C) Complexation, chemical interactions Povidone can form fairly stable association compounds or complexes with a number of active substances. The best known example is PVP-iodine which is the subject of a separate leaflet. The ability of Kollidon to form a water-soluble complex with insoluble active substances can be used in pharmaceuticals to improve the release rate and solubility of drugs. There are a few substances such as the polyphenols that form stronger complexes that can precipitate in neutral or acidic media. It must be noted that if povidone is combined with strongly alkaline substances such as lithium carbonate or sodium hydroxide it can crosslink and become insoluble, particularly at elevated temperatures. In extreme cases, this can increase the viscosity of liquid presentation forms and delay bioavailability in solid presentation forms.
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application The main applications of the soluble Kollidon grades are summarized in Table 6. Binder Tablets, capsules, granules Bioavailability enhancement Tablets, capsules, granules, pellets, suppositories, transdermal systems Film formation Opthalmic solutions, tablets, medical plastics Solubilization Oral, parenteral and topical solutions Lyophilising agent Injection preparations, oral lyophilisates Stabilisation of suspensions Oral and parenteral suspensions Oral instant beverage powders and granules for redispersion Viscosity modifier Ophthalmic formulations Adhesives Transdermal systems, adhesive gels Drug stabilisation Enzymes in diagnostics Table 6: Main applications of the soluble Kollidon grades of medium and high molecular weight The adhesive, film-forming, dispersing and thickening properties of the soluble Kollidon grades are used in the various modifications of granulation technologies for tablet production, film coating and in the preparation of other dosage forms. The improvement in the solubility of active ingredients brought about by complexatior or association, and the thickening effect find use mainly in the manufacture of liquid presentation forms. The grade of Kollidon that is selected depends mainly on its molecular weight, as this dictates the viscosity, binding effect, the complexation capacity and how readily it is eliminated from the body. A detailed description of the applications is to be found in the book, Kollidon, poly- vinylpyrrolidone for the Pharmaceutical Industry. Tablet binding Kollidon 25, Kollidon 30, Kollidon 30 LP and Kollidon 90 F When applied for granulation in high shear mixers or fluid-bed granulators the resultinc granules with Kollidon 25, Kollidon 30 and Kollidon 90 F are hard, free flowing with a low proportion of fines. Binding strength is excellent to achieve hard and stable tablets. Kollidon 25 and Kollidon 30 require binder quantities of 2% and 5% related to the tablet weight. As Kollidon 90 F has a higher binding capacity the required quantities are 2% or even less. The high viscosity of binder solutions of Kollidon 90 F sometimes requires precautions to ensure the granules to be evenly wetted. Kollidon 25, 30 and 90 F are also suitable for the direct compression of tablets without granulation. This technique requires a certain relative humidity, as the powder mixture must have a certain moisture content to bind properly. If Kollidon is used in addition to microcrystalline cellulose, it not only makes the tablets harder but also gives them stronger edges. For best results in direct compression, all the excipients should have acertain moisture content. This applies to starch, micro- crystalline cellulose and lactose monohydrate as fillers. It can be seen from Fig. 2 that there is hardly any difference in the hardness of lactose placebo tablets made with Kollidon 25 and Kollidon 30. However, the same quantity (3% of the tablet weight) of Kollidon 90 F almost doubles the hardness, compared with Kollidon 25.
Fig. 2: Lactose monohyarate tablets with 3% Kollidon (wet granulation) Kollidon is also suitable as a binder in fluidized-bed granulation processes. Thanks to their relatively low viscosity, solutions of Kollidon 25 and Kollidon 30 can be prepared relatively quickly, and sprayed easily, to quickly give stable granules. Co-precipitation, co-milling Kollidon 25, 30 The dissolution rate and therefore the absorption rate of drugs that do not dissolve readily in water can be greatly improved by co-milling or coprecipitation with Kollidon 25 or Kollidon 30, as the complex formed is, in effect, a solid solution of the drug in the Kollidon. This requires an excess of Kollidon to maintain the (partially) amorphous form of the active substance. Suitable processes include mixing, co-milling or melt extrusion of the Kollidon-drug mixture, or coprecipitation, granulation onto a carrier or spray-drying a solution containing the drug and Kollidon. The literature contains hundreds of publications on this application. The most frequently tested active substance mentioned is probably nifedipine. Stabilizers of suspensions Kollidon 25, 30, 90 F These grades can be used to stabilize oral and topical suspensions with a wide range of active ingredients, e.g. acyclovir, ibuprofen, magaldrate, nystatin, phenytoin, trimethoprim, sulfonamides and antibiotics, as well as sugar-coating suspensions. Combinations of Kollidon 90 F with Kollidon CL-M have often given very good results. Thickener Kollidon 90 F Because of its good solubility in water and alcohol, Kollidon 90 F can be used as a thickener for aqueous or aqueous-alcoholic solutions for oral application (viscosity curve, see Figure 1).
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage condition: 6. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technica representative. Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data For information on toxicological issues please refer to the tox abstract which can be supplied on request. More/detailed toxicological information for Kollidon grades is available on request under Secrecy Agreement.
10. PRD and Article numbers 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30034967 _ Kollidon 25 57254799 25 kg Cardboard boxes 50348143 0.5 kg Plastic pail 30697299 Kollidon 25 50574244 50 kg Plastic drums 50574245 0.5 kg Plastic pail 30034974 Kollidon 30 Origin Germany 57254693 25 kg Cardboard boxes 50347950 0.5 kg Plastic pail 30525451 Kollidon 30 Origin Germany 50022331 50 kg Plastic drums 50347978 0.5 kg Plastic pail 30403404 Kollidon 30 Origin USA 55238758 1 kg PE-Bottle 55087337 50 kg PE-Drum, removable head 30660388 Kollidon 30 Origin China 50486018 50 kg Plastic drums 50498559 0.5 kg Plastic pail 30255812 Kollidon 30 LP 50347979 0.5 kg Plastic pail 50796353 25 kg Cardboard boxes 30034978 Kollidon 90 F 50347976 0.5 kg Plastic pail 51031936 25 kg Cardboard boxes BASFs commercial product number. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information = Registered trademark of BASF in many countries.
1. Introduction Historical aspects of polyvinylpyrrolidone The modern acetylene chemistry was developed at BASF by Reppe in the 1930s. One of the many products that emerged from this work are the soluble polyvinyl- pyrrolidone grades, obtained by radical polymerization of the monomer unit N-vinyl- pyrrolidone. Separate Technical Information Sheets are available for the Povidones with the mediurr and high molecular weights, for the insoluble Kollidon grades (Crospovidone) and fo Kollidon VA 64, the copolymer consisting of N-vinylpyrrolidone and vinyl acetate (Copovidone). More information on Kollidon grades may be found in the book, Kollidon, Poly- vinylpyrrolidone for the Pharmaceutical Industry. 2. Technical properties Description The low molecular weight Povidones grades Kollidon 12, Kollidon 12 PF and Kollidon 17 PF are polymerized and finally spray dried polymer powders. They come as white powders with faint, characteristic odor. Trivial names Soluble polyvinylpyrrolidone is also known as povidon(e), povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone) and PVP. CAS number 9003-39-8
Molecular weights In general, the average molecular weight of polymers can be expressed in three different ways, either as weight average molecular weight (M,,), as number average molecular weight (Mn) or as viscosity average molecular weight (M.). The molecular weight of povidones is usually expressed as K-value, from which it is possible to calculate the viscosity average molecular weight (M.). However, the weight average molecular weight (M,,) is found more frequently in the literature. It is determined by methods such as size exclusion chromatographie (SEC) using light scattering detection, a method to determine an absolute molecular weight without the need to apply a reference material. For different grades of Kollidon the following M,, values were determined in as shown in table 1: M,, [AMU] Kollidon 12 2000 3000 Kollidon 12 PF 2000 3000 Kollidon 17 PF 7000 11000 Tablet Solubility The solubility of Kollidon varies considerably from one solvent to another. In Table 2 below, soluble signifies that a solution of at least 10% can be prepared, and insoluble signifies that the solubility is less than 1%. Soluble in: chloroform n-butanol cyclohexanol n-propanol ethanol abs. polyethylene glycol 300 glycerine polyethylene glycol 400 isopropanol propylene glycol methanol triethanolamine methylene chloride water Insoluble in: cyclohexane pentane diethyl ether carbon tetrachloride ethyl acetate toluene liquid paraffin xylene Table 2: Solubility of low molecular weight Kollidon grades Grades (12, 12 PF and 17 PF) Glass transition temperature Tg Product Tg [C] Kollidon 12 102 Kollidon 12 PF 102 Kollidon 17 PF 138
Particle size The particle size distributions of the spray dried polymers can be described with the following ranges (to be considered as characteristic values only): Product d(0.1), um = (0.5), um_s (0.9), um =~Ss;D[4.3], pm Kollidon 12 PF 10 +/-3 35 +/- 5 80 +/- 10 42 +/-5 Kollidon 17 PF 10 +/-3 33 +/- 5 75 +/- 10 38 +/- 5 Table 4 The determination was performed with a Malvern Mastersizer 2000. The air pressure was set to 1 bar. Bulk density Bulk density of Kollidon is determined according to Ph. Eur. current edition method 2.9.34. Product Bulk density Kollidon 12 400 - 600 g/L Kollidon 12 PF 400 - 600 g/L Kollidon 17 PF 400 600 g/L Table 5: Bulk density of the Kollidon grades Particle size distribution and bulk density are considered characteristic values. The are not part of the product specification. Endotoxin testing Kollidon 12 PF and Kollidon 17 PF are intended for the use in parenteral pharma- ceutical formulations and thus tested for bacterial endotoxins.
Viscosity Fig. 1 shows the relationship between the viscosity of aqueous solutions of the different grades of Kollidon and their concentration. Fig. 1: Viscosity of Kollidon solutions (Ubbelohde viscometer, 25 C) Hygroscopicity The hygroscopic nature of Kollidon is important in many applications. There is hardly any difference between the individual grades so that the same curve applies to all Povidone grades (Fig. 2). Fig. 2: Hygroscopicity of soluble Kollidon
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application Kollidon 12 PF, 17 PF Solubilizing agents, dispersants and crystallization inhibitors in solutions or lyophilisates for injection. The low-molecular grades, Kollidon 12 PF and Kollidon 17 PF are intended for use as solubilizing agents, dispersants and crystallization inhibitors particularly for injectables. These properties are of particular interest for antibiotics in solution or in lyophilized powder form. Stabilizers for parenteral suspensions The low-molecular weight endotoxin tested grades of Kollidon can be used to stabilize parenteral suspensions. This applies in particular for formulations of antibiotics. Kollidon 12 Solubilisation of APIs in soft-gels Oe gf Furthermore, liquid formulations for soft gel capsules contain the low-molecular weight grade Kollidon 12 as solubilizer. Like in other formulations for oral application, a grade tested for endotoxins is not required. 5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage condition: Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technical representative. 8. Regulatory status Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data Toxicological and biochemical studies have been carried out with the individual Kollidon grades. Abridged reports summarizing the toxicological results are available on request. The original reports can be provided when secrecy agreements are in place.
10. PRD and Article numbers 10. PRD and Article numbers Packaging PRD-No. Product name Article numbers 30553394 Kollidon 12 50269252 100 kg PE drum with PE-inliner 30034972 ~~ Kollidon 12 PF 50444166 50 kg PE drum with EVOH-inliner 30034981 Kollidon 17 PF 50029276 50 kg PE drum with EVOH-inliner BASFs commercial product number. 11. Publications http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.

Table of contents Introduction Polyethylene glycol portfolio 5 Typical chemical and physical properties 6 Applications 8 Tablets, liquids, and suspensions 9 Softgels 10 Ensuring softgel performance with low aldehyde Kollisolv? PEGs 13 Topicals 20 Hydrophilic ointment formulation 20 Emulgel formulation 21 Suppository formulation 22 Product details and key benefits 24 Product and sample article numbers 25 ZoomLab, RegXcellence, & MyProductWorld 26 Introduction Polyethylene glycol portfolio
Polyethylene glycol portfolio Kollisolv PEGs are colorless, almost odorless, and tasteless liquids or white solids at room temperature. These products are manufactured by alkali-catalyzed polymerization of ethylene oxide with subsequent neutralization of the catalyst. The number in the name of the product indicates its average molecular weight. Chemical name CAS number Our portfolio of Kollisolv PEGs offers assurance of high-quality production in cGMP manufacturing conditions that meet the compendial requirements of USP-NF and Ph. Eur. At low molecular weights, our Kollisolv? PEGs are present as colorless liquids, and at higher molecular weights these products exist as white semi-solids and solids.
Unlike standard grade PEGs with a total aldehyde content of 50 ppm, our low aldehyde Kollisolv PEGs are restricted to an aldehyde content maximum of 10 ppm and offer assurance of control. With a restricted total aldehyde content to a maximum of 10 ppm, these excipients are especially suited for sensitive APIs and applications, including softgel shells and fills. Colorless, almost odorless, and tasteless liquid at room temperature Average molecular weight (g/mol) 285 to 315 380 to 420 380 to 420 570 to 630 570 to 630 Melting point (C) -15 to -8 4to8 4to8 15 to 25 15 to 25 Hydroxyl value (ng KOH/g) 340 to 394 264 to 300 264 to 300 178 to 197 178 to 197 Viscosity at 25 C (mPa:s) 80 to 105 105 to 130 105 to 130 Solid Solid Viscosity at 99 C (mm?/s) 5.4 to 6.4 6.8 to 8.0 6.8 to 8.0 9.9 to 11.3 9.9 to 11.3 fery soluble in water and alcohol, practically insoluble in oils and fa
Tablets, liquids, and suspensions Kollisolv PEGs can be used in tablet applications as a component of the core or coating. They can also serve as lubricants in the processing of a tablet. In tablet core applications, solic Kollisolv PEGs can be used as a binder or additive. Solid and semi-solid Kollisolv? PEGs can be used in coating applications as a plasticizer and film former. Polyethylene glycols, or macrogols, are mainly used as solubilizers, surfactants, and solvents. As multifunctional ingredients, these excipients play an essential role in various oral and topical formulations. Low-molecular-weight liquid polyethylene glycols are excellent solvents for numerous substances that do not readily dissolve in water. They are widely used as solvents and solubilizing agents for active substances and excipients in liquid and semi-solid preparations. They can also be used as plasticizers in tablets, capsule shells, and film coatings.
Softgels Figure 1. Solubility of Kollidon VA 64 in Kollisolv PEG 300, 400, and 600 at room temperature. BASF offers a range of liquid Kollisolv? PEGs and other complementary products for softgel applications. From solubility enhancement to crystallization inhibition, these products make for easier softgel formulation with greater predictability and reliability. BASF solubilizers such as Kolliphor RH 40 (Ph. Eur.: macrogolglycerol hydroxystearate; USP-NF: polyoxyl 40 hydrogenated castor oil), Kolliphor EL (Ph. Eur.: macrogolglycerol ricinoleate, USP-NF: polyoxyl 35 castor oil), or Kolliphor HS 15 (Ph. Eur.: macrogol 15 hydroxystearate; USP-NF: polyoxyl 15 hydroxystearate) can be used in combination with liquid Kollisolv PEGs to increase the solubilization capacity, allowing for the enhanced dissolution of challenging APIs. Crystallization inhibitors such as Kollidon VA 64 (Ph. Eur., USP-NF: copovidone), Kollidon 30 (Ph. Eur., USP-NF: povidone), and Kollidon 12 PF (Ph. Eur., USP-NF: povidone) can be used with liquid Kollisolv PEGs to prevent drug recrystallization. These crystallization inhibitors form homogenous blends at common processing and filling temperatures, and provide an additional benefit of increasing fill viscosity. This increased fill viscosity allows for more consistent filling and lower weight variance between softgels capsules. Blends of Kollisolv PEGs with Kollidon crystallization inhibitors are stable at room temperature up to 40% concentration by weight. Figure 2. Solubility of Kollidon 30 in Kollisolv PEG 300, 400, and 600 at room temperature. Figure 3. Solubility of Kollidon 12 PF in Kollisolv PEG 300, 400, and 600 at room temperature.
Advancements in increased temperature control for softgel encapsulation machines provide opportunities to use fills with greater crystallization inhibitor concentration. Use of common processing temperatures of 40 or 60 C leads to as much as 80% reduction in fill viscosity. This gives significant advantages by increasing processing speed with lower flow resistance of fills and increasing softgel shelf stability with greater crystallization inhibitor content when using liquid Kollisolv? PEGs with Kollidon crystallization inhibitors. Softgels are oral formulations that are composed of a pharmaceutical grade shell which encapsulates the liquid fill. Shell-fill compatibility requires the strategic selection of excipients to minimize degradation byproducts known to be harmful for softgel stability. To ensure capsu integrity and dissolution reproducibility, the fill must be compatible with the shell, and neither prematurely rupture the shell nor restrict release of the active post-delivery. Aldehydes are a common concern in softgels, especially soft gelatin capsules, where chemical crosslinking of the gelatin peptide backbone will cause insoluble films or pellicles that disrupt dissolution testing. The consequence of crosslinking is often an altered dissolution behavior of the capsule, one that will fail dissolution testing in vitro. While this crosslinking does not always translate to failure in vivo, where enzymes can cleave the peptide backbone, the USP <711> recommends a two-tiered dissolution investigation when in vitro dissolution failure arises from crosslinking. The complicated testing protocol includes pH-dependent enzyme selection and, as elaborated in USP <1094>, additional testing on the compatibility of any surfactants includec in the medium. These additional tests require cumbersome method development and validation, lengthening the time and complexity of going to market. Figure 4. Viscosity vs. concentration of Kollidon VA 64 in Kollisolv PEG 300 at 25, 40 and 60 C.
To study the effect of degradation byproducts, particularly aldehydes, on softgel performance, five lots of polyethylene glycol 400 (PEG 400) of varying grades and storage conditions were selected for testing (Table 1). Two fresh lots of Kollisolv? PEG 400 LA were evaluated, as well as one Kollisolv PEG 400 LA at the 2-year retest. A compendial grade of PEG 400 that met Ph. Eur. and USP monographs was included, as well as a standard, non-pharmacopoeia PEG 400. The standard grade PEG 400 was a forced-aged compendial PEG 400 sample, stressed through aging at 60 C for 9 days and 80 C for 7 days. The starting aldehyde levels for each sample was determined by an in-house R&D method (Figure 7). Kollisolv PEG 400 LA had the lowest aldehyde concentration, under 10 ppm, with nc difference between fresh and at 2-year retest. The compendial PEG 400 sample had an aldehyde concentration almost two-fold higher than Kollisolv PEG 400 LA. Standard PEG 400 was nearl six-fold higher. Figure 7. Starting aldehyde levels for each grade of PEG 400. Table 1. PEG 400 samples for softgel formulations. Sample # Material Age to retest Grade 1 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 2 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 3 Kollisolv PEG 400 LA At 2-year retest Low aldehyde (Ph. Eur., USP) 4 Compendial PEG 400 Compendial (Ph. Eur., USP) 5 PEG 400 Standard Samples 1 and 2 represented two different freshly opened lots.
Brilliant Blue, serving as a model active pharmaceutical ingredient (API), was formulated at eque parts in the five PEG 400 samples. After the formulations were filled into softgel capsules using lab-scale filling equipment, the capsules were then stored at ambient (25 C, 60% RH) and accelerated (40 C, 75% RH) conditions for a 12-month period. In vitro dissolution of the softgel capsules was performed to evaluate the effect of aldehyde content on dissolution. The dissolution time to release 80% of the loaded Brilliant Blue was captured for each sample (Fig. 9). Softgels containing Kollisolv PEG 400 LA demonstrated an equivalent dissolution time over the full 12 months under ambient conditions; while even the compendial grade PEG 400 containing softgels exhibited delayed dissolution within 6 months. When stored at ambient conditions, the softgel capsules composed of Kollisolv? PEG 400 LA demonstrated superior stability over compendial and standard PEG 400 (Fig. 8). Over the course of 12 months, the softgels filled with fresh and 2-year Kollisolv? PEG 400 LA showed a stable release profile with no evidence of crosslinking or change in dissolution. The equivalence of performance with product age, fresh and at two years, demonstrates the stability of Kollisolv PEG 400 LA and reliability of performance. Figure 9. Dissolution time (until 80% release) of softgels stored at ambient (25 C, 60% RH) conditions taken as the time in minutes. In contrast, the softgel consisting of compendial PEG 400 increasingly delayed dissolution, with significant changes in dissolution evident by month 6. To an exaggerated degree, the softgel containing standard PEG 400 showed retarded dissolution and evidence of near-immediate crosslinking within the first month. Figure 8. Dissolution of softgels stored at ambient (25 C, 60% RH) conditions over a 12-month period. In accordance with USP<711>, formulations made with the compendial PEG 400 would require proof of gelatin crosslinking via spectroscopic methods and complicated dissolution tests. Comparatively, formulations that consisted of Kollisolv? PEG 400 LA would not require further investigation regarding crosslinking or dissolution. Even under stressed aging in accelerated storage conditions, softgels consisting of Kollisolv PEG 400 LA within the full 2-year retest period exhibited equivalent performance, demonstrating stability of the product within its shelf-life. Under accelerated storage, dissolution of capsules of fresh and retest-aged Kollisolv PEG 400 LA remained equivalent through 3 months (Fig. 10). In contrast, compendial PEG 400 mirrored the failure of standard, non- pharmacopoeia PEG 400, and both products showed immediately delayed dissolution within the first month, failing due to crosslinking of soft gelatin capsules. In this case, even meeting Ph. Eur. and USP standards for a pharmaceutical excipient did not impart stability over a non- pharmaceutical grade of PEG 400.
Figure 10. Dissolution of softgels stored at accelerated (40 C, 75% RH) conditions over a 6-month period. Under accelerated conditions, Kollisolv? PEG 400 LA offered improved stability of the dissolutior profile. Regardless of age, the three Kollisolv? PEG LA samples demonstrated an equivalent dissolution time over 3 months, suggesting stability studies under these conditions is feasible through 3 months (Fig. 11). In contrast, both compendial and standard, non-pharmacopoeia grades of PEG 400 exhibited delayed dissolution immediately, failing accelerated stability studies under these conditions. Aldehyde content within the softgels was determined at time points within both storage conditions. As softgel fills, Kollisolv? PEG 400 LA samples demonstrated minimal changes in the aldehyde content over a 2-year retest period. Evaluation of the aldehyde content showed that storage condition did not significantly impact the total aldehyde amount present in the softgel fill. Ultimately, Kollisolv PEG 400 LA did not develop aldehyde content over time when formulated in softgels, whether fresh or at retest, under ambient or accelerated storage (Fig. 12). Figure 12. Aldehyde development of Kollisolv PEG 400 LA in softgels, over 12 months at under ambien and accelerated storage. Figure 11. Dissolution time (until 80% release) of softgels stored at ambient (40 C, 75% RH) conditions taken as the time in minutes. In summary, Kollisolv? PEG 400 LA outperformed compendial PEG 400. The dissolution profiles from softgels at both ambient and accelerated storage conditions reflected a pre dilection towards Kollisolv PEG 400 LA, with stable release seen for longer than from compendial PEG 400. When using Kollisolv PEG 400 LA as the softgel fill, aldehydes did not develop over time at either ambient or accelerated storage conditions. Rather, the source and quality of the products had the greatest effect on the aldehyde levels. Fresh and at-retest Kollisolv PEG 400 LA samples offered a 50% reduction in starting average aldehyde content in comparison to compendial grade PEG 400. The repeatable and stable dissolution profiles seen for Kollisolv PEG 400 LA bring the advantages of rapid development and ease of qualification.
Topicals Emulgel formulation When used for topical applications, solid and liquid Kollisolv PEGs be combined to form water-soluble bases for ointments, suppositor and ovula. Low-molecular-weight Kollisolv? PEGs can be used as solvents, conditioners, adhesion promoters, and humectants. These products, like Kollisolv PEG 300, Kollisolv PEG 400, and Kollisolv PEG 1000, promote ease of application, softening on contact with skin, and localization of active delivery. High-molecular-weight Kollisolv PEGs can be used as structuring agents and thickeners to increase the viscosity of formulations. These include Kollisolv PEG 1450, Kollisolv PEG 3350, and Kollisolv PEG 8000. Hydrophilic ointment formulation Kollisolv PEG ointments can be used as an alternative to traditional petrolatum-based ointmen formulations. By pairing different amounts of high- and low-molecular-weight chains, PEG ointments can be tuned for desirable rheological profiles and sensory. Procedure 1. Prepare phase A by weighing ingredients into an appropriately sized beaker. 2. Heat the mixture to 60 C and continue heating until the mixture has completely melted. Try to minimize the heating time as much as possible. 3. Once all the components have melted, place phase A underneath an overhead mixer. Stir at a low shear rate until cooled to room temperature. Kollisolv PEG 3350 is commercially available only in the USA and Canada as an excipient.
Suppositories allow formulators to accurately deliver active ingredients through an alternative route. Kollisolv PEG suppositories are ideal for the formulation of suppository matrices, offering a melting temperature range within physiologically relevant conditions and compatibility with hydrophilic druas.
Product details and key benefits Product details Regulatory Manufacturing site Manufacturing process Re-test period Certified Handling Safety data sheet Retest date and storage conditions Specification Regulatory status Key benefits Supply reliability & consistent quality Sustainability Technical service BASF Virtual Pharma Assistants Kollisolv? PEGs USP-NF, Ph. Eur. Geismar, Louisiana (USA) Synthetic 24 months Kosher, Halal Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRPI). For current specification, please speak to your local BASF sales or technical representative. Please refer to Quality & Regulatory Product Information (QRPI). Kollisolv PEGs are manufactured in a GMP compliant facility in the U.S. ensuring: Consistent quality and safety @ Reliable, vertically integrated supply BASF is a proud member of the Pharmaceutical Supply Chain Initiative (PSCl), whose vision is to establish and promote responsible practices that will continuously improve human rights, health, safety, and environ- mentally sustainable outcomes for supply chains worldwide. @ World class expertise in excipient chemistry Formulation guidance with ZoomLab @ Regulatory documentation available in RegXcellence Product details available via MyProductWorld @ Full pharma regulatory documentation and submission support Product details and key benefits

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Technical Information Linear alcohols and esters, medium-chain triglycerides: Emollients for topical applications. February 2019 Supersedes issue dated June 2013 Last change WF-No. 137282 = Registered trademark of BASF in many countries.
1. Introduction While the products cover a wide range of application fields, e.g. oral dosage forms for lipophilic APIs, this technical information sheet is designed to provide an overview on our pharmaceutical-grade emollients for topical pharmaceutical applications. With the inherently low potential for irritation, our petrolatum-free emollients are designed to create mild formulations that are easy to apply even onto large areas, and leave a pleasant feeling on the skin. The products are based on vegetable resources, and manufactured under IPEC-PQG GMP conditions. Trade name Compendial name Highlights for use as an Emollient ollicream 3 C Ph.Eur.: Cocoyl Solubilizer/penetration enhancer Caprylocaprate for some topical APIs ollicream CP 15 Ph.Eur.: Cetyl Palmitate 15 Replacement for spermaceti (from whales); relatively high melting point makes it a viscosity building agent in semi-solid creams, lotions and oils. ollicream DO Ph.Eur.: Decyl Oleate Enhancing skin-penetration of some APIs by disordering stratum corneum lipid domains with its branched C,, chain. ollicream IPM Ph.Eur.: Isopropyl Myristate Skin penetration enhancer for USP/NF: Isopropyl Myristate lipophilic actives. ollicream OA U h.Eur.: Oleyl Alcohol SP/NF: Oleyl Alcohol Cc. Enhancing skin-penetration of some APIs by disordering stratum corneum lipid domains with its branched C,, chain. ollicream OD U h.Eur.: Octyldodecanol ISP/NF: Octyldodecanol Cc Medium spreading, non-ester emollient, therefore inherently stable towards hydrolysis. Rapid plasticizer for com- promised skin. ollisolv? MCT 70 U h.Eur.: Triglycerides, Medium-Chain USP/NF: Medium-Chain Triglycerides Versatile solubilizer for lipophilic drugs, skin protectant through moisture retention. 2. Technical properties Description Kollicream grades are either comprised of esters of fatty acids (8 C, CP 15, DO, IPM), or of natural (OA), as well as naturally derived (OD) long-chain alcohols. Except for CP 15, which is provided in the form of waxy pellets, all other members of the Kollicream family, as well as Kollisolv@ MCT 70, are transparent, colorless liquids at room tempreature. The raw material base is coconut oil, and/or palm kernel oil.
Fatty Acid Fatty Alcohol Molar Weight of Ester [g/mol] ee ee 208 ae 478 478 450 450 450 422 422 304 Kolliwax CP 15 Kollicream 3 C Stearyl (C,,) 422 Cetyl (C,,) 394 Cetyl (C,,) 366 Kollicream 3 C ire 1; Overview on all esters contributing to the products Kollicream CP 15 (top) an Kollicream 3 C (bottom), ordered by molecular weight. The former name is deriv from Cetyl Palmitate, the ester of palmitic acid and cetyl alcohol, which was historic made from Spermaceti, a waxy substance found in the head cavity of sperm wh However, Kollicream CP 15 is, as all our emollients, derived entirely from vegete resources. The name Cocoyl Caprylocaprate (Kollicream 3 C) arises from coconut alcohol, mixture of lauryl (C,,), and myristyl (C,,) alcohol, as well as caprylic (C,) and capric (( acid, which are among the most prevalent fatty acids in the triglycerides of cocoi oll.
Brookfield Viscosities The following graph summarizing the product viscositites is for guidance only: please refer to the individual specification sheets for detailed viscosity information. Brookfield viscosities were measured in a temperature-controlled glass vial of approx. 35 mm inner diameter at 100 rpm using a DV8T device with LV-73 spindle. Figure 2: Brookfield Viscosities (values given in cP), measured at three different temperatures. Due to the relatively high melting point, Kollicream CP 15 could not be measured at the first two temperatures. Spreading The spreading is defined as the surface area (in mm,) of human skin of a test panelist, covered by 4 mg of emollient within 10 min in a room conditioned to 23 C and 60% rel. humidity. Typically, four separate measurements are done with each panelist, whereby a reference oil with known spreading behavior is used Picture 1. In addition to this in vivo method, spreading can also be measured in vitro. Picture 1: Test design to determine spreading of an emollient on human skin.
Emollient Spreading value Emollience [mm] Kollicream 3 C 800 Medium Kollicream CP 15 n/a Rich Kollicream DO 700 Medium Kollicream IPM 1200 Light Kollicream OA 700 Medium Kollicream OD 600 Medium Kollisolv? MCT 70 550 Medium The spreading value of an emollient has an important impact on the skin-feel of the resulting emulsion. Using a high amount of fast spreading emollients in your formulation will result in a smooth feeling on the skin perceived immediately upon application, but disappearing fast. In contrast, slow spreading emollients entail a rather subtle, but long-lasting smoothness. Combining emollients with different spreading behavior allows to tailor formulations towards the desired time profile of smooth skin feel Picture 2. Picture 2: Time profiles of emollients with different spreading behavior. Water Permeability The permeability/occlusivity of a film applied to the skin describes the ability to allow or prevent the passage of water, whereby a highly occlusive material (e.g. petrolatum) retains moisture by creating a barrier that prevents water from evaporating off the skin. Occlusivity is an important consideration for pharmaceutical formulations and the selection of emollients influences the permeability of an emulsion after spreading on the skin. Low permeability films can lead to hydration of the skin, increasing the flexibility of the stratum corneum. Trade name Water permeability Kollicream 3 C medium Kollicream CP 15 low Kollicream DO medium to low Kollicream IPM high Kollicream OA medium Kollicream OD medium Kollisolv@ MCT 70 medium
Solubility Parameters Using Formulating for Efficacy Software (Adaptive Cosmetic Technology Solutions Corp.), Hansen Solubility Parameters (HSP) were computed for the Kollicream products, as well as for light mineral oil. With this set of three parameters, the three major forces that influence the behavior of solute in solvent are considered: polarity (6P), degree of hydrogen bonding (8H), as well as dispersive forces (6D). Solutes and solvents can be mapped in the three-dimensional space that is given by the three parameters. When the HSP of a solute is close to that of a solvent, it is very likely that the solute sanll ARaAviAR A AIA wal dhAilifty In tan anhsant (Cin 9\ Figure 3: Hansen Parameters of some oils shown as a 3D plot.
3. Application Skin Tolerance/Mildness Clinical patch test studies on chronic contact dermatitis sufferers demonstrated that Kollicream 3 C, OD, IPM and CP 15 are very mild. Patch testing is considered to be the standard methodology for evaluating contact dermatitis. A list of standard allergens (70 substances) has been generated and recommended for standard diagnostic testing by the North American Contact Dermatitis Society. Dr. Joseph Fowler, and his team at Forefront Dermatology have been completing patch testing for over 15 years. Test subjects were patients wh have presented with chronic dermatitis with an undetermined cause these were highly sensitive patients. Finn Chambers were used to apply test substances to the backs of patients, per a globally standardized protocol. BASF Kollicream product: were applied at 35% in petrolatum. Patches were removed, and sites evaluated anc scored after 48 72 hours. Study was concluded after 500 patients were treated The following table lists the tested Kollicream grades and the number of patient: that showed no reaction at all to the application. Test material (at 35%) Kollicream 3 C Kollicream IPM Kollicream OD Kollicream CP 15 # of patients (out of 500) with no reaction 500 500 500 500 Effects on API Penetration Through Skin Studies on sodium ibuprofen in 96-well PAMPA system Studies were conducted to determine the effect of the Kollicream products and Kollisolv? MCT 70 on the permeation of Sodium Ibuprofen through a synthetic skin model membrane (Parallel Artificial Membrane Permeation Assay) in a 96 well format (in collaboration with Pion Inc., Billerica, MA, USA). Simple emulsions were prepared with the following composition: 45% w/w% water, 40 w/w% PEG 400 (Kollisolv? PEG 400), 2% Polysorbate 60 (Kolliphor PS 60), 5 w/w% Na-lbuprofen, and 8 w/w% of one of following; Kollicream 3 C, Kollicream OD, Kollicream DO, Kollicream IPM, Kollicream OA or Kollisolv? MCT 70. (The control or blank in this study was the same composition but without any lipophile. Water content was increased to 53 w/w% to compensate.) Figure 4: Cutout of the PAMPA setup for the measurement of AP! penetration through mode membranes. The setup allows 96 parallel measurements. The synthetic skin model membrane was sandwiched between an upper plate and a lower receiver plate. The lower wells were filled with phosphate buffered saline. The test emulsions were applied in the upper wells (6 12 replicates per sample). Both the test emulsions and the receptor solutions were stirred with small magnetic stirrers throughout the test period. The entire set-up was incubated at 37 C for one hour and then the lower plate was removed and sodium ibuprofen concentration (uM) was measured in each well by means of a 96-well UV/VIS spectrophotometer.
The results of the emollient screening indicate that not all lipophilic fluids tested behave in the same way. While Kollicream 3 C and OA, as well as Kollisolv? MCT 70 expressed the greatest impact on sodium ibuprofen permeation through the model membrane during the one-hour incubation period, emulsions with Kollicream IPM, DO, as well as OD were not significantly different from the control experiment. Test substance [Na IBU] (uM) Standard % increase in in receptor Deviation permeation vs (+/-) control Kollicream OD 3602 785 0.3 Kollicream DO 3890 810 8.4 Kollicream IPM 4042 437 12.6 Kollicream OA 4238 280 18.1 Kollisolv? MCT 70 4531 657 26.2 Kollicream 3 C 4700 369 30.0 Control/Blank 3589 280 om Studies of Clotrimazole permeation through Strat-M membrane Studies with 1% Clotrimazole creams were conducted to investigate the effect of different oil phase compositions on the skin permeation of the Clotrimazole. Creams were prepared as in the following table: Ingredient Description Dosage [wt.-%] Kollisolv PG Propylene glycol 8.0 Kolliwax CSA 50 Cetostearyl alcohol 7.0 Variable Lipophilic fluid (oil) 12.0 Kolliphor CS 20 Polyoxyl 20 cetostearyl ether 3.0 Active Ingredient Clotrimazole 1.0 Water -- 68.9 Euxyl 320 Phenoxyethanol 0.1 The lipophilic fluids (oils) subject to test were Kollicreams 3 C, OD, IPM and mineral oil. Clotrimazole permeation through a skin model membrane (Strat-M) was measured using Franz Cells: for each test, the cream was applied to the top surface of the membrane, in the donor compartment, at an infinite dose (= 200 uL). Samples were collected from the receptor phase at 0.5, 1, 2, 4, 6 and 8 hours, and analyzed for Clotrimazole concentration. The flux profile for each formulation is illustrated in the following chart. igure 5: Time profiles of Clotrimazole permeation through a model membrane for different emollients: IPM = Kollicream IPM, MO = Mineral Oil, 3 C = Kollicream 3 C, OD = Kollicream OD.
Note that the different lipophiles had differing influences on Clotrimazole flux rates. In this study the Kollicream IPM-containing cream had the highest flux rate while the Kollicream 3 C-containing cream had the lowest. The mineral oil and Kollicream OD- containing creams had very similar flux rates. Clotrimazole is typically intended to prevent or treat fungal/yeast infections on mucosal membranes, so inhibition of permeation is desirable. In this case the Kollicream 3 C-containing cream had the most desirable performance. Example Formulations The following cream formulations can all be prepared by the same basic procedure: THIS TOWOWITTY Cea lh PONMTUIAUOTIS Call all US PIeValoU VY WIE SGI Udol& VIUCCUUIe. 1. Blend all ingredients in phase A together and heat to 80 C under stirring, until the blend is a clear liquid. 2. Blend all of the ingredients in phase B and heat to 80 C under stirring, until homo: geneous. 3. While strirring phase B vigorously (e.g. by means of a propeller mixer at 500 rpm), pour phase A into phase B and mix until a homogeneous emulsion forms (generally within a few minutes). 4. Transfer the mixture to a high-shear rotor-stator homogenizer and homogenize at approx. 5000 rpm for about ten minutes, making sure that the entire batch is homogenized. 5. Return the mixture to a propeller mixer and stir at 200 rpm whitout heating. After the mixtures has cooled to 45 C, add the preservative. Continue mixing, until homogeneous. 6. Remove from mixer and fill to appropriate packaging, after the cream has cooled to 30 C or below. 1. Cream Formulation with Kolliphor PS 80 This composition yields a medium viscosity cream with a high loading (20 w/w%) of Kollicream 3 C, emulsified by Kolliphor PS 80. The high oil content will allow for solubilization of lipophilic APIs, smooth and pleasing sensory properties, and the benefits of a moisture barrier after application. Phase Ingredient Name Amount [%] A Kollicream 3 C Cocoyl caprylocaprate 20 Kolliphor PS 80 Polysorbate 80 Kolliwax GMS II Glycerol monostearate 40-55 (type Il) Kolliwax CSA 70 Cetostearyl alcohol 5 B Deionized water 68 Preservative Euxyl PE 9010
2. Rich Cream based on Kollisolv MCT 70 and Kollicream IPM This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as consistency factor and emulsifier, respectively, to create a very stiff cream that offers a rich and cushioned feeling when rubbed into the skin. Kollicream IPM is a fast spreading oil for topical semi-solid formulations and a penetration enhancer for some APIs. Phase Ingredient Name Amount [%] A Kolliwax CSA 70 Cetostearyl alcohol 7.0 Kolliwax GMS II Glycerol monostearate 40-55 2.5 (type Il) Kolliphor PS 60 Polysorbate 60 4.2 Kollisolv@ MCT 70 Medium chain triglycerides 11.5 Kollicream IPM Isopropyl myristate 1.3 B Deionized water 69.2 Glycerol 33 Cc Euxyl PE 9010 Phenoxyethanol 1.0 3. Cream based on Kollisolv? MCT 70 Kollisolv? MCT 70 can be a good solvent and carrier for lipophilic APIs, but exhibits rather slow spreading behavior due to its relatively high viscosity. Kollicream IPM was added to reduce the overall viscosity of the oil phase and increase spreading after application. Phase Ingredient Name Amount [%] A Kolliwax CSA 70 Cetostearyl alcohol 7.0 Kolliwax GMS II Glycerol monostearate 40-55 2.5 (type Il) Kolliphor PS 60 Polysorbate 60 4.2 Kollisolv@ MCT 70 Medium chain triglycerides 11.5 Kollicream IPM Isopropyl myristate 1.3 B Deionized water 69.2 Glycerol 3:3 Cc Euxyl PE 9010 Phenoxyethanol 1.0 4. Cream with Kollicream OD and Kolliphor CS 20 Kollicream OD is widely used in creams and lotions and can easily penetrate the skin and aid in the permeation of APIs, while remaining mild and non-irritating. It can also serve as a solvent for lipophilic APIs. It is emulsified by Kolliphor CS 20, an unbranched linear alkyl PEG ether. Both are stable in a wide range of pH values. Creams prepared with Kollicream OD and Kolliphor CS 20 yield a medium viscosity, non-greasy formulation. Phase Ingredient Name Amount [%] A Kollicream OD Octyldodecanol 12.0 Kolliphor CS 20 Polyoxyl-20 cetosteary! ether 3.1 Kolliwax S Stearic acid 0.1 Kolliwax CSA 50 Cetostearyl alcohol 7.5 Kolliwax GMS II Glycerol monostearate 40-55 0.5 (type Il) B Deionized water 15.8 Cc Euxyl PE 9010 1.0
5. Gel Formulation: Emulgel At concentrations above 15%, Poloxamers 188 and 407 can be used to make gel and viscous emulsions by both emulsifying and forming phases and networks via the hydrophobic and hydrophilic interactions driven by PPO and PEO segments of the polymer, respectively. Kolliphor P 407 helps emulsify the Kollicream 3 C in this formulation, resulting in a translucent white gel with a cream-like structure visible underneath the microscope. Both Kolliphor P 407 and Kollicream 3 C have been shown to be very mild, in vitro and in vivo. Phase Ingredient Name Amount [%] A Ethanol 200 Proof 10 Kollisolv@ PEG 400 Polyethylene glycol 400 15 Glycerol 5 B Kolliphor P 407 Poloxamer 407 18 Deionized Water 42 Cc Kollicream 3 C Cocoyl caprylocaprate 10 FLCy 1. Keep mix of components listed under B refrigerated at 5 C for 24 h, or until all Kolliphor P 407 is dissolved. 2. Mix all C and A ingredients to phase A, stir slowly until Kolliphor has gelled. GUO! (WUIU PIUeGoso)s, Preparation (Hot Process): Preparation (Hot Process): 1. Prepare phase B by adding Kolliohor to water preheated to 70 C. Stir this mixture for at least 1h to ensure proper dissolution of the poloxamer. 2. As solution B is cooling down to room temperature, add component mixtures A and C while stirring until a robust gel is formed. 6. Model Foam Formulation: General Aerosol Foams Growing in popularity, topical foams can sometimes be preferred over a cream due to their pleasing sensory application. The four foam formulations below retain their shape upon application onto the skin, spreading easily and drying quickly. Foams made with Kolliphor CS 12 tend to demonstrate a higher viscosity and stiffness than foams formulated with Kolliphor CS 20. Additionally, poloxamers such as Kolliphor P 188 or Kolliphor P 407 can be added to formulations as needed to create richer, creamier foams. This richness is aided by the use of an aerosol. Picture 3: Macrostructures of aerosol foams.
Figure 6: Viscosity profiles of aerosol foams. Phase Ingredient Name Amounts [%] A B Cc OD Kolliwax CSA 50 Cetostearyl alcohol 3 3 3 3 Kolliphor CS 12 Macrogol cetostearyl ether 12 0 0 6 5 Kolliphor CS 20 Macrogol cetostearyl ether 20 5 6 0 0 Kollicream 3 C Cocoyl caprylocaprate 3 3 3 8 Kolliphor P 188 Poloxamer 188 1 0 0 1 Deionized Water 82 82 82 82 A46 Propane/Isobutane 6 6 6 6 Preparation 1. Mix formulation ingredients in a beaker, using slight heat if necessary to ensure uniform distribution of the components. 2. Place the mixture in an aerosol container, charge with desired propellant. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment. 5. Product Specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions.
7. PRD and Article numbers 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554439 ollicream 3 C 50268489 800 kg Composite IBC (31HA1) 50363006 175 kg Steel drum 50259481 0.5 kg Plastic bottle 30554443 ollicream CP 15 50253253 20 kg Plastic film bag 50259485 0.5 kg Plastic bottle 30554441 ollicream DO 50253252 175 kg Steel drum 50259484 0.5 kg Plastic bottle 30554463 ollicream IPM 50264409 850 kg Composite IBC (31HA1) 50253267 175 kg Steel drum 50259491 0.5 kg Plastic bottle 30554462 ollicream OA 50253265 175 kg Steel drum 50259490 0.5 kg Plastic bottle 30554460 ollicream OD 50253259 175 kg Steel drum 50259489 0.5 kg Plastic bottle 30554489 ollisolv? MCT 70 50253413 190 kg Steel drum 50259496 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html Disclaimer This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Fatty acids and alcohols: Consistency factors for topical formulations, and excipients for solid oral dosage forms. Oktober 2021 WF-No. 137189 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes fatty acids and alcohols that can be used as (co-) emulsifiers and consistency factors in topical pharmaceutical applications, but may also function as excipients in solid oral dosage forms, e.g., as matrix formers and lubricants. This document focuses on fatty acids and alcohols of the Kolliwax family. Please refer to the individual technical information sheet for specific information on our two glyceride based grades Kolliwax GMS II and Kolliwax HCO (Glycerol Monostearate, and Hydrogenated Castor Oil, respectively). Trade name Compendial Name Kolliwax CA Ph.Eur.: Cetyl Alcohol USP/NF: Cetyl Alcohol Kolliwax CSA 50 Ph.Eur.: Cetostearyl Alcohol USP/NF: Cetostearyl Alcohol JP: Cetostearyl Alcohol Kolliwax CSA 70 Ph.Eur.: Cetostearyl Alcohol Kolliwax MA USP/NF: Myristyl Alcohol Kolliwax SA Ph.Eur.: Stearyl Alcohol Kolliwax SA Fine USP/NF: Stearyl Alcohol JP: Stearyl Alcohol Kolliwax S Ph.Eur.: Stearic Acid 50 Kolliwax S Fine USP/NF: Stearic Acid 50 llPe Stearic Acid 50 Table 1: Compendial names for fatty alcohols and acids of the Kolliwax family. Description 2. Technical properties Kolliwax grades are white to slightly yellowish, waxy substances derived from natural ressources, namely coconut oil, palm kernel oil, and/or palm stearine. With melting points above room temperature, these products are either supplied as powder, pearls, or pelletts (see table1 and table 2 for details). The numeric part of the name of the two grades of Kolliwax CSA represents the approximate weight percentage of stearyl alcohol. es ene Trade name Chemical nature CAS-No. Melting ranges [cy Kolliwax CA Cetyl Alcohol (C,,) 36653-82-4 46-52 Koliwax CSA S0_ Cety/Stearyl Alcohol 7769 97.9 1666 Kolliwax CSA70_ (Cie/Cra) Kolliwax MA Myristyl Alcohol (C,,) 112-72-1 36-42 Kolliwax SA Stearyl Alcohol (C,,) 112-92-5 57-60 Kolliwax SA Fine Koliwax?S Stearic/Palmitio Acid g 7754 93.05 308 Kolliwax S Fine (Cil/Cy6) Values given for guidance only, see specification sheets for detailed information on melting and/or freezing temperatures. Table 2: Properties of fatty alcohols and acids of the Kolliwax family.
Figure 1: Typical appearance of the Kolliwax grades. The scale in the back is metric, with 1 mm per mark. For detailed information on particle size distributions, please refer to the individual product specification sheets. Scanning electron mircroscopy (SEM) igure 2: SEM images of Kolliwax S, and Kolliwax S Fine. Please refer to the individu: specification sheets for detailed information on particle size distributions.
3. Application Overview The following table 3 gives an overview on the most important applications and functions of the Kolliwax fatty alcohols and acids: while fatty acids and alcohols are generally used as consistency factors, our fine grades of stearic acid and stearyl alcoho (Kolliwax S Fine and Kolliwax SA Fine, respectively) allow to use these substances in the preparation of solid dosage forms, where they can aid as lubricants or matrix formers. Table 3: Application of the Kolliwax grades. Emulsions Exhibiting excellent skin tolerance, the Kolliwax grades can be used for all kinds of topical pharmaceutical applications, such as creams, gels, lotions, and ointments. The typical usage concentration in emulsions is about 1- 5%. All Kolliwax grades will act as consistency factors and co-emulsifiers at the same time. With their amphiphilic structure, they will stabilize the interface between oil and water and will help to enhance the viscosity by building up a liquid crystalline network (lamellar sheet structure). Stabilizing w/o and 0/w emulsions, they also aid in bringing a unique softness and creaminess to the targeted formulation. Lubricants In tableting processes for solid oral dosage forms, lubricants are used to prevent ingredients from clumping to undesired aggregates and from sticking to the tablet punches or capsule filling machine. In addition, lubricants hamper the friction that would hinder tablet formation and ejection. Among inorganic materials (e.g. talc or silica), fat based substances like vegetable stearin, magnesium stearate or stearic acid are commonly used as lubricants in tablets or hard gelatin capsules. Lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. Formulation examples Guideline for the preparation of the model formulations: MaYIGenne 1Or UWle PrepalrauviOrl OF WIE MIOQE! fOMTIUlAvOrls. 1. Heat components of phase A to 80 - 85 C and stir until transformed into a homo- geneous melt. 2. Heat components of phase B to 80 85 C. Under constant stirring, slowly add phase A to phase B, homogenize for 5 min at 5000 rpm. Let cream cool to 35 C while mixing at 200 rpm, and add preservative.
Model formulation Rich Cream: This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as emulsifiers to create avery stiff cream that offers a slow spread and a cushioned feeling when rubbing into the skin. Its high immediate smoothness results from the utilization of Kollicream IPM, a fast spreading oil with broad penetration enhancement properties that can aid as a solubilizer for lipophilic drugs. Ingredient Phase Ph. Eur. name Role Amount [wt.-%] A __ Kolliwax CSA 70 Cetostearyl Alcohol Consistency Factor, 7.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 25 40-55 (Type Il) Co-Emulsifier Kolliphor PS 60 Polysorbate 60 Emulsifier 4.2 Kollisolv@ MCT 70 Medium Chain Emollient 11.5 Triglycerides Kollicream IPM Isopropyl Myristate Emollient 1.3 B Deionized Water 69.2 Solvent _____. Glycerol 3.3 C_ Euxyl PE 9010 Preservative 1.0 Table 4: Model formulation for a rich Cream. Model formulation Light Cream: This formulation is a smooth cream with easy distribution, medium viscosity, and a glossy finish. Due to the difference in HLB values, the blending ratio of Kolliphor CS 12 and Kolliphor CS 20 can be used as a factor to maximize emulsion stability. Phase Ingredient Ph. Eur. name Role Amount [wt.-%] A_ Kolliwax CSA 50 Cetostearyl Alcohol Consistency Factor, 4.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 5.0 40-55 (Type Il) Co-Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Emulsifier 2.0 Ether 20 Kolliphor CS 12 Macrogol Cetostearyl Emollient 0.8 Ether 12 Kollicream CP 15 Cetyl Palmitate 15 Emollient 0.8 Kollicream IPM Isopropyl Myristate Emollient TA B__ Deionized Water 74.0 Solvent Glyerol 5.0) C_ Euxyl PE 9010 Preservative 1.0 in Si Pe Table 5: Model formulation for a light cream. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment.
5. Product specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554718 olliwax CA 50253459 25 kg Plastic film bag 50259499 0.5 kg Plastic bottle 30554719 olliwax CSA 50. 50253501 25 kg Plastic film bag 50259500 0.5 kg Plastic bottle 30554721 olliwax CSA 70 50253504 25 kg Plastic film bag 50259502 0.5 kg Plastic bottle 30554492 olliwax MA 50375472 20 kg Corrugated fiberboard box with PE liner 50259498 0.5 kg Plastic bottle 30554720 olliwax SA 50253503 25 kg Plastic film bag 50259501 0.5 kg Plastic bottle 30563963 olliwax SA Fine 50284249 25 kg Plastic film bag 50372378 0.5 kg Plastic bottle 30554752 olliwax S 50253532 25 kg Plastic film bag 50259521 0.5 kg Plastic bottle 30554750 olliwax S Fine 50253810 25 kg Plastic film bag 50259508 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information = Registered trademark of BASF in many countries.
1. Introduction Historical aspects of polyvinylpyrrolidone The modern acetylene chemistry was developed at BASF by Reppe in the 1930s. One of the many products that emerged from this work are the soluble polyvinyl- pyrrolidone grades, obtained by radical polymerization of the monomer unit N-vinyl- pyrrolidone. Separate Technical Information Sheets are available for the Povidones with the mediurr and high molecular weights, for the insoluble Kollidon grades (Crospovidone) and fo Kollidon VA 64, the copolymer consisting of N-vinylpyrrolidone and vinyl acetate (Copovidone). More information on Kollidon grades may be found in the book, Kollidon, Poly- vinylpyrrolidone for the Pharmaceutical Industry. 2. Technical properties Description The low molecular weight Povidones grades Kollidon 12, Kollidon 12 PF and Kollidon 17 PF are polymerized and finally spray dried polymer powders. They come as white powders with faint, characteristic odor. Trivial names Soluble polyvinylpyrrolidone is also known as povidon(e), povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone) and PVP. CAS number 9003-39-8
Molecular weights In general, the average molecular weight of polymers can be expressed in three different ways, either as weight average molecular weight (M,,), as number average molecular weight (Mn) or as viscosity average molecular weight (M.). The molecular weight of povidones is usually expressed as K-value, from which it is possible to calculate the viscosity average molecular weight (M.). However, the weight average molecular weight (M,,) is found more frequently in the literature. It is determined by methods such as size exclusion chromatographie (SEC) using light scattering detection, a method to determine an absolute molecular weight without the need to apply a reference material. For different grades of Kollidon the following M,, values were determined in as shown in table 1: M,, [AMU] Kollidon 12 2000 3000 Kollidon 12 PF 2000 3000 Kollidon 17 PF 7000 11000 Tablet Solubility The solubility of Kollidon varies considerably from one solvent to another. In Table 2 below, soluble signifies that a solution of at least 10% can be prepared, and insoluble signifies that the solubility is less than 1%. Soluble in: chloroform n-butanol cyclohexanol n-propanol ethanol abs. polyethylene glycol 300 glycerine polyethylene glycol 400 isopropanol propylene glycol methanol triethanolamine methylene chloride water Insoluble in: cyclohexane pentane diethyl ether carbon tetrachloride ethyl acetate toluene liquid paraffin xylene Table 2: Solubility of low molecular weight Kollidon grades Grades (12, 12 PF and 17 PF) Glass transition temperature Tg Product Tg [C] Kollidon 12 102 Kollidon 12 PF 102 Kollidon 17 PF 138
Particle size The particle size distributions of the spray dried polymers can be described with the following ranges (to be considered as characteristic values only): Product d(0.1), um = (0.5), um_s (0.9), um =~Ss;D[4.3], pm Kollidon 12 PF 10 +/-3 35 +/- 5 80 +/- 10 42 +/-5 Kollidon 17 PF 10 +/-3 33 +/- 5 75 +/- 10 38 +/- 5 Table 4 The determination was performed with a Malvern Mastersizer 2000. The air pressure was set to 1 bar. Bulk density Bulk density of Kollidon is determined according to Ph. Eur. current edition method 2.9.34. Product Bulk density Kollidon 12 400 - 600 g/L Kollidon 12 PF 400 - 600 g/L Kollidon 17 PF 400 600 g/L Table 5: Bulk density of the Kollidon grades Particle size distribution and bulk density are considered characteristic values. The are not part of the product specification. Endotoxin testing Kollidon 12 PF and Kollidon 17 PF are intended for the use in parenteral pharma- ceutical formulations and thus tested for bacterial endotoxins.
Viscosity Fig. 1 shows the relationship between the viscosity of aqueous solutions of the different grades of Kollidon and their concentration. Fig. 1: Viscosity of Kollidon solutions (Ubbelohde viscometer, 25 C) Hygroscopicity The hygroscopic nature of Kollidon is important in many applications. There is hardly any difference between the individual grades so that the same curve applies to all Povidone grades (Fig. 2). Fig. 2: Hygroscopicity of soluble Kollidon
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application Kollidon 12 PF, 17 PF Solubilizing agents, dispersants and crystallization inhibitors in solutions or lyophilisates for injection. The low-molecular grades, Kollidon 12 PF and Kollidon 17 PF are intended for use as solubilizing agents, dispersants and crystallization inhibitors particularly for injectables. These properties are of particular interest for antibiotics in solution or in lyophilized powder form. Stabilizers for parenteral suspensions The low-molecular weight endotoxin tested grades of Kollidon can be used to stabilize parenteral suspensions. This applies in particular for formulations of antibiotics. Kollidon 12 Solubilisation of APIs in soft-gels Oe gf Furthermore, liquid formulations for soft gel capsules contain the low-molecular weight grade Kollidon 12 as solubilizer. Like in other formulations for oral application, a grade tested for endotoxins is not required. 5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage condition: Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technical representative. 8. Regulatory status Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data Toxicological and biochemical studies have been carried out with the individual Kollidon grades. Abridged reports summarizing the toxicological results are available on request. The original reports can be provided when secrecy agreements are in place.
10. PRD and Article numbers 10. PRD and Article numbers Packaging PRD-No. Product name Article numbers 30553394 Kollidon 12 50269252 100 kg PE drum with PE-inliner 30034972 ~~ Kollidon 12 PF 50444166 50 kg PE drum with EVOH-inliner 30034981 Kollidon 17 PF 50029276 50 kg PE drum with EVOH-inliner BASFs commercial product number. 11. Publications http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
November 2012 ) = Registered trademark of BASF in many countries.
PRD-No., Article-No. and CAS.-No. PRD-No. PRD-No. Article-No. CAS.-No. 30554748 50253533 102-76-1 30554748 See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access) Specifications Regulatory Status Kollisolv GTA meets the test requirements of the following monographs Triacetin Ph. Eur. and Triacetin USP Triacetin ist a clear, colorless, slightly viscous oily liquid that is widely used in pharma- ceutical formulations. Triacetin is a triester of glycerol and acetic acid. Product characteristics Chemical structure Figure 1: Chemical structure of Triacetin Application Kollisolv GTA is mainly used as a solvent and as a solubilizer for pharmaceutical applications. For solid oral dosage forms it can be used as a plasticizer in film coating for tablets In semi-solid formulations it is also been used regularly as a humectant. Raw material origin Kollisolv GTA is based on vegetable and synthetic origin. Toxicology The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreement. In original sealed containers Kollisolv GTA can be stored for at least one year. It is important that it is protected from moisture and stored at less than 30 C. Please carefully reseal the container after opening. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions of safe and proper handling and disposal. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Table of contents Introduction Polyethylene glycol portfolio 5 Typical chemical and physical properties 6 Applications 8 Tablets, liquids, and suspensions 9 Softgels 10 Ensuring softgel performance with low aldehyde Kollisolv? PEGs 13 Topicals 20 Hydrophilic ointment formulation 20 Emulgel formulation 21 Suppository formulation 22 Product details and key benefits 24 Product and sample article numbers 25 ZoomLab, RegXcellence, & MyProductWorld 26 Introduction Polyethylene glycol portfolio
Polyethylene glycol portfolio Kollisolv PEGs are colorless, almost odorless, and tasteless liquids or white solids at room temperature. These products are manufactured by alkali-catalyzed polymerization of ethylene oxide with subsequent neutralization of the catalyst. The number in the name of the product indicates its average molecular weight. Chemical name CAS number Our portfolio of Kollisolv PEGs offers assurance of high-quality production in cGMP manufacturing conditions that meet the compendial requirements of USP-NF and Ph. Eur. At low molecular weights, our Kollisolv? PEGs are present as colorless liquids, and at higher molecular weights these products exist as white semi-solids and solids.
Unlike standard grade PEGs with a total aldehyde content of 50 ppm, our low aldehyde Kollisolv PEGs are restricted to an aldehyde content maximum of 10 ppm and offer assurance of control. With a restricted total aldehyde content to a maximum of 10 ppm, these excipients are especially suited for sensitive APIs and applications, including softgel shells and fills. Colorless, almost odorless, and tasteless liquid at room temperature Average molecular weight (g/mol) 285 to 315 380 to 420 380 to 420 570 to 630 570 to 630 Melting point (C) -15 to -8 4to8 4to8 15 to 25 15 to 25 Hydroxyl value (ng KOH/g) 340 to 394 264 to 300 264 to 300 178 to 197 178 to 197 Viscosity at 25 C (mPa:s) 80 to 105 105 to 130 105 to 130 Solid Solid Viscosity at 99 C (mm?/s) 5.4 to 6.4 6.8 to 8.0 6.8 to 8.0 9.9 to 11.3 9.9 to 11.3 fery soluble in water and alcohol, practically insoluble in oils and fa
Tablets, liquids, and suspensions Kollisolv PEGs can be used in tablet applications as a component of the core or coating. They can also serve as lubricants in the processing of a tablet. In tablet core applications, solic Kollisolv PEGs can be used as a binder or additive. Solid and semi-solid Kollisolv? PEGs can be used in coating applications as a plasticizer and film former. Polyethylene glycols, or macrogols, are mainly used as solubilizers, surfactants, and solvents. As multifunctional ingredients, these excipients play an essential role in various oral and topical formulations. Low-molecular-weight liquid polyethylene glycols are excellent solvents for numerous substances that do not readily dissolve in water. They are widely used as solvents and solubilizing agents for active substances and excipients in liquid and semi-solid preparations. They can also be used as plasticizers in tablets, capsule shells, and film coatings.
Softgels Figure 1. Solubility of Kollidon VA 64 in Kollisolv PEG 300, 400, and 600 at room temperature. BASF offers a range of liquid Kollisolv? PEGs and other complementary products for softgel applications. From solubility enhancement to crystallization inhibition, these products make for easier softgel formulation with greater predictability and reliability. BASF solubilizers such as Kolliphor RH 40 (Ph. Eur.: macrogolglycerol hydroxystearate; USP-NF: polyoxyl 40 hydrogenated castor oil), Kolliphor EL (Ph. Eur.: macrogolglycerol ricinoleate, USP-NF: polyoxyl 35 castor oil), or Kolliphor HS 15 (Ph. Eur.: macrogol 15 hydroxystearate; USP-NF: polyoxyl 15 hydroxystearate) can be used in combination with liquid Kollisolv PEGs to increase the solubilization capacity, allowing for the enhanced dissolution of challenging APIs. Crystallization inhibitors such as Kollidon VA 64 (Ph. Eur., USP-NF: copovidone), Kollidon 30 (Ph. Eur., USP-NF: povidone), and Kollidon 12 PF (Ph. Eur., USP-NF: povidone) can be used with liquid Kollisolv PEGs to prevent drug recrystallization. These crystallization inhibitors form homogenous blends at common processing and filling temperatures, and provide an additional benefit of increasing fill viscosity. This increased fill viscosity allows for more consistent filling and lower weight variance between softgels capsules. Blends of Kollisolv PEGs with Kollidon crystallization inhibitors are stable at room temperature up to 40% concentration by weight. Figure 2. Solubility of Kollidon 30 in Kollisolv PEG 300, 400, and 600 at room temperature. Figure 3. Solubility of Kollidon 12 PF in Kollisolv PEG 300, 400, and 600 at room temperature.
Advancements in increased temperature control for softgel encapsulation machines provide opportunities to use fills with greater crystallization inhibitor concentration. Use of common processing temperatures of 40 or 60 C leads to as much as 80% reduction in fill viscosity. This gives significant advantages by increasing processing speed with lower flow resistance of fills and increasing softgel shelf stability with greater crystallization inhibitor content when using liquid Kollisolv? PEGs with Kollidon crystallization inhibitors. Softgels are oral formulations that are composed of a pharmaceutical grade shell which encapsulates the liquid fill. Shell-fill compatibility requires the strategic selection of excipients to minimize degradation byproducts known to be harmful for softgel stability. To ensure capsu integrity and dissolution reproducibility, the fill must be compatible with the shell, and neither prematurely rupture the shell nor restrict release of the active post-delivery. Aldehydes are a common concern in softgels, especially soft gelatin capsules, where chemical crosslinking of the gelatin peptide backbone will cause insoluble films or pellicles that disrupt dissolution testing. The consequence of crosslinking is often an altered dissolution behavior of the capsule, one that will fail dissolution testing in vitro. While this crosslinking does not always translate to failure in vivo, where enzymes can cleave the peptide backbone, the USP <711> recommends a two-tiered dissolution investigation when in vitro dissolution failure arises from crosslinking. The complicated testing protocol includes pH-dependent enzyme selection and, as elaborated in USP <1094>, additional testing on the compatibility of any surfactants includec in the medium. These additional tests require cumbersome method development and validation, lengthening the time and complexity of going to market. Figure 4. Viscosity vs. concentration of Kollidon VA 64 in Kollisolv PEG 300 at 25, 40 and 60 C.
To study the effect of degradation byproducts, particularly aldehydes, on softgel performance, five lots of polyethylene glycol 400 (PEG 400) of varying grades and storage conditions were selected for testing (Table 1). Two fresh lots of Kollisolv? PEG 400 LA were evaluated, as well as one Kollisolv PEG 400 LA at the 2-year retest. A compendial grade of PEG 400 that met Ph. Eur. and USP monographs was included, as well as a standard, non-pharmacopoeia PEG 400. The standard grade PEG 400 was a forced-aged compendial PEG 400 sample, stressed through aging at 60 C for 9 days and 80 C for 7 days. The starting aldehyde levels for each sample was determined by an in-house R&D method (Figure 7). Kollisolv PEG 400 LA had the lowest aldehyde concentration, under 10 ppm, with nc difference between fresh and at 2-year retest. The compendial PEG 400 sample had an aldehyde concentration almost two-fold higher than Kollisolv PEG 400 LA. Standard PEG 400 was nearl six-fold higher. Figure 7. Starting aldehyde levels for each grade of PEG 400. Table 1. PEG 400 samples for softgel formulations. Sample # Material Age to retest Grade 1 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 2 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 3 Kollisolv PEG 400 LA At 2-year retest Low aldehyde (Ph. Eur., USP) 4 Compendial PEG 400 Compendial (Ph. Eur., USP) 5 PEG 400 Standard Samples 1 and 2 represented two different freshly opened lots.
Brilliant Blue, serving as a model active pharmaceutical ingredient (API), was formulated at eque parts in the five PEG 400 samples. After the formulations were filled into softgel capsules using lab-scale filling equipment, the capsules were then stored at ambient (25 C, 60% RH) and accelerated (40 C, 75% RH) conditions for a 12-month period. In vitro dissolution of the softgel capsules was performed to evaluate the effect of aldehyde content on dissolution. The dissolution time to release 80% of the loaded Brilliant Blue was captured for each sample (Fig. 9). Softgels containing Kollisolv PEG 400 LA demonstrated an equivalent dissolution time over the full 12 months under ambient conditions; while even the compendial grade PEG 400 containing softgels exhibited delayed dissolution within 6 months. When stored at ambient conditions, the softgel capsules composed of Kollisolv? PEG 400 LA demonstrated superior stability over compendial and standard PEG 400 (Fig. 8). Over the course of 12 months, the softgels filled with fresh and 2-year Kollisolv? PEG 400 LA showed a stable release profile with no evidence of crosslinking or change in dissolution. The equivalence of performance with product age, fresh and at two years, demonstrates the stability of Kollisolv PEG 400 LA and reliability of performance. Figure 9. Dissolution time (until 80% release) of softgels stored at ambient (25 C, 60% RH) conditions taken as the time in minutes. In contrast, the softgel consisting of compendial PEG 400 increasingly delayed dissolution, with significant changes in dissolution evident by month 6. To an exaggerated degree, the softgel containing standard PEG 400 showed retarded dissolution and evidence of near-immediate crosslinking within the first month. Figure 8. Dissolution of softgels stored at ambient (25 C, 60% RH) conditions over a 12-month period. In accordance with USP<711>, formulations made with the compendial PEG 400 would require proof of gelatin crosslinking via spectroscopic methods and complicated dissolution tests. Comparatively, formulations that consisted of Kollisolv? PEG 400 LA would not require further investigation regarding crosslinking or dissolution. Even under stressed aging in accelerated storage conditions, softgels consisting of Kollisolv PEG 400 LA within the full 2-year retest period exhibited equivalent performance, demonstrating stability of the product within its shelf-life. Under accelerated storage, dissolution of capsules of fresh and retest-aged Kollisolv PEG 400 LA remained equivalent through 3 months (Fig. 10). In contrast, compendial PEG 400 mirrored the failure of standard, non- pharmacopoeia PEG 400, and both products showed immediately delayed dissolution within the first month, failing due to crosslinking of soft gelatin capsules. In this case, even meeting Ph. Eur. and USP standards for a pharmaceutical excipient did not impart stability over a non- pharmaceutical grade of PEG 400.
Figure 10. Dissolution of softgels stored at accelerated (40 C, 75% RH) conditions over a 6-month period. Under accelerated conditions, Kollisolv? PEG 400 LA offered improved stability of the dissolutior profile. Regardless of age, the three Kollisolv? PEG LA samples demonstrated an equivalent dissolution time over 3 months, suggesting stability studies under these conditions is feasible through 3 months (Fig. 11). In contrast, both compendial and standard, non-pharmacopoeia grades of PEG 400 exhibited delayed dissolution immediately, failing accelerated stability studies under these conditions. Aldehyde content within the softgels was determined at time points within both storage conditions. As softgel fills, Kollisolv? PEG 400 LA samples demonstrated minimal changes in the aldehyde content over a 2-year retest period. Evaluation of the aldehyde content showed that storage condition did not significantly impact the total aldehyde amount present in the softgel fill. Ultimately, Kollisolv PEG 400 LA did not develop aldehyde content over time when formulated in softgels, whether fresh or at retest, under ambient or accelerated storage (Fig. 12). Figure 12. Aldehyde development of Kollisolv PEG 400 LA in softgels, over 12 months at under ambien and accelerated storage. Figure 11. Dissolution time (until 80% release) of softgels stored at ambient (40 C, 75% RH) conditions taken as the time in minutes. In summary, Kollisolv? PEG 400 LA outperformed compendial PEG 400. The dissolution profiles from softgels at both ambient and accelerated storage conditions reflected a pre dilection towards Kollisolv PEG 400 LA, with stable release seen for longer than from compendial PEG 400. When using Kollisolv PEG 400 LA as the softgel fill, aldehydes did not develop over time at either ambient or accelerated storage conditions. Rather, the source and quality of the products had the greatest effect on the aldehyde levels. Fresh and at-retest Kollisolv PEG 400 LA samples offered a 50% reduction in starting average aldehyde content in comparison to compendial grade PEG 400. The repeatable and stable dissolution profiles seen for Kollisolv PEG 400 LA bring the advantages of rapid development and ease of qualification.
Topicals Emulgel formulation When used for topical applications, solid and liquid Kollisolv PEGs be combined to form water-soluble bases for ointments, suppositor and ovula. Low-molecular-weight Kollisolv? PEGs can be used as solvents, conditioners, adhesion promoters, and humectants. These products, like Kollisolv PEG 300, Kollisolv PEG 400, and Kollisolv PEG 1000, promote ease of application, softening on contact with skin, and localization of active delivery. High-molecular-weight Kollisolv PEGs can be used as structuring agents and thickeners to increase the viscosity of formulations. These include Kollisolv PEG 1450, Kollisolv PEG 3350, and Kollisolv PEG 8000. Hydrophilic ointment formulation Kollisolv PEG ointments can be used as an alternative to traditional petrolatum-based ointmen formulations. By pairing different amounts of high- and low-molecular-weight chains, PEG ointments can be tuned for desirable rheological profiles and sensory. Procedure 1. Prepare phase A by weighing ingredients into an appropriately sized beaker. 2. Heat the mixture to 60 C and continue heating until the mixture has completely melted. Try to minimize the heating time as much as possible. 3. Once all the components have melted, place phase A underneath an overhead mixer. Stir at a low shear rate until cooled to room temperature. Kollisolv PEG 3350 is commercially available only in the USA and Canada as an excipient.
Suppositories allow formulators to accurately deliver active ingredients through an alternative route. Kollisolv PEG suppositories are ideal for the formulation of suppository matrices, offering a melting temperature range within physiologically relevant conditions and compatibility with hydrophilic druas.
Product details and key benefits Product details Regulatory Manufacturing site Manufacturing process Re-test period Certified Handling Safety data sheet Retest date and storage conditions Specification Regulatory status Key benefits Supply reliability & consistent quality Sustainability Technical service BASF Virtual Pharma Assistants Kollisolv? PEGs USP-NF, Ph. Eur. Geismar, Louisiana (USA) Synthetic 24 months Kosher, Halal Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRPI). For current specification, please speak to your local BASF sales or technical representative. Please refer to Quality & Regulatory Product Information (QRPI). Kollisolv PEGs are manufactured in a GMP compliant facility in the U.S. ensuring: Consistent quality and safety @ Reliable, vertically integrated supply BASF is a proud member of the Pharmaceutical Supply Chain Initiative (PSCl), whose vision is to establish and promote responsible practices that will continuously improve human rights, health, safety, and environ- mentally sustainable outcomes for supply chains worldwide. @ World class expertise in excipient chemistry Formulation guidance with ZoomLab @ Regulatory documentation available in RegXcellence Product details available via MyProductWorld @ Full pharma regulatory documentation and submission support Product details and key benefits
For sample requests contact us at pharma-solutions@basf.com This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to th extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matte in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2022 BASF Corporation. All Rights Reserved.
November 2012 Hard Fat for suppository masses
PRD-No., Article-No. and CAS.-No. PRD-No. Article-No. CAS.-No. Novata B PH 30531224 50209107 67701-26-2 Novata BC PH 30531225 50209108 67701-26-2 Novata BCF PH 30531226 50209109 67701-26-2 Novata BD PH 30531227 50209110 67701-26-2 See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). All Novata PH Grades are complying to the Monograph Hard fat Ph. Eur. Regulatory Status Product characteristics All Novata PH grades are white to slightly yellowish, brittle pellets which are used for the production of suppositories. On account of its mean hydroxyl value range and the melting point, the product can be used as universal suppository mass, alsc in the chemists shop. Typical Properties Novata B PH BC PH BCF PH BD PH Acid value <0.5 <0.5 <0.5 <0.5 lodine value <3.0 $3.0 <3.0 <3.0 Peroxide value <3.0 <3.0 <3.0 <3.0 Alcaline impurities (mL) <0.15 <0.15 <0.15 <0.15 Total ash (%) <0.05 <0.05 <0.05 <0.05 Unsaponifialble (%) <0.6 <0.6 <0.6 <0.6 Hydroxyl value 20-30 30 - 40 20-30 5-15 Saponification value 225 240 225-240 225-240 230-245 Melting point (C) 33.5-35.5 33.0-34.5 35-37 33.5-35.5 Heavy metals as sum <10.0 <10.0 <10.0 <10.0 Pb (ppm)
Application The main application of the Novata PH Grades are suppositories. Suppository is a drug delivery system that is inserted into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository), where it dissolves or melts. Suppositories may be used for patients (e.g. children) in case it may be easier tc administer than tablets or syrups. Suppositories may also be used when a patient has a vomiting tendency, as oral medication can be vomited out. Another benefit of suppositories is, that drugs which often cause stomach upset during oral intake, for example diclofenac sodium are better tolerated in suppository form. Suppositories are made from a greasy or waxy base, containing different Novata PH grades in which the active ingredient and the other excipients are dissolved. The main important point in formulating a suppository, is adjust the melting temperature of the complete formulation to the body temperature. Apart from suppository manufacturing, solid triglycerides (hard fats) are used as carriers in capsule fillings, inlets, ointments and creams and in dental products. In topical formulation they can act as a sensory enhancer, because of their low melting point. All Novata grades are based on vegetable origin. The raw material origin is coconut or palm kernel oil. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreement Toxicology In the original sealed containers all Novata grades can be stored for at least 18 month, protected from moisture at below 30 C. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions c safe and proper handling and disposal. Handling and Disposal Formulations 1. Pain Relief Suppository with Novata B PH Ingredient Tuts Amount (g) Kollisolv MCT 70 Medium Chain Triglycerides 0.200 Phenacetin 0.300 Codeinphosphate 0.010 Acetyl Salicylic Acid 0.500 Soya Lecithin 0.010 Il Novalgin 0.200 Ill Novata B PH Hard Fat ad. 2.000 Remark Tube rise melting point: 34.5 C. Preparation Phase is suspended and triturated with Phase II. Phase Ill is melted on a water bath at 50 C after cooling to 38 C is mixed to a pasty consistency with the additive trithiratinn Ciihean ant ta avan dictrihi tian of all additivee the cammn ind 2 EE EE Phase is suspended and triturated with Phase II. Phase Ill is melted on a water bath at 50 C after cooling to 38 C is mixed to a pasty consistency with the additive trituration. Subsequent to even distribution of all additives, the compound is cast into moulds at 33 C.
2. Suppository with Novata BC PH against Hemorrhoids Ingredient Name Amount (g) Zink Oxide 0.100 Perugen 0.040 Novata BC PH Hard fat ad. 2.000 Witch hazel extract, dest. 0.200 Bismuth Gallate, basic 0.100 Remark Tube rise melting point: 34 C. Preparation Phase is melted 45 C, it is suspended with Phase Il at 45 C. Phase Ill is triturated, added at 40 C to the melt and cast into moulds at 38 C. ai Et RARER ES Phase is melted 45 C, it is suspended with Phase Il at 45 C. Phase Ill is triturated, added at 40 C to the melt and cast into moulds at 38 C. 3. Pain relief suppository 6 ES EEE SAR eee: Ingredient Name Amount (g) Isopropyl Phenazone 0.300 Novata BD PH Hard Fat ad. 2.000 Coffein 0.050 Remark 34.4C Tube rise melting point: an ee er Melt Phase at 50 C on a water bath. At a temperature of 38 C cast the compounc into slightly cooled moulds. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
PVP-lodine grade Povidone, iodinated Ph. Eur., Povidone-lodine USP Supersedes issue dated August 2010 Disinfectant Disinfectant
Introduction Specifications, methods Production Properties Description Solubility Viscosity Particle size distribution Stability Incompatibilities Supplementary analytical methods K value Free iodine (dialysis) Application General points pH Concentration of PVP-lodine Formulations Product number Packaging Stability Safety data sheet Physiological effects Microbiological efficacy Literature survey Page an 13 13 13 13 13 14 15 Introduction Specifications, methods
Introduction lodine was formerly used in the form of iodine tincture or Lugols solution fo! disinfecting minor wounds. Despite its good efficacy there were obstacles to its broad use because these two formulations triggered a number of side effects such as strong irritation, allergies etc. PVP-lodine was first reported in the early 1950s. This compound is a complex of polyvinyl pyrrolidone and iodine. Studies by H.U. Schenk et al [1] showed that the solid product probably has the following structure (Fig. 1): Fig. 1: Chemical structure of PVP-lodine (n:m = 1 : 18) In connection with the structure and the methods of determination it seems important to explain some terms. line = iodine that can be titrated with sodium thiosulphate = lodide + titratable iodine = non-complexed iodine that can be determined in a dialysis test [3] = iodine that can be extracted with heptane from an aqueous PVP-lodine solution of defined concentration free iodine that can be determined in an electrochemica model [2] = lodide concentration required to form an iodine complex An interesting and important factor in this context is the dependence of the co! centration of free iodine on the concentration of PVP-lodine or available iodine, shown in Fig. 2. Looking at this curve, two facts about the commonly used cor centrations of PVP-lodine preparations (1 10% PVP-lodine = 1-10 g availab iodine/ ) stand out: 1. The free iodine content is extremely low at 1-8 ppm 2. The free iodine content is inversely proportional to the concentration of PVP-lodine or available iodine. An interesting and important factor in this context is the dependence of the con- centration of free iodine on the concentration of PVP-lodine or available iodine, as shown in Fig. 2. Looking at this curve, two facts about the commonly used con- centrations of PVP-lodine preparations (1 10% PVP-lodine = 1-10 g available iodine/ ) stand out: 1. The free iodine content is extremely low at 1-8 ppm 2. The free iodine content is inversely proportional to the concentration of PVP-lodine or available iodine. Tests on micro-organisms have shown that the rate of microbicidal action is proportional to the free iodine content.
y. 2 Relationship between the free iodine concentration and the concentration of available iodine in aqueous solution. Specifications PVP-lodine 30/06 Identity corresponds Available iodine (potentiometric) 9.0- 12.0% lodide = 6.0% PH (10% in water) 1.5-5.0 Nitrogen 9.5- 11.5% Heavy metals = 10.0 ppm Losses on drying = 8.0% Ash =0.1% The methods can be found in the current monographs Povidone, iodinated (Ph. Eur.) or Povidone-lodine (USP). Product meets current Povidone, iodinated Ph. Eur., USP, JP and IP monographs. Regulatory status For the production of PVP-lodine 30/06 a Povidone K 30 is used that meets the requirements of the corresponding pharmacopoeia in accordance with the above Ph. Eur. monograph. The figure 30 in the PVP-lodine 30/06 nomenclature indicates the K value and thus the molecular weight of the povidone used. Production
Properties PVP-lodine 30/06 is a brown, free-flowing powder. Description Water Ethanol Propanol Acetone Chloroforn Methylene Heptane Hexane Solubility Water Ethanol 5% 2 2 10% 7 5 20% 230 20 These guide values are based on measurements at 25 C and are given in mPa-s. PVP-lodine 30/06 Smaller than 20 um - Smaller than 50 um <25% Greater than 250 um < 5% Particle size distribution These data are guide values. The values were determined on a dispersion of PVP-lodine in heptane with a Malvern Mastersizer. In the case of PVP-lodine 30/06 they can also be measured with an air jet sieve.
The following rapid test, corresponding to storage for about 15 months at room temperature, is suitable for easy and fast assessment of the stability of PVP-lodine in aqueous preparations. It can be used for assessing the stability of PVP-lodine from different sources and for preparing new formulations. A PVP-lodine solution containing 1% available iodine is produced. This solutior is stored in a sealed glass flask for 14 days at 52 C or 15 hours at 80 C. The available iodine content is determined and the iodine loss calculated before and after storage. An indication of stability is incorporated in the product name PVP-lodine 30/06. The figure O6 indicates that the iodine loss in the above stress test does not exceed 6%. One of the above stress tests was employed to predict the stability of practically all aqueous formulations that have been developed in the BASF laboratory. These tests are also highly suitable for predicting the compatibility of PVP-lodine with different excipients and packaging materials. Fig. 3 shows by way of example the result of testing the compatibility of aqueous PVP-lodine solutions with glass and two high- and low-density polyethylene grades (Lupolen) using one of these stress tests. Fig. 3: Influence of the concentration of aqueous solutions and packaging material on the stability of PVP-lodine solutions PVP-lodine is not stable in combination with reducing agents and many surfactants. Even some other excipients or their impurities like rests of solvents (e.g. Acetone) can impair the stability of PVP-lodine preparations. Furthermore, a pH above 5 has a marked adverse effect on the stability of a formulation (see Fig. 4). Incompatibilities
Supplementary analytical methods The average molecular weight of the povidone contained in PVP-lodine 30/06 can be indicated by the K value. It is determined in accordance with the Ph. Eur monograph Povidones, but to measure the relative viscosity the solution must be decolourised before being adjusted to a concentration of 1% povidone by adding a 25% solution of sodium thiosulphate. K value Determination is carried out e. g. in a Dianorm dialysis machine as shown on page 8. The dialysis cells are filled by means of automatic pipettes with 2.00 ml PVP-lodine solution on one side and water on the other side. The membrane between the two sides consists of HDPE (e. g. Lupolen 1804 H) with a thickness of 50 - 70 um. The dialysis time at a speed of 20 rpm is about 5 hours for normal aqueous PVP-lodine solutions. 0.25 ml of a 10% potassium iodide solution are placed in the measuring cells. 1.00 ml is taken from the water side of the dialysis cells and added quickly to the potassium iodide solution. After brief shaking the absorption is measured at 351 nm against a mixture of 0.25 ml potassium iodide solution and 1.00 ml water. The free iodine content is calculated by the following equation:
Application PVP-lodine is noted for its wide range of uses. Its major applications are in the field of prophylaxis: General points skin and mucous membrane antisepsis surgical and hygienic hand disinfection and in the field of treatment: treatment of burns, decubitus and varicose ulcers use in the treatment of dermatomycosis, pyoderma and acne use in the treatment of vaginitis The advantage of PVP-lodine is that it can be incorporated in a wide range of formulations. The pH of the PVP-lodine preparation can be of great importance for its stability. As Fig. 4 shows, a pH of about 4.5 for aqueous solutions is a good compromise between good skin compatibility and acceptable stability. Fig. 4: Influence of the pH on the stability of PVP-lodine 30/06 solutions Concentration of PVP-lodine The concentration of PVP-lodine in the preparation also has an influence on its stability. Fig. 5 shows why the commonly used concentrations are therefore never below 1% PVP-lodine. At lower values stability is too poor. Fig. 5: Influence of the concentration on the stability of PVP-lodine 30/06 solutions

Details of the following formulations (e. g. the stability) and also further examples of preparations can be taken from the file or the CD-ROM Generic Drug Formulations. The sources of supply of the excipients listed are given on page 19. Formulations Formulation 1 Formulation 2 PVP-lodine 30/06 Kolliphor P 407 Kollisolv PEG 300 Citric acid-phosphate PVP-lodine 30/06  DIINO First of all the buffer solution is produced and the other liquid components added. The PVP-lodine powder is added steadily to the clear solution while stirring until a clear brown solution is obtained. Formulation 3 (seamless solution) Water pH of the solution: 2.95 Kolliphor P 407 is added to the water and Natrosol 250 HR is incorporated. As soon as the Natrosol 250 HR has dissolved, the PVP-lodine is added while Stirring. The sodium hydroxide solution is then added to the finished solution. Formulation 4 PVP-lodine 30/06 Neutronyx S 60 Super Amide L-9 \Niater Water Fs EAE TE Super Amide L-9 is dissolved in a little water at 60 C. The remaining water is then added. PVP-lodine is dissolved while stirring. Neutronyx S 60 is then added to the clear solution. There are a limited number of substitutes available for Neutronyx S 60 anc Super Amide L-9. Substitutes for Neutronyx S 60: Kolliphor SLS Lutensit AES Substitutes for Super Amide L-9: Comperlan LD Kolliphor SLS Lutensit AES Comperlan LD A suitable product for perfuming the liquid soap is the FDO product Floral Bouquet No. PC 516 715 (FDO, USA).
Formulation 5 Formulation 5 PVP-lodine 30/06 Super Amide L-9 Natrosol HR 250 Neutronyx S 60 Neutronyx S 60 Water Super Amide L-9 and Natrosol 250 HR are dissolved in water at 50 60 C. PVP-lodine is then dissolved in this and cooled, after which Neutronyx S 60 is added. The viscosity can be adjusted with Natrosol 250 HR. Formulation 6 PVP-lodine 30/06 Water Perfume oil e.g. Syndet base 5078 PVP-lodine 30/06 PVP-lodine is dissolved in water and mixed together with the perfume oil in the soap noodles. The mixture is passed four times through the roller mills for complete homogenisation and then pressed three times through a fine perforated screen. The soap pieces are then extruded through a large perforated screen in combination with a plodder attachment, preheated to 50 C. The machine required is manufactured by Weber + Seelander, Helmstedt (FRG) and others. Formulation 7 Formulation 7 PVP-lodine 30/06 Kollisolv@ PEG 400 Sodium hydroxide 1 NV Kollisolv PEG 4000 Water pH-value: 4 PVP-lodine is dissolved in the mixture of Kollisolv? PEG 4000, water and sodium hydroxide solution and heated to 60 - 65 C, when the Kollisolv? PEG 4000 is added while stirring vigorously. The mixture is then allowed to cool while stirring. Formulation 8 PVP-lodine 30/06 Sodium chloride Kolliphor P 407 Sodium hydroxide 1 Ne ig as PVP-lodine 30/06 Kolliphor P 407 PVP-lo ine and NaCl are dissolved in water and Kolliphor P 407 is added at approx. 6 C. The sodium hydroxide solution is then added.
Formulation 9 Formulation 9 PVP-lodine and saccharin are dissolved in H,O and then mixed with Il. The solution contains 7.5 g PVP-lodine in 100 ml. It can be diluted before use. Packaging Homogenization of the product is recommended prior to sampling or partial removal of the PVP-lodine powder from an individual drum. Safety data sheets are available on request and are sent with every consignment. Safety data sheet 1 Acute toxicity Physiological effects LD,, rats oral: 5990 mg/kg LD,,, mice i. p.: 360 mg/kg 2. Compatibility with the skin and mucous membranes Both 1% and 10% solutions were checked for compatibility with the skin and mucous membranes, and no negative results were observed. 3 Mutagenicity Tests on Chinese hamsters, the micronucleus test, and the dominant lethal test. No indications of mutagenicity were obtained.
Microbiological efficiency Organisms Strains PVP-I Time of contact (mg/kg iodine) (seconds) Staphylococcus aureus 2 000 15 1 67 60 1 000 30 1 000 30 85 000 30 6 100 180 13 2500 60 Proteus mirabilis 4 000 120 7 2500 90 2 2500 60 Proteus vulgaris 1 000 60 5 2500 90 Escherichia coli 3 000 120 1 000 60 1 000 60 9 000 30 6 2500 60 2 000 30 2 200 120 Enterobacter aerogenes 2500 60 Enterobacter spp. 3 000 60 Streptococcus faecalis 4 10 2 2500 300 2 200 60 Streptococcus pyogenes 000 60 2500 60 Streptococcus hemolyticus 2 000 15 Salmonella typhimurium 2 000 30 Salmonella typhosa 2 000 15 Salmonella Type C-1 2500 60 Salmonella spp. 2 2500 60 Serratia marcescens 2 2500 60 200 120 Serratia spp. 1000 60 4 2500 60 Shigella sonni 2 1000 30 Pseudomonas aeruginosa 2 1000 15 1000 900 13 25 900 2 2500 300 2 500 60 Klebsiella pneumoniae 500 60 Diplococcus pneumoniae 000 60 2 2500 60 Mycobacterium tuberculosis 2500 60 Bacillus subtilis 000 30 Clostridium tetani 000 30 Clostridium septicum 000 30 Bacillus subtilis spores 2 10000 7200 Trichophyton rubrum 000 60 Candida albicans 4 10 000 120 000 60 000 30 500 60 Trichomonas vaginalis 4 400 30 000 30 Aspergillus flavus 000 30 Aspergillus niger 000 30
Microbiological efficacy of preparations Assessment of the in-vitro efficacy differs widely from country to country depending on the test model, and the requirements can also vary greatly. A literature survey follows, giving a small selection of publications on the individual fields of application. Literature review Analysis of chemical structure Structure of Polyvinylpyrrolidone-lodine. Schenck H. U., Simak P., Haedicke E.; J. Pharm. Sci. 68, 1505-1509 (1979). Der Gehalt an freiem lod in waBrigen L6sungen von PVP-lod. Gottardi W.; Hyg. + Med. 8, 203-209 (1983). Physical-chemical Fundamentals of the Microbicidal Action of Povidone- lodine. Horn D., Ditter W.; Proceedings of the International Symp. on Povidone (1983). Microbiological Efficiacy of PVP-lodine. A critical Review (A. F. Petersen). Pseudobacteremia Attributed to Contamination of Povidone-lodine with Pseudomonas cepacia. Berkelman, R. et al.; Ann. of Intern. Medicine 95, 32-36 (1981). Increased Bactericidal Activity of Dilute Preparations of Povidone-lodine Solutions. Berkelman, R., Holland B. W., Anderson R. L.; J. Clin. Microbiol., 15, 6835-639 (1982). Jodophore zur Desinfektion? 1. Mitteilung: Scheinbar bakterizide Wirkung im Suspensionstest. H.-P. Werner; Hyg. + Med. 7, 205-212 (1982). dophore zur Desinfektion? 2. Mitteilung: Verminderte bakterizide Wirksamkeit in Gegenwart von Blut H.-P. Werner und E. Heuberger; Hyg. + Med. 7, 142-147 (1984). Chirurgische Hande- und Hautdesinfektion. Surgical Scrub and Skin Disinfection. G. A. J. Ayliffe; Hyg. + Med. 9, 423-426 (1984). Agrardiffusionsuntersuchungen zur Wirksamkeit von PVP-lod P. Knolle, R. H. Faber und G. Lebek; Krankenhaushygiene + nfektionsverhtitung 3, 148-150 (1983). Comparison of 4% Chlorhexidine Gluconate in a Detergent Base (Hibiclens) and Povidone-lodine (Betadine) for the Skin Preparation of Hemo dialysis Patients and Personnel Simeon E. Goldblum, M. D., John A., Ulrich, Ph. D., Richard S. Goldman, M. D., William P. Reed, M. D. and Pratap S. Avasthi, M. D. Amer. J. Kidney Dis. von Il, 548-582 (1983). [13] Comparative Evaluation of Chlorhexidine Gluconate (Hibiclens) and Povidone-lodine (E-Z Scrub) Sponge/Brushes for Presurgical hand crubbing Raza Aly, Ph. D. and Howard . Maibach, M. D. Research Vol. 34, No. 4, 740-745. [14] Wirksamkeitsvergleich von Desinfektionsverfahren zur chirurgischen Handedesinfektion unter experimentellen und klinischen Bedingungen. P. Heeg, W. OBwald und N. Scheuser Hyg. + Med. 11, 107-110 (1986). [15] Vorschlag einer neuen quantitativen Methode zur Prtifung der Eignung vo Praparaten zur pra- und postoperativen Hautdesinfektion. B. Christianser Ch Hdller tind K -A. Giindermann: Hvaq + Med 9. 471-472 (1984) Microbiological efficacy/skin and hand disinfection
16) 17 18) 19) 20 21 22 23 24 25 26 27 28 29 Topical application of Povidone-lodine in the management of decubitus and stasis ulcers. Lee B.Y., Frainor F. S., Thoden W. R.; J. Am.Geria tr. Soc. 27, 302-306 (1979). Irrigation of subcutaneous tissue with Providone-lodine solution for prevention of surgical wound infections. Sindelar W. F., Mason J. R.; Surg., Gynecol. Obstet. 148, 227-231 (1979). Prophylactic Povidone-lodine in minor wounds. Naunton Morgan T. C., Firmin R., Mason B., Monks V., Caro D.; Injury 12, 104-106 (1980). A critical evaluation of Povidone-lodine absorption in thermally injured patients. Hunt J. L., Sato R., Heck E. L., Baxter C. R.; J. Trauma 20, 127-129 (1980). The effect of topical Povidone-lodine on wound infection following abdominal surgery. Gray J. G., Lee J. R.; Br. J. Surg 68, 310-313 (1981) Sindelar W. F., mason Y. R.; Surg. Gynecol. Obstet. 148, 227-231 (1979). An Experimental Evaluation of the Germicidal Efficacy of three Topical Antimicrobial Agents in Burns. H. Rode, P. M. de Wet et al.; Prog. Pediatr. Surg. 14, 189-208 (1981). Disinfection of Surgical Wounds without Inhibition of Normal Wound Healing. Viljanto J.; Arch. Surg. 115, 253-256 (1980). Tierexperimentelle Untersuchungen zur lokalen Anwendung von Silver- sulfadiazin, Cefsulodin und PVP-lod bei Brandwunden. W. Kaiser, H. von der Lieth, J. Potel, H. Heymann; Infection 12 (1984) Nr. 1, S. 31-35. Bactericidal Activity and Toxicity of lodine-Containing Solutions in Wounds. Rodeheaver G., Bellamy W., Kody M., Spatafora G., Fitton L., Leyden K., Edlich R.; Arch. Surg. 117, 181-186 (1982). Normal and Abnormal Responses of the Thyroid to Excess lodine. Ingbar S., Proceedings of the International Symp. on Povidone (1983). Lexington. Protein-linked lodotyrosine in Serum after Topical Application of Povidone-lodine. Alexander N., Nishimoto M.; J. Clin. Endocrinol Metab. 53, 105-108 (1981). Gefahren von Povidon-lod bei SchilddrUsenkranken und Neugeborenen. Hermann J.; Dt. Arzteblatt 79, 39-40 (1982). Lack of influence of Povidone-lodine on Tests of Thyroid Function. Lividas D. P., Piperingos G. D., Stontouris J., Koutras D. A., nt. Med. Res. 6, 406-408 (1978). Fuhrt PVP-lod-Desinfektion von Neugeborenen zur transienten Hypothyresoe Bericht Uber 6 Falle und prospektive Studie von 19 frulhoperierten Sauglingen mit Hilfe von T4- und TSH-Bestimmungen in getrockneten Blutstropfen. H. Bucher, T. Torresani, B. Sobradillo, H. Frisch, B. Iseli, R. lllig, Schweiz. med. Wschr. 113, 671-679 (1983). 30 31 32 33 34 35 36 Bacteriological and systemic effects of intraoperative segmental bowel preparation with Povidone-lodine. Arango A., Lester J. L., Martinez O.V., Malinin T. ., Zeppa R.; Arch. Surg. 114, 154-157 (1979). Lirrigation lavage du prigoine a la PVP-lode dans les peritonites aignes generalises. Dupre A., Carpentier F., Guignier M., Peralta J. L.; Ann. Anaesthesiol. Fr. 20, 123-126 (1979). Intraperitoneal irrigation with Povidone-lodine solution for the prevention of intraabdominal abscesses in the bacterially contaminated abdomen. Sindelar W. F., Mason G. R.; Surg. Gynecol. Obstet. 148, 409-411 (1979). Antisepsis in der Behandlung der diffusen, bakteriellen Bauchfellentztindung. Weissenhofer W.; Acta Chir. Austriaca 31, 3-20 (1979). Various Intraperitoneal Irrigation Solutions in Treating Experimental Fecal Peritonitis. Lally K.L., Nichols R. L.; South Med. J. 74, 789-791 (1981). An experimental evaluation of the germicidal efficacy of three topical antimicrobials in burns. Rode H., de Wet P. M., Davies M. R., Cynres S.; Prog. Pediatr. Surg. 14, 189-208 (1981). Polyvidon-lod-Schleimhautdesintiziens eine Alternative zu antibiotischen Praparationen bei der Bauchhdhlenversorgung beim Rind. Bruhn J., Andresen P., Grding G., Dtsch. tierarztl. Wschr. 89, 250-252 (1982).
37 38 39 40 [44 42 43 44 45 46 47 48 49 50. 51 52 A clinical trial of a vaginal preparation regimen for the prophylaxis of Gonorrhea. Limsuwan A. et al.; J. Med. Assoc. Thai 61, 435-440 (1978). Passagere TSH-Erhhung des Neugeborenen nach vaginaler Polyvinylpyrrolidon-lod-Applikation sub partu. Neeb U., Ceasar J., Krause E.; Geburtshilfe, Frauenheilkunde 39, 973-974 (1979). Quantitative and qualitative effects of Povidone-lodine liquid and gel on the aerobic and anaerobic flora of the female genital tract. Monif G. R., Thompson . L., Stephens H. D., Bear H.; Am. J. Obstt. Gynecol. 137, 482-438 (1980). Vaginal Absorption of Povidone-lodine, Vorherr H., Vorherr U. F. Mehta P., Ullrich J.A., Messer R. H.; JAMA 244, 2628-2629 (1980). Effect of Chronic Douching with PVP-lodine on lodine Absorption and Thyroidfuncion. Safran M., Braverman L.; J. Obstetrics & Gynecology 60, No. 1, 35-40 (1982). Antimicrobial effect of chlorhexidine and povidone iodine on vaginal bacteria. H. Vorherr, U. F. Vorherr, P. Mehta, H. A. Ullrich and R. H. Messer, I. of Infection 8, 195-199 (1984). Wewalka, F., W. Koller, M. Rotter, G. Wagner and T. Riel: Investigations to evaluate Procedures for vaginal Disinfection. (Untersuchungen zur Beurteilung von Verfahren fur die Vaginaldesinfektion) Zbl. Bakt. Hyg., . Abt. Orig. B 179, pp. 555-565, 1984. Genetic Effects of Povidone-lodine. Wlodkowski T. J., Speck W. T., Rosenkranz H. S.; J. Pharm. Sci 84, 1235 (1975). Absence of Povidone-lodine-induced Mutagenicity in Mice and Hamsters. Merkle J., Zeller H.; J. Pharm. Sci 68, 100-102 (1971). Assessment of somatogenicity of Povidone-lodine using two in-vitro assay Kessler F. K., Lasin D. L. Borzelleca J. F., Carchman R. A.; J. Environ, Palhol. Toxicol. 4, 327-335 (1980). Malignant Transformation and DNA Damage by Povidone-lodine in culture mamalian cells. Long S. D., et al.; Proc. Am. Assoc. Cancer Research, 22, 72. Meeting 122 (1981). Teratologische Untersuchungen eines niedermolekularen Polyvinyl- pyrrolidon-lod-Komplexes am Hamster. B. Siegemund, W. Weyers; Arzneim.-Forschung 37, 340-341 (1987). Inactivation of HIV by Povidone-lodine. Paul G. Goldenhem; JAMA, 257, 2434 (1987). Inactivation of HIV by Povidone-lodine. M. Asanaka, T. Kurimura; Yonaga Acta Medica, 30, 89-92 (1987). Inactivation of HIV by Povidone-lodine. A. Durny, J. Kaplan, R. Schooley; Proceedings of the 2.Symp. on Povidone Lextington (1987). Desinfektionsmittel gegen das AIDS-Virus. J. Peters, G. Spicker; DAZ, 127, 450-451 (1987). This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Chemical names of active ingredient Omega-3 Fatty Acids Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA) Solubility Practically insoluble in water, very soluble in acetone, in ethanol (96 per cent), in heptane and in methanol. Articles Specification Specification Assay Country of origin as ethyl ester Ph. Eur. 2063/2.4.29 EPA (Eicosapentaenoic acid) min. 150 mg/g DHA (Docosahexaenoic acid) min. 500 mg/g EPA & DHA (Eicosapentaenoic & min. 650 mg/g Docosahexaenoic acid) Total Omega-3 fatty acids min. 700 mg/g Not rway Description PronovaPure 150:500 EE is a light yellow fish oil ethyl ester concentrate. PronovaPure 150:500 EE is a light yellow fish oil ethyl ester concentrate. ee ie ee The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Scombridae and Carangidae). The product is an ethyl ester (EE), rich in omega-3 fatty acids. The content of EPA (Eicosapentaenoic acid expressed as EE) and DHA (Docosahexaenoic acid expressed as EE) is min. 650 mg/g. as free fatty acid Ph. Eur. 2063/2.4.29 For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Composition i ailaallidnes 1 alaiiiaaitl aailiabi Ingredients in descending order of weight: Fish oil ethyl ester concentrate, tocopherol-rich extract (E 306). Standards Produced under cGMPand HACCP principles. mainly derived from soybean (from identity preserved, not genetically modified origin)
Applications Monographs and Regulations Se ee MO nny eis PronovaPure 150:500 EE meets the require- ments for an omega-3 fatty acid source in most countries. The product complies with the Ph. Eur. monograph on Omega-3-acid ethyl esters 60 (2063). Further, the product conforms to the voluntary GOED monograph in the current version. Fish oil ethyl ester concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed.  LAIGtalY SUPPICITICH I PronovaPure 150:500 EE is intended for use in dietary supplements such as in soft gel capsules. SE FN Se ae ES Ea. PronovaPure 150:500 EE is intended for use in dietary supplements such as in soft gel capsules. Note PronovaPure 150:500 EE must be handled in accordance with the Material Safety Data Sheet. PronovaPure 150:500 EE must be handled in accordance with the Material Safety Data Sheet. Stability, Storage and Handling Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 36 months. The product is sensitive to oxygen, light and heat. It should therefore be stored in the tightly sealed, lightproof packaging in a cool place. Once opened, it is recommended to use the remaining contents as quickly as possible. Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 36 months. This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: Detween you and BASF: a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, an) liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of () death or personal injury to the extent caused by BASFs sole negligence, (i) BASFs willful misconduct, fraud or fraudulent misrepresentation or (i) any matter in respect of whict it would be unlawful for BASF to exclude or restrict liability under the applicable laws; b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided hereit may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicabl law; and d) This document or any information provided herein must not be used for purposes of pharmaceutical registrations. if you have any further questions or need additional support, please contact your BASF sales representative.

Table of contents Introduction Polyethylene glycol portfolio 5 Typical chemical and physical properties 6 Applications 8 Tablets, liquids, and suspensions 9 Softgels 10 Ensuring softgel performance with low aldehyde Kollisolv? PEGs 13 Topicals 20 Hydrophilic ointment formulation 20 Emulgel formulation 21 Suppository formulation 22 Product details and key benefits 24 Product and sample article numbers 25 ZoomLab, RegXcellence, & MyProductWorld 26 Introduction Polyethylene glycol portfolio
Polyethylene glycol portfolio Kollisolv PEGs are colorless, almost odorless, and tasteless liquids or white solids at room temperature. These products are manufactured by alkali-catalyzed polymerization of ethylene oxide with subsequent neutralization of the catalyst. The number in the name of the product indicates its average molecular weight. Chemical name CAS number Our portfolio of Kollisolv PEGs offers assurance of high-quality production in cGMP manufacturing conditions that meet the compendial requirements of USP-NF and Ph. Eur. At low molecular weights, our Kollisolv? PEGs are present as colorless liquids, and at higher molecular weights these products exist as white semi-solids and solids.
Unlike standard grade PEGs with a total aldehyde content of 50 ppm, our low aldehyde Kollisolv PEGs are restricted to an aldehyde content maximum of 10 ppm and offer assurance of control. With a restricted total aldehyde content to a maximum of 10 ppm, these excipients are especially suited for sensitive APIs and applications, including softgel shells and fills. Colorless, almost odorless, and tasteless liquid at room temperature Average molecular weight (g/mol) 285 to 315 380 to 420 380 to 420 570 to 630 570 to 630 Melting point (C) -15 to -8 4to8 4to8 15 to 25 15 to 25 Hydroxyl value (ng KOH/g) 340 to 394 264 to 300 264 to 300 178 to 197 178 to 197 Viscosity at 25 C (mPa:s) 80 to 105 105 to 130 105 to 130 Solid Solid Viscosity at 99 C (mm?/s) 5.4 to 6.4 6.8 to 8.0 6.8 to 8.0 9.9 to 11.3 9.9 to 11.3 fery soluble in water and alcohol, practically insoluble in oils and fa
Tablets, liquids, and suspensions Kollisolv PEGs can be used in tablet applications as a component of the core or coating. They can also serve as lubricants in the processing of a tablet. In tablet core applications, solic Kollisolv PEGs can be used as a binder or additive. Solid and semi-solid Kollisolv? PEGs can be used in coating applications as a plasticizer and film former. Polyethylene glycols, or macrogols, are mainly used as solubilizers, surfactants, and solvents. As multifunctional ingredients, these excipients play an essential role in various oral and topical formulations. Low-molecular-weight liquid polyethylene glycols are excellent solvents for numerous substances that do not readily dissolve in water. They are widely used as solvents and solubilizing agents for active substances and excipients in liquid and semi-solid preparations. They can also be used as plasticizers in tablets, capsule shells, and film coatings.
Softgels Figure 1. Solubility of Kollidon VA 64 in Kollisolv PEG 300, 400, and 600 at room temperature. BASF offers a range of liquid Kollisolv? PEGs and other complementary products for softgel applications. From solubility enhancement to crystallization inhibition, these products make for easier softgel formulation with greater predictability and reliability. BASF solubilizers such as Kolliphor RH 40 (Ph. Eur.: macrogolglycerol hydroxystearate; USP-NF: polyoxyl 40 hydrogenated castor oil), Kolliphor EL (Ph. Eur.: macrogolglycerol ricinoleate, USP-NF: polyoxyl 35 castor oil), or Kolliphor HS 15 (Ph. Eur.: macrogol 15 hydroxystearate; USP-NF: polyoxyl 15 hydroxystearate) can be used in combination with liquid Kollisolv PEGs to increase the solubilization capacity, allowing for the enhanced dissolution of challenging APIs. Crystallization inhibitors such as Kollidon VA 64 (Ph. Eur., USP-NF: copovidone), Kollidon 30 (Ph. Eur., USP-NF: povidone), and Kollidon 12 PF (Ph. Eur., USP-NF: povidone) can be used with liquid Kollisolv PEGs to prevent drug recrystallization. These crystallization inhibitors form homogenous blends at common processing and filling temperatures, and provide an additional benefit of increasing fill viscosity. This increased fill viscosity allows for more consistent filling and lower weight variance between softgels capsules. Blends of Kollisolv PEGs with Kollidon crystallization inhibitors are stable at room temperature up to 40% concentration by weight. Figure 2. Solubility of Kollidon 30 in Kollisolv PEG 300, 400, and 600 at room temperature. Figure 3. Solubility of Kollidon 12 PF in Kollisolv PEG 300, 400, and 600 at room temperature.
Advancements in increased temperature control for softgel encapsulation machines provide opportunities to use fills with greater crystallization inhibitor concentration. Use of common processing temperatures of 40 or 60 C leads to as much as 80% reduction in fill viscosity. This gives significant advantages by increasing processing speed with lower flow resistance of fills and increasing softgel shelf stability with greater crystallization inhibitor content when using liquid Kollisolv? PEGs with Kollidon crystallization inhibitors. Softgels are oral formulations that are composed of a pharmaceutical grade shell which encapsulates the liquid fill. Shell-fill compatibility requires the strategic selection of excipients to minimize degradation byproducts known to be harmful for softgel stability. To ensure capsu integrity and dissolution reproducibility, the fill must be compatible with the shell, and neither prematurely rupture the shell nor restrict release of the active post-delivery. Aldehydes are a common concern in softgels, especially soft gelatin capsules, where chemical crosslinking of the gelatin peptide backbone will cause insoluble films or pellicles that disrupt dissolution testing. The consequence of crosslinking is often an altered dissolution behavior of the capsule, one that will fail dissolution testing in vitro. While this crosslinking does not always translate to failure in vivo, where enzymes can cleave the peptide backbone, the USP <711> recommends a two-tiered dissolution investigation when in vitro dissolution failure arises from crosslinking. The complicated testing protocol includes pH-dependent enzyme selection and, as elaborated in USP <1094>, additional testing on the compatibility of any surfactants includec in the medium. These additional tests require cumbersome method development and validation, lengthening the time and complexity of going to market. Figure 4. Viscosity vs. concentration of Kollidon VA 64 in Kollisolv PEG 300 at 25, 40 and 60 C.
To study the effect of degradation byproducts, particularly aldehydes, on softgel performance, five lots of polyethylene glycol 400 (PEG 400) of varying grades and storage conditions were selected for testing (Table 1). Two fresh lots of Kollisolv? PEG 400 LA were evaluated, as well as one Kollisolv PEG 400 LA at the 2-year retest. A compendial grade of PEG 400 that met Ph. Eur. and USP monographs was included, as well as a standard, non-pharmacopoeia PEG 400. The standard grade PEG 400 was a forced-aged compendial PEG 400 sample, stressed through aging at 60 C for 9 days and 80 C for 7 days. The starting aldehyde levels for each sample was determined by an in-house R&D method (Figure 7). Kollisolv PEG 400 LA had the lowest aldehyde concentration, under 10 ppm, with nc difference between fresh and at 2-year retest. The compendial PEG 400 sample had an aldehyde concentration almost two-fold higher than Kollisolv PEG 400 LA. Standard PEG 400 was nearl six-fold higher. Figure 7. Starting aldehyde levels for each grade of PEG 400. Table 1. PEG 400 samples for softgel formulations. Sample # Material Age to retest Grade 1 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 2 Kollisolv PEG 400 LA Fresh Low aldehyde (Ph. Eur., USP) 3 Kollisolv PEG 400 LA At 2-year retest Low aldehyde (Ph. Eur., USP) 4 Compendial PEG 400 Compendial (Ph. Eur., USP) 5 PEG 400 Standard Samples 1 and 2 represented two different freshly opened lots.
Brilliant Blue, serving as a model active pharmaceutical ingredient (API), was formulated at eque parts in the five PEG 400 samples. After the formulations were filled into softgel capsules using lab-scale filling equipment, the capsules were then stored at ambient (25 C, 60% RH) and accelerated (40 C, 75% RH) conditions for a 12-month period. In vitro dissolution of the softgel capsules was performed to evaluate the effect of aldehyde content on dissolution. The dissolution time to release 80% of the loaded Brilliant Blue was captured for each sample (Fig. 9). Softgels containing Kollisolv PEG 400 LA demonstrated an equivalent dissolution time over the full 12 months under ambient conditions; while even the compendial grade PEG 400 containing softgels exhibited delayed dissolution within 6 months. When stored at ambient conditions, the softgel capsules composed of Kollisolv? PEG 400 LA demonstrated superior stability over compendial and standard PEG 400 (Fig. 8). Over the course of 12 months, the softgels filled with fresh and 2-year Kollisolv? PEG 400 LA showed a stable release profile with no evidence of crosslinking or change in dissolution. The equivalence of performance with product age, fresh and at two years, demonstrates the stability of Kollisolv PEG 400 LA and reliability of performance. Figure 9. Dissolution time (until 80% release) of softgels stored at ambient (25 C, 60% RH) conditions taken as the time in minutes. In contrast, the softgel consisting of compendial PEG 400 increasingly delayed dissolution, with significant changes in dissolution evident by month 6. To an exaggerated degree, the softgel containing standard PEG 400 showed retarded dissolution and evidence of near-immediate crosslinking within the first month. Figure 8. Dissolution of softgels stored at ambient (25 C, 60% RH) conditions over a 12-month period. In accordance with USP<711>, formulations made with the compendial PEG 400 would require proof of gelatin crosslinking via spectroscopic methods and complicated dissolution tests. Comparatively, formulations that consisted of Kollisolv? PEG 400 LA would not require further investigation regarding crosslinking or dissolution. Even under stressed aging in accelerated storage conditions, softgels consisting of Kollisolv PEG 400 LA within the full 2-year retest period exhibited equivalent performance, demonstrating stability of the product within its shelf-life. Under accelerated storage, dissolution of capsules of fresh and retest-aged Kollisolv PEG 400 LA remained equivalent through 3 months (Fig. 10). In contrast, compendial PEG 400 mirrored the failure of standard, non- pharmacopoeia PEG 400, and both products showed immediately delayed dissolution within the first month, failing due to crosslinking of soft gelatin capsules. In this case, even meeting Ph. Eur. and USP standards for a pharmaceutical excipient did not impart stability over a non- pharmaceutical grade of PEG 400.
Figure 10. Dissolution of softgels stored at accelerated (40 C, 75% RH) conditions over a 6-month period. Under accelerated conditions, Kollisolv? PEG 400 LA offered improved stability of the dissolutior profile. Regardless of age, the three Kollisolv? PEG LA samples demonstrated an equivalent dissolution time over 3 months, suggesting stability studies under these conditions is feasible through 3 months (Fig. 11). In contrast, both compendial and standard, non-pharmacopoeia grades of PEG 400 exhibited delayed dissolution immediately, failing accelerated stability studies under these conditions. Aldehyde content within the softgels was determined at time points within both storage conditions. As softgel fills, Kollisolv? PEG 400 LA samples demonstrated minimal changes in the aldehyde content over a 2-year retest period. Evaluation of the aldehyde content showed that storage condition did not significantly impact the total aldehyde amount present in the softgel fill. Ultimately, Kollisolv PEG 400 LA did not develop aldehyde content over time when formulated in softgels, whether fresh or at retest, under ambient or accelerated storage (Fig. 12). Figure 12. Aldehyde development of Kollisolv PEG 400 LA in softgels, over 12 months at under ambien and accelerated storage. Figure 11. Dissolution time (until 80% release) of softgels stored at ambient (40 C, 75% RH) conditions taken as the time in minutes. In summary, Kollisolv? PEG 400 LA outperformed compendial PEG 400. The dissolution profiles from softgels at both ambient and accelerated storage conditions reflected a pre dilection towards Kollisolv PEG 400 LA, with stable release seen for longer than from compendial PEG 400. When using Kollisolv PEG 400 LA as the softgel fill, aldehydes did not develop over time at either ambient or accelerated storage conditions. Rather, the source and quality of the products had the greatest effect on the aldehyde levels. Fresh and at-retest Kollisolv PEG 400 LA samples offered a 50% reduction in starting average aldehyde content in comparison to compendial grade PEG 400. The repeatable and stable dissolution profiles seen for Kollisolv PEG 400 LA bring the advantages of rapid development and ease of qualification.
Topicals Emulgel formulation When used for topical applications, solid and liquid Kollisolv PEGs be combined to form water-soluble bases for ointments, suppositor and ovula. Low-molecular-weight Kollisolv? PEGs can be used as solvents, conditioners, adhesion promoters, and humectants. These products, like Kollisolv PEG 300, Kollisolv PEG 400, and Kollisolv PEG 1000, promote ease of application, softening on contact with skin, and localization of active delivery. High-molecular-weight Kollisolv PEGs can be used as structuring agents and thickeners to increase the viscosity of formulations. These include Kollisolv PEG 1450, Kollisolv PEG 3350, and Kollisolv PEG 8000. Hydrophilic ointment formulation Kollisolv PEG ointments can be used as an alternative to traditional petrolatum-based ointmen formulations. By pairing different amounts of high- and low-molecular-weight chains, PEG ointments can be tuned for desirable rheological profiles and sensory. Procedure 1. Prepare phase A by weighing ingredients into an appropriately sized beaker. 2. Heat the mixture to 60 C and continue heating until the mixture has completely melted. Try to minimize the heating time as much as possible. 3. Once all the components have melted, place phase A underneath an overhead mixer. Stir at a low shear rate until cooled to room temperature. Kollisolv PEG 3350 is commercially available only in the USA and Canada as an excipient.
Suppositories allow formulators to accurately deliver active ingredients through an alternative route. Kollisolv PEG suppositories are ideal for the formulation of suppository matrices, offering a melting temperature range within physiologically relevant conditions and compatibility with hydrophilic druas.
Product details and key benefits Product details Regulatory Manufacturing site Manufacturing process Re-test period Certified Handling Safety data sheet Retest date and storage conditions Specification Regulatory status Key benefits Supply reliability & consistent quality Sustainability Technical service BASF Virtual Pharma Assistants Kollisolv? PEGs USP-NF, Ph. Eur. Geismar, Louisiana (USA) Synthetic 24 months Kosher, Halal Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRPI). For current specification, please speak to your local BASF sales or technical representative. Please refer to Quality & Regulatory Product Information (QRPI). Kollisolv PEGs are manufactured in a GMP compliant facility in the U.S. ensuring: Consistent quality and safety @ Reliable, vertically integrated supply BASF is a proud member of the Pharmaceutical Supply Chain Initiative (PSCl), whose vision is to establish and promote responsible practices that will continuously improve human rights, health, safety, and environ- mentally sustainable outcomes for supply chains worldwide. @ World class expertise in excipient chemistry Formulation guidance with ZoomLab @ Regulatory documentation available in RegXcellence Product details available via MyProductWorld @ Full pharma regulatory documentation and submission support Product details and key benefits
For sample requests contact us at pharma-solutions@basf.com This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to th extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matte in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2022 BASF Corporation. All Rights Reserved.
Technical Information Poly (Vinyl Acetate) Dispersion 30 per Cent Ph. Eur. Polyvinyl Acetate Dispersion USP. January 2019 Supersedes issue dated October 2010 Last change WF-No. 137134 = Registered trademark of BASF in many countries.
1. Introduction Kollicoat SR 30 D is a polyvinyl acetate dispersion stabilized with povidone and sodium lauryl sulfate. The dispersion is suitable for the manufacture of pH-independent sustained-release formulations. 2. Technical properties Description The dispersion consists of about 27% polyvinyl acetate, 2.7% povidone and 0.3% sodium lauryl sulfate. The low viscosity product has a weak characteristic odor and a milky white or slightly yellowish appearance. Trivial name Poly (Vinyl Acetate) Dispersion 30 per cent CAS-number 9003-20-7 Structural formula Solubility Kollicoat SR 30 D is miscible with water in any ratio while retaining its milky-white appearance. Mixing the product with ethanol or isopropyl alcohol in a 1 : 5 ratio produces a slightly turbid and somewhat viscous solution; a solution in acetone is more turbid. When organic solvents are added, the polymer precipitates at first, but then dissolves when further solvent is added. Kollicoat SR 30 D is insoluble in dilute alkaline or acidic solutions. Kollicoat SR 30 D is insoluble in dilute alkaline or acidic solutions.
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application Application Sustained-release coated formulations Kollicoat SR 30 D is used mainly for the manufacture of sustained-release dosage forms. Very effective control of drug release is achieved by coating pellets, granules and crystals. Sustained-release matrix formulations Matrix tablets can be produced by granulating active ingredients, for example in the fluidized bed process, followed by compression. Processing information The dispersion is not particularly vulnerable to external influences. Nevertheless, the following factors could result in coagulate formation that precludes urther use of the dispersion: UNIET Use Ol Ul& UloVerolUrl. addition of finely dispersed pigments high shear gradients in stirrers and mills addition of emulsifiers, stabilizers or wetting agents pH changes organic solvents foaming The minimum film-forming temperature (MFT) of the pure dispersion is 18 C. It can b lowered by adding plasticizers. The dispersion can theoretically also be used without plasticizers, but these additives enhance film formation and the flexibility of the films. The following are suitable as plasticizers or gloss enhancers: ne folowing are Sultapdle as plasticizers OF gloss ennancers: e 1,2-propylene glycol e triethyl citrate polyethylene glycols and e triacetin The recommended plasticizer content is 0 - 10% with reference to the dried polymer substance. 1,2-Propylene glycol offers advantages for processing the dispersion and for film properties. Plasticizer supplement MFT 2.5% 5% 10% 15% 2.5% 5% 10% 15% propylene glycol propylene glycol propylene glycol propylene glycol triethyl citrate triethyl citrate triethyl citrate triethyl citrate 18C 16 C 14C 12C 10C 8C 1C <0C Triethyl citrate lowers the MFT more than propylene glycol. Kollicoat SR 30 D films without plasticizer are relatively brittle in the dry state; when wet, however, they are very flexible (elongation at break > 100%). A small plasticizer supplement also increases the flexibility of the polymer in the dry state. Elongation at break values of more than 250% can be achieved using 5% triethyl! citrate or 10% propylene glycol. Crack formation in coats, due for example to pronounced swelling of the core, is thereby prevented.
Fig. 1: Correlation of elongation at break of isolated films and plasticizer content The permeability of the water-insoluble but swellable films can be varied by: e the layer thickness of the coat e the use of pore formers (Kollidon VA 64, Kollidon 30, HPMC, Avicel PH 105) The required content depends on the desired release profile. The layer thickness should not be less than 1.5 mg/cm? (= about 15 pm) since otherwise film defects and burst effects are to be expected. Kollicoat SR 30 D can be applied using either a top spray or bottom spray in the fluidized-bed coater. Kollicoat SR 30 D has no charged or ionizable groups and consequently results ir pH-independent film coats. Using talc in the spray formulations reduces the sticking tendency thereby preventing agglomeration of small particles in the fluidized bed as well as adhesion effects. Mixing the coated particles with 0.1 0.5% Aerosil 200 prevents cohesion during storage even at elevated temperatures. Cleaning recommendation As polyvinyl acetate is insoluble in water, acid and alkali, residues cannot simply be removed with aqueous solutions. However, they can be soaked in hot water until they swell and then reomoved with high pressure or hot water cleaners or mechanically with brushes and conventional cleansers. As polyvinyl acetate is soluble in ethanol and 2-propanol, these alcohols can also be used. This is of particular interest for the cleaning of smaller apparatus parts such a: nozzles and tubes.
Formulation examples Theophylline sustained-release pellets Theophylline sustained-release pellets Composition of spray suspension Composition of spray suspension The formulation is designed for 500 g pellets (diameter 0.8 1.3 mm) Parts by weight Composition [g] [%] Polymer suspension Kollicoat SR 30 D 223.67 50.0 Propylene glycol 6.71 1.5 Water 149.86 33.5 Pigment suspension Kollidon 30 2.24 0.5 Titanium dioxide 2.24 0.5 Sicovit Red 30 2.24 0.5 Talc 15.66 3.5 Water 44.73 10.0 447.35 100.0 Preparation of spray suspension Polymer suspension Propylene glycol followed by Kollicoat SR 30 D are added to the stated quantity o water with stirring. Pigment suspension Kollidon 30 is dissolved in the stated quantity of water. Sicovit Red 30, titanium dioxide and talc are added with vigorous stirring and the mixture is homogenized with a corundum disk mill. Spray suspension The pigment suspension is incorporated into the polymer suspension with stirring. The suspension must be stirred during the spray process to prevent settling. Machine parameters Aeromatic Strea-1 fluidized bed granulator Machine Aeromatic Strea-1 fluidized bed granulator Batch size 500 g Inlet air temperature 60 C Outlet air temperature 37C Product temperature 38 C Air flow 80 m/h Spraying pressure 1 bar Spraying rate 11.5 g/min Spraying time 39 min Secondary drying 45 C/5 min Coating level 2 mg film former/cm?
The spray suspension is sprayed continuously onto the fluidized, pre-heated pellets by the top spray method. The spray suspension is sprayed continuously onto the fluidized, pre-heated pellet: by the top spray method. The coating level of 2 mg film former/cm? stated here was established for the pellets by surface area determination. Since the particle size distribution and surface structure influence the required polymer quantity, calculating the surface area is recommended as a means of estimating the required coating level in each specific case. Fig. 2: Dissolution of Theophylline sustained-release pellets
Caffeine sustained-release pellets Composition of pellets 10% caffeine, 43.75% Avicel PH 101, 43.75% lactose, 2.5% Kollidon VA 64 Composition of spray suspension The formulation is designed for 500 g pellets (diameter 0.7 1.4 mm) Parts by weight Composition [g] [%] Polymer suspension Kollicoat SR 30 D 269.44 49.3 Propylene glycol 8.09 1.5 Water 188.61 34.5 Pigment suspension Kollidon 30 Qf 0.5 Titanium dioxide 27 0.5 Sicovit Red 30 2.7 0.5 Talc 18.87 3.4 Water 53.89 9.8 547.99 100.0 Preparation of spray suspension See Working Theophylline sustained-release pellets (page 5). Machine parameters Aeromatic Strea-1 fluidized bed granulator Machine Aeromatic Strea-1 fluidized bed granulator Batch size 500 g Inlet air temperature 60 C Outlet air temperature 36 C Product temperature 37 C A\r flow 80 m%/h Spray pressure 1 bar Spraying rate 12 g/min Spraying time 45 min Secondary drying 45 C/5 min Coating level 3 mg film former/cm? The spray suspension is sprayed continuously onto the fluidized, pre-heated pellets by the top spray method. The coating level of 3 mg film former/cm? stated here was established for the pellets by surface area determination. Since the particle size distribution and surface structure influence the required polymer quantity, calculating the surface area is recommended as a means of estimating the required coating level in each specific case.
Fig. 3: Dissolution rate of Caffeine sustained-release pellets at different coating levels Curing (Thermal postcoating treatment) of the pellets is not necessary. Fig. 4: Dissolution rate of Caffeine sustained-release pellets with and without curing
Fig. 5: Dissolution rate of Caffeine sustained-release pellets with and without curing The release of caffeine pellets is DH independent. Propranolol sustained-release pellets Composition of pellets 20.0% propranolol, 51.66% Avicel PH 101, 25.84% lactose, 2.5% Kollidon VA 64 Composition of spray suspension The formulation is designed for 500 g pellets (diameter 0.4 - 1.5 mm) Parts by weight Composition [9] [%] Polymer suspension Kollicoat SR 30 D 249.41 49.2 Propylene glycol 7.49 1.5 Water 174.59 34.5 Talc suspension Talc 29.94 5.9 Water 44.91 8.9 506.34 100.0 Preparation of spray suspension See Working Theophylline sustained-release pellets (page 5).
Machine parameters Aeromatic Strea-1 fluidized bed granulator Fig. 6: Dissolution rate of Propranolol sustained-release pellets
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technical representative. Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data The toxicological abstract is available on request. 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30067541 Kollicoat SR 30 D 51597817 1 kg Plastic bottle 50893290 25 kg Plastic jerricans BASFs commercial product number. 11. Publications http://pharmaceutical.basf.com/en.html Inis aocument, or any answers or Information proviaea nerein Dy BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Kolliphor Grades - Emulsifier for topical pharmaceutical application: January 2014 ) = Registered trademark of BASF in many countries.
Rebranding As a result of the integration of former Cognis excipients in the BASF portfolio a rebranding was conducted. The rebranding should increase the reliability and compliance for the supply of pharmaceutical excipients. The following table shows a comparison of old versus new trade names. Tradename Former Tradename Kolliphor CS 12 Eumulgin B1 PH Kolliphor CS 20 Eumulgin B2 PH Kolliphor CSS Lanette E PH Kolliphor CS A Lanette N PH Kolliphor CSL Lanette SX PH Tradename Table 1: New Tradenames Old Tradenames PRD-No., Article-No. and CAS.-No. Tradename PRD-No. Article-No. CAS.-No. Kolliphor CS 12 30554458 50253256 68439-49-6 Kolliphor CS 20 30554459 50253257 68439-49-6 Kolliphor CSS 30554486 50253269 68955-20-4 Kolliphor CS A 30554487 50253281 67762-27-0 68955-20-4 Kolliphor CSL 30554435 50253856 67762-27-0 161-21-3 68955-20-4 Table 2: PRD and Article and CAS number of the Kolliphor Grades See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Regulatory Status In table 3 you can find all the monographs for the Kolliphor Grades. New Name Monograph Tests Kolliphor CS 12 Ph. Eur. : Macrogol Cetostearyl Ether 12 Kolliphor CS 20 Ph. Eur. : Macrogol Cetostearyl Ether 20 USP/NF: Polyoxyl 20 Cetostearyl Ether Kolliphor CSS Ph. Eur. : Sodium Cetostearyl Sulphate Kolliphor CS A Ph. Eur. : Cetostearyl Alcohol (Type A), Emulsifying Kolliphor CSL not monographed Table 3: Compendial names
An emulsion is a dispersion of droplets of a non-miscible liquid in a continuous phase. The polar (hydrophilic) aqueous phase and the non-polar (lipophilic) oil phase of an emulsion cannot be combined in a stable and homogenous way without a surface-active additive. Product groups Emulsifiers are interfacial active substances that reduce the interfacial tension between the oil and the water phase. The emulsifier is adsorbed at the interface, giving a film between both phases, which prevents coalescence of droplets. Due to its amphiphilic structure, the polar part of the emulsifier has an affinity to the water phase and the non-polar part of the emulsifier to the oil phase. Emulsifiers can be defined according to their hydrophilic/lipophilic characteristics In 1949 W.C. Griffin proposed the HLB (Hydrophilic- Lipophilic Balance) system in which non-ionic surfactants have been classified on a scale from 0 to 20. Emulsifiers with a strong lipophilic character have low HLB values between 3 to 8 and tend to form W/O emulsions. Emulsifiers of the HLB range of 8 to 18 are hydrophilic and form O/W emulsions. HLB values from 12 to 18 are most favorable for solubilization to enhance bio- availability of active ingredients. Emulsifiers can be classified according the chemical structure in non-ionic and ionic emulsifiers or emulsifying waxes. Non-lonic Emulsifier Ethoxylates Chemical structure Figure 1: Chemical structure Kolliphor CS 12 and Kolliphor CS 20 Typical Properties Product R-Lipo- N-Hydro- Appearance HLB Usage pH phil phil value concen- working tration range Kolliphor CS 12 C,,,C,, 12xEO White or 13 05-5% 2-12 yellowish white waxy powder Kolliphor CS 20 C,,,C,, 20xEO White or 15 05-5% 2-12 yellowish white waxy powder Table 4: Typical properties Kolliphor CS 12 and Kolliphor CS 20
lonic Emulsifier Kolliphor CSS Chemical Structure Figure 4: Chemical structure Kolliphor CSS (n=15 or 17) Typical properties olliphor CSS_ White or pale yellow amorphous >40 0.5-2% 7- or crystalline powder Emulsifying Waxes (Cream-bases) are a combination of a consistency factor (eg. Fatty alcohols) and an emulsifier. They are especially designed to enable an effective and short development time of a topical pharmaceutical formulation. Cream-bases/Emulsifying Waxes Typical properties Typical properties Product Ingredients Appearance HLB Usage pH value concen- working tration range Kolliphor CS A Cetostearyl Alcohol White or pale 7.0 0.5-5% 6-12 Sodium Cetostearyl vet waxy Sulphate pellets Kolliphor CSL Cetostearyl Alcohol Pellets 75 0.5-5% 6-12 Sodium Lauryl with a faint Sulfate characteristic odor Sodium Ceteary Sulfate Table 6: Typical property of the creambases/emulsifying waxes
Application The choice of emulsifiers for specific applications depends on the desired pro- perties of the formulation (e.g. stability, viscosity, skin feel and API), or on the desired processing technology (e.g. PIT, Hot or cold processing). The traditional processing technology for emulsion is the so called hot process, where you combine both water and oil phase at a temperature of 70 85 C. With this technology you are very flexible in the ingredients you can choose in your emulsion. Beside the well-known hot process of emulsification, there is also the possibility to formulate an emulsion with a processing temperature at room temperature. The processing of O/W emulsions at room temperature has several significant benefits. For example, it is no longer necessary to heat the water and oil phase to 70 80 C. This saves considerable amounts of energy and reduces the production time as the cooling step is eliminated. Another very important advantage is that heat-sensitive APIs can be added t the emulsions at any point. On the other hand the possible ingredients are limited as there is not melting step of the oil phase. In the BASF portfolio of emulsifier for topical pharmaceutical applications only Kolliphor PS 60 is suitable for this kind of processing technology. Another very interesting processing technology is the Phase Inversion Technology (PIT) as it leads to water thin emulsions with a very small droplet sizes and thus these emulsions are very stable. This processing technology uses the temperature dependency of the HLB value of non-ionic emulsifiers as this kind of emulsifier change solubility behavior with elevated temperature. This can be used for pharma- ceutical applications where a very thin emulsion is needed, which is easy to distribute over the skin (e.g. sorayable wound sprays etc.). = a\e >. 8\8 ee 5 B/2/E = F/JE o el fete! S] She a 2s 5 o 2) dD) 33), 5/2 9 S\5\5 3/8 E)E R ele] S/S) 0/5] 8] Pia Wy} 2) OE) 19) a) s 2i0 QS/Z\ S/S 3 ss 8 4/85 Product Ph. Eur. S\SIGISIESEAAZIGA Kolliphor CS 12} Marcrogol Cetosteary x x x x x]x x Ether 12 Kolliphor CS 20} Marcrogol Cetosteary x x x x x]x x Ether 20 Kollliphor CS A Cetostearylalcohol x bay xX x x (Type A), Emulsifying i _ Kollliphor CSS__ Sodium Cetosteary! x ba x x Sulphate Kollliphor CSL x Ba X x x Table 7: Application fields in topical pharmaceutical formulations of the Kolliphor grades
Skin Tolerance All Kolliphor grades are based on vegetable and synthetic raw materials. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreemen In originally sealed containers all Kolliphor types can be stored for at least two years. It is important that they are protected from moisture and stored at less than 30 C. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal Handling and Disposal This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. January 2014
Technical Information Hydrogenated castor oil powder for pharmaceutical use. Mai 2023 Supersedes issue dated November 2018 Last change WF-No. 136683 = Registered trademark of BASF in many countries.
1. Introduction Kolliwax HCO consists of Hydrogenated Castor Oil in powder form intended for pharmaceutical use. At room temperature it is a hard wax with a high melting point (85 88 C). The primary function of Kolliwax HCO is its use as an excipient in both oral and topical pharmaceuticals. For example,in solid oral dose formulations, Kolliwax HCO is a highly effective lubricant, as well as a matrix lipid for the preparation of sustained release formulations. In topical preparations, Kolliwax HCO is a structure- building consistency factor that can provide stiffness, viscosity and various sensorial properties. 2. Technical properties Description Kolliwax HCO is obtained by hydrogenation of castor oil. It mainly consists of the trigiceride of 12-hydrostearic acid. Hydrogenated castor oil is vegetable origin (castor oil) and is compatible with most natural vegetable and animal waxes. Structural formula The chemical structure of Kolliwax HCO is represented in Figure 1. Figure 1: Chemical structure of hydrogenated castor oil CAS number 8001-78-3 Particle size distribution Kolliwax HCO is milled to its final particle size distribution; an example of a typical lot of Kolliwax HCO is shown in Figure 2. Typical Particle size distribution _D (10) D (50) D (90) D (4,3) Kolliwax HCO 3.8um 26.14 um 72.9umM 33.0~um 7 100 6 5 80 & 4 60 E 3 2 40 > 2 1 20 Oo oO 01 1 10 100 100 300 Particle size [um]
Dynamic vapor sorption DVS was measured for Kolliwax HCO under the following conditions: DVS was measured for Kolliwax HCO under the following conditions: Time between cycles 20 min, Min. time per cycle 50 min, Max. time per cycle 36 h Equilibrium condition 0.05 % per 15 minutes. The maximal water uptake at 90% rel humidity was at 0.1%. Therefore the materia is considered to be not hygroscopic. Solubility As per the Ph. Eur. Monograph. Castor oil, hydrogenated Kolliwax HCO is practically insoluble in water, slightly soluble in methylene chloride, very slightly soluble in anhydrous ethanol and practically insoluble in petroleum. Differential scanning calorimetry (DSC) Test conditions: Heating range 10 K/min Sample amount 6-7mg First heating cycle -20 - 120 C Cooling cycle 120 - -20 C Second heating cycle -20- 120C Cycle T Onset Tmax1 Tmax 2 T max 3 T Offset AH (C) (C) (C) (?C) (?C) J/g 1. Heating 59 79 87 / 91 142 (+0.6) (+0.2) (+0,0) (+0.2) (41) 2. Heating 51 60 80 86 89 135 (40.3) (+0.4) (40.2) (+0.1) (+0.1) (#1) 3. Cooling 51 60 80 86 89 135 (40.3) (+0.4) (40.2) (+0.1) (+0.1) (#1) Table 2: DSC Summary Figure 2: Typical DSC curve of Kolliwax HCO
Flowability data Kolliwax HCO is a finely milled powder and exhibits flowability consistent with fine powders. Typical powder properties are listed in the following table. Typical powder properties Value Unit Angle of repose blocked Typical powder properties Value Unit Angle of repose blocked Density Typical powder properties Value Unit Bulk density g/mL 0.38 Tap density g/mL 0.52 Hausner factor 8 1,3743.2 ek Typical powder properties Value Unit Bulk density g/mL 0.38 Tap density g/mL 0.52 Hausner factor 8 1,3743.2 Scanning Electron Microscopy Pictures (SEM) Images of a typical lot of Kolliwax HCO are shown in the following SEM images a various magnifications.
3. Handling Please refer to the individual Material Safety Data sheet (MSDS) for instructions or safe and proper handling and disposal. 4. Example Application Lubrication Lubrication is an essential part of solid oral dose preparation, where specifically, lubri- cants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction. Consequently, lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. In solid oral dose formulations Kolliwax HCO can be used as an effective alternative lubricant to magnesium stearate. Furthermore, it is compatible with a large number of actives, and does not provide a metallic taste. The following study elaborates the optimal working concentration of Kolliwax HCC as a lubricant. This study was performed on direct compressible placebo formulations using Ludipress. The Sweet Spot diagram shows the optimal working concentratior balancing the lubrication effectiveness with the ejection force and the tablet characteristic (e.g. disintegration and hardness). Study design ey Seen ee a Formulation 1 2 3 Ludipress 99.5% 99.0% 97.0% Kolliwax HCO 0.5% 1.0% 3.0% Blending time: Turbula blender with 2 / 5 / 10 minutes mixing time Turbula blender with 2 / 5 / 10 minutes mixing time Korsch XL 100 rotary press, 10 mm flat, 300 mg tablet mass 3kKN/5KN/10kN/ 15 kN / 20 Kn Compression: Evaluation parameter Evaluation parameter Compression behavior: Compression force upper punch, Compression force lower punch, Ejection force Tablet characteristics: Weight, Height, Diameter, Hardness, Tensile strength, Disintegration time Weight, Height, Diameter, Hardness, Tensile strength, Disintegration time
Sweet spot diagram Diagrammm 2: Sweet spot diagram for optimal working concentration of Kolliwax HCO as lubricant The optimal working concentration of Kolliwax HCO as a lubricant is starting a 1.5% w/w. Modified release As either a lipid-based matrix, or a coating ingredient, Kolliwax HCO may be used to prepare a sustained released formulation for water soluble APIs (e.g. Alfuzosin HCL, Aminophylline, Lithium Carbonate, Niacin, Sulfanilamide, Theophylline). Kolliwax HCO can be used as a standalone matrix ingredient or in combination with other sustained release excipients. Typical concentrations for matrices and coatings can range from 5% to greater than 20% w/w. Topical application In topical formulations Kolliwax HCO can be used as consistency factor to enhance the viscosity of the formulation. The typical concentration it at about 0.1 - 2%. Kolliwax HCO is compatible with most natural vegetable and animal waxes and can therefore be used in combination with fatty alcohols and other consistency factors (e.g. Cetyl Alcohol, Steary! Alcohol). Waxes can also affect the sensory profile and the stability of a topical formulation. They are solid at ambient temperatures and stabilize emulsions as the viscosity is increased by formation of lamellar structures in oil-in-water formulations. Specifically, Kolliwax HCO can be used as consistency factor in a multitude of O/W, W/O or anhydrous formulations. Kolliwax HCO has a special advantage because of its high melting point and is able to support the formulation stability particularly at elevated temperatures. However, it is critical that the oil phase of the formulation is thoroughly melted and well mixed prior to emulsification. Below is a placebo formulatior example, which can be used as a starting point for further formulation work with different types of APIs.
Cream formulation Phase Tradename Chemical Function % Di Water Water Solvent 70.8 Glycerin Glycerin Humectant 5.0 Kolliphor CSS Sodium cetostearyl sulfate Emulsifier 1.0 ll Kollicream IPM Isopropyl myristate Emollient 5.0 Kolliwax HCO Hydrogenated castor oil Consistency factor} 2.0 Kolliwax CSA 50 Cetostearyl alcohol Consistency factor! 6.0 Hl Preservative Preservative Preservative 0.2 IV API Active pharmaceutical API 10.0 ingredient Procedure: Heat the mixture phase and Il separately to 85 - 90 C: Make sure that Kolliwax HCO is molten. Mix phase and II, homogenize 2 minutes at about 5000 rpm, transfer to impeller mixer, 4 flat blades at 250 rpm. At 40 C add Ill, cool down to 30 C and add to a sealed glass container. Allow tc equilibrate for 24 hours prior to analytical testing and or evaluation. Anhydrous formulation Phase Tradename Chemical Function % Novata BC PH Hard Fat Consistency factor 21.6 White wax Cera alba Consistency factor 4.2 Kolliwax GMS II Glyceryl monostearate Consistency factor 3.9 Kolliwax HCO Hydrogenated castor oil Consistency factor} 2.6 Kollicream CP 15 Cetyl Palmitate Emollient 4.9 Kollicream 3C Cocoyl caprylocaprate Emollient 18.1 ll Kollicream OD Octyldodecanol Emollient/Solvent 19.7 Kollisolv? MCT 70 Medium chain triglycerides Solvent 23.0 API Active pharmaceutical API 2.0 ingredient Procedure: Heat phase to 85 - 90 C: Make sure that Kolliwax HCO is molten. Heat phase separately to 70 C or until API is solubilized. Mix phase using an impeller mixer, 4 flat blades at 500 rpm. At 70 C add phase II. Cool to 30 C while stirring at 250 rpm and add to a sealed glass container. Allow to equilibrate for 24 hours prior to analytical testing and or evaluation.
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage condition: 6. Retest date and storage condition: Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technica representative. . Regulatory status Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data The toxicological abstracts are available on request. 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30674274 Kolliwax HCO 50487016 20 kg Fibreboard boxes 50520786 0.5kg Plastic bottle BASFs commercial product number. 11. Publications http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Fatty acids and alcohols: Consistency factors for topical formulations, and excipients for solid oral dosage forms. Oktober 2021 WF-No. 137189 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes fatty acids and alcohols that can be used as (co-) emulsifiers and consistency factors in topical pharmaceutical applications, but may also function as excipients in solid oral dosage forms, e.g., as matrix formers and lubricants. This document focuses on fatty acids and alcohols of the Kolliwax family. Please refer to the individual technical information sheet for specific information on our two glyceride based grades Kolliwax GMS II and Kolliwax HCO (Glycerol Monostearate, and Hydrogenated Castor Oil, respectively). Trade name Compendial Name Kolliwax CA Ph.Eur.: Cetyl Alcohol USP/NF: Cetyl Alcohol Kolliwax CSA 50 Ph.Eur.: Cetostearyl Alcohol USP/NF: Cetostearyl Alcohol JP: Cetostearyl Alcohol Kolliwax CSA 70 Ph.Eur.: Cetostearyl Alcohol Kolliwax MA USP/NF: Myristyl Alcohol Kolliwax SA Ph.Eur.: Stearyl Alcohol Kolliwax SA Fine USP/NF: Stearyl Alcohol JP: Stearyl Alcohol Kolliwax S Ph.Eur.: Stearic Acid 50 Kolliwax S Fine USP/NF: Stearic Acid 50 llPe Stearic Acid 50 Table 1: Compendial names for fatty alcohols and acids of the Kolliwax family. Description 2. Technical properties Kolliwax grades are white to slightly yellowish, waxy substances derived from natural ressources, namely coconut oil, palm kernel oil, and/or palm stearine. With melting points above room temperature, these products are either supplied as powder, pearls, or pelletts (see table1 and table 2 for details). The numeric part of the name of the two grades of Kolliwax CSA represents the approximate weight percentage of stearyl alcohol. es ene Trade name Chemical nature CAS-No. Melting ranges [cy Kolliwax CA Cetyl Alcohol (C,,) 36653-82-4 46-52 Koliwax CSA S0_ Cety/Stearyl Alcohol 7769 97.9 1666 Kolliwax CSA70_ (Cie/Cra) Kolliwax MA Myristyl Alcohol (C,,) 112-72-1 36-42 Kolliwax SA Stearyl Alcohol (C,,) 112-92-5 57-60 Kolliwax SA Fine Koliwax?S Stearic/Palmitio Acid g 7754 93.05 308 Kolliwax S Fine (Cil/Cy6) Values given for guidance only, see specification sheets for detailed information on melting and/or freezing temperatures. Table 2: Properties of fatty alcohols and acids of the Kolliwax family.
Figure 1: Typical appearance of the Kolliwax grades. The scale in the back is metric, with 1 mm per mark. For detailed information on particle size distributions, please refer to the individual product specification sheets. Scanning electron mircroscopy (SEM) igure 2: SEM images of Kolliwax S, and Kolliwax S Fine. Please refer to the individu: specification sheets for detailed information on particle size distributions.
3. Application Overview The following table 3 gives an overview on the most important applications and functions of the Kolliwax fatty alcohols and acids: while fatty acids and alcohols are generally used as consistency factors, our fine grades of stearic acid and stearyl alcoho (Kolliwax S Fine and Kolliwax SA Fine, respectively) allow to use these substances in the preparation of solid dosage forms, where they can aid as lubricants or matrix formers. Table 3: Application of the Kolliwax grades. Emulsions Exhibiting excellent skin tolerance, the Kolliwax grades can be used for all kinds of topical pharmaceutical applications, such as creams, gels, lotions, and ointments. The typical usage concentration in emulsions is about 1- 5%. All Kolliwax grades will act as consistency factors and co-emulsifiers at the same time. With their amphiphilic structure, they will stabilize the interface between oil and water and will help to enhance the viscosity by building up a liquid crystalline network (lamellar sheet structure). Stabilizing w/o and 0/w emulsions, they also aid in bringing a unique softness and creaminess to the targeted formulation. Lubricants In tableting processes for solid oral dosage forms, lubricants are used to prevent ingredients from clumping to undesired aggregates and from sticking to the tablet punches or capsule filling machine. In addition, lubricants hamper the friction that would hinder tablet formation and ejection. Among inorganic materials (e.g. talc or silica), fat based substances like vegetable stearin, magnesium stearate or stearic acid are commonly used as lubricants in tablets or hard gelatin capsules. Lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. Formulation examples Guideline for the preparation of the model formulations: MaYIGenne 1Or UWle PrepalrauviOrl OF WIE MIOQE! fOMTIUlAvOrls. 1. Heat components of phase A to 80 - 85 C and stir until transformed into a homo- geneous melt. 2. Heat components of phase B to 80 85 C. Under constant stirring, slowly add phase A to phase B, homogenize for 5 min at 5000 rpm. Let cream cool to 35 C while mixing at 200 rpm, and add preservative.
Model formulation Rich Cream: This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as emulsifiers to create avery stiff cream that offers a slow spread and a cushioned feeling when rubbing into the skin. Its high immediate smoothness results from the utilization of Kollicream IPM, a fast spreading oil with broad penetration enhancement properties that can aid as a solubilizer for lipophilic drugs. Ingredient Phase Ph. Eur. name Role Amount [wt.-%] A __ Kolliwax CSA 70 Cetostearyl Alcohol Consistency Factor, 7.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 25 40-55 (Type Il) Co-Emulsifier Kolliphor PS 60 Polysorbate 60 Emulsifier 4.2 Kollisolv@ MCT 70 Medium Chain Emollient 11.5 Triglycerides Kollicream IPM Isopropyl Myristate Emollient 1.3 B Deionized Water 69.2 Solvent _____. Glycerol 3.3 C_ Euxyl PE 9010 Preservative 1.0 Table 4: Model formulation for a rich Cream. Model formulation Light Cream: This formulation is a smooth cream with easy distribution, medium viscosity, and a glossy finish. Due to the difference in HLB values, the blending ratio of Kolliphor CS 12 and Kolliphor CS 20 can be used as a factor to maximize emulsion stability. Phase Ingredient Ph. Eur. name Role Amount [wt.-%] A_ Kolliwax CSA 50 Cetostearyl Alcohol Consistency Factor, 4.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 5.0 40-55 (Type Il) Co-Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Emulsifier 2.0 Ether 20 Kolliphor CS 12 Macrogol Cetostearyl Emollient 0.8 Ether 12 Kollicream CP 15 Cetyl Palmitate 15 Emollient 0.8 Kollicream IPM Isopropyl Myristate Emollient TA B__ Deionized Water 74.0 Solvent Glyerol 5.0) C_ Euxyl PE 9010 Preservative 1.0 in Si Pe Table 5: Model formulation for a light cream. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment.
5. Product specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554718 olliwax CA 50253459 25 kg Plastic film bag 50259499 0.5 kg Plastic bottle 30554719 olliwax CSA 50. 50253501 25 kg Plastic film bag 50259500 0.5 kg Plastic bottle 30554721 olliwax CSA 70 50253504 25 kg Plastic film bag 50259502 0.5 kg Plastic bottle 30554492 olliwax MA 50375472 20 kg Corrugated fiberboard box with PE liner 50259498 0.5 kg Plastic bottle 30554720 olliwax SA 50253503 25 kg Plastic film bag 50259501 0.5 kg Plastic bottle 30563963 olliwax SA Fine 50284249 25 kg Plastic film bag 50372378 0.5 kg Plastic bottle 30554752 olliwax S 50253532 25 kg Plastic film bag 50259521 0.5 kg Plastic bottle 30554750 olliwax S Fine 50253810 25 kg Plastic film bag 50259508 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information isoluble Kollidon grades Crospovidone Ph. Eur., USP and JP Crospovidone as excipient for the pharmaceutical industry Crospovidone as excipient for the pharmaceutical industry January 2019 Supersedes issue dated September 2011 Last change WF-No. 136636 = Registered trademark of BASF in many countries
1. Introduction The insoluble grades of Kollidon are widely used in the pharmaceuticals industry because of their swelling properties. They are thus predominantly used as disintegrants in solid oral dosage forms such as tablets. Furthermore their application as pharmaceutical excipients is triggered by their ability to hydrophilize insoluble drugs, to stabilize suspensions and to form complexes. 2. Technical properties Description The insoluble Kollidon grades are supplied as fine white or almost white powders. They have a slight characteristic odor and are practically tasteless. They are insoluble in all of the usual solvents. The insoluble grades of Kollidon (Crospovidone) are manufactured by a polymerization process that yields crosslinked insoluble polyvinylpyrrolidone in the form of a popcorn polymer. The polymerisation is performed using an aqueous system. Neither organic solvents nor radical starters are involved at any stage. The crosslinking is of chemical and physical nature. The latter one, mainly achieved by entanglement of the polymer chains, dominates the product properties. This is supported by comparisons of the infrared spectra of the soluble and insoluble grades of polyvinylpyrrolidone which do not reveal any differences. In contrast, the infrared spectrum of chemically crosslinked insoluble vinylpyrrolidone polymer prepared in the laboratory is quite different. Details that are beyond the scope of this brochure can be found in the books, Kollidon, Polyvinylpyrrolidone for the pharmaceutical industry, published by BASF or Polyvinylpyrrolidone-Excipients for Pharmaceuticals, published by Springer-Verlag, ISBN 3-540 23412-8 Synonyms Crospovidone, crospovidonum, insoluble polyvinylpyrrolidone, crosslinked PVP. Product range Due to the fact that Crospovidone is completely insoluble the corresponding products cannot be named according to a K-value or a molecular weight. The product differentiation is done mainly by the particle size distribution. The followinc products are available: Kollidon CL Kollidon CL-F Kollidon CL-SF Kollidon CL-M The products differ not only in their particle size distributions but in other physical pro- perties, too, such as in their bulk density and their swelling behavior. CAS-number 9003-39-08
Picture 1: Crospovidone Hygroscopicity The hygroscopic properties of the Kollidon grades are important in many applications. There is hardly any difference between the individual grades so that they can all be represented by a single curve (Fig. 1). The curve shows the amount of water absorbed after seven days exposure to different conditions of relative humidity. Fig. 1: Hygroscopicity of the Kollidon CL-grades
Swelling and hydration properties One of the most important properties of the insoluble Kollidon CL-grades used as tablet disintegrants is their property to swell very fast and predictably without forming a gel. A number of methods are described in the literature for measuring swelling properties in aqueous media. The data for the swelling pressure shown in table 1 were measured with a powder mass of 0.3 g and a punch diameter of 25 mm. The swelling pressure of Kollidon CL powder in water is much higher than that one of Kollidon CL-M, Kollidon CL-SF and Kollidon CL-F. The pressure increase per time depends on the particle size distribution and is highest for Kollidon CL, followed by Kollidon CL-F and Kollidon CL-SF. The relative high swelling pressure of Kollidon CL-M is achieved after a comparably long swelling time. Table 1: Swelling pressure [kpa] and time to reach 90% of the maximum swelling pressure [s] of the insoluble Kollidon grades (typical values) VJ eve! varus] Kollidon Kollidon Kollidon Kollidon CL CL-F CL-SF CL-M Swelling pressure, kPa approx. 170 approx. 30 approx. 25 approx. 70 Time to reach 90% of <10 <15 <35 > 100 the maximum swelling pressure, S Swelling can also be measured in terms of the adsorption of water, or hydration. It is determined as follows: Weigh 2.0 g of Kollidon CL into a 100 ml centrifuge tube, add 40 ml of water and shake vigorously until the powder is suspended. Re-suspend after 5 and again after 10 minutes. Then centrifuge for 15 minutes at 2000 rpm. Decant the supernatant liquid, then weigh again. The hydration capacity is calculated as the quotient of the weight after hydration and the initial weight. The hydration capacity is shown in Table 2. Table 2: Hydration capacity of the insoluble Kollidon grades (typical values) Kollidon Kollidon Kollidon Kollidon CL CL-F CL-SF CL-M g water/g polymer 3.5 -5.5 5.0 - 6.6 7.0-8.5 3.0-4.5 Particle size distribution (PSD) The particle size distribution of the solid ingredients must be taken into account when formulating tablets, particularly if they are to be made by direct compression. The following table gives some typical values for particle size distributions, determined using an air jet sieve after 5 min at 20 mbar: Table 3: Particle sizes of the insoluble Kollidon grades (typical values) Kollidon Kollidon Kollidon Kollidon CL CL-F CL-SF CL-M <15 um - - - = 90% >50 um max. 80% max. 60% max. 30% = >100 um max. 60% max. 20% max. 10% a For the determination of the PSD of Kollidon CL-M laser diffraction is applied.
Bulk density, tap density Table 4 gives typical values for the bulk and tap densities after 500 taps of the insoluble Kollidon grades. One of the major differences between Kollidon CL and Kollidon CL-M lies in their bulk densities, and this affects their applications. Table 4: Bulk and tap densities of the insoluble Kollidon grades (typical values) Bulk density Tap density (500 taps) Kollidon CL 0.30 - 0.40 g/ml 0.40 0.50 g/ml Kollidon CL-F 0.18 - 0.28 g/ml 0.25 0.35 g/ml Kollidon CL-SF 0.10 -0.16 g/ml 0.18 - 0.25 g/ml Kollidon CL-M 0.15 - 0.25 g/ml 0.25 - 0.35 g/ml Specific surface area The insoluble grades of Kollidon have different specific surface areas, as can be seen from Table 5. Table 5: Specific surface areas of the insoluble Kollidon grades determined according to DIN 66131-132 (typical values) GClCrnea aCCOoraing lO VIN OD lol loe (lypiCdl Values) Product Specific surface area (N2-BET) Kollidon CL <1 m%/g Kollidon CL-F approx. 1.5 m/g Kollidon CL-SF approx. 3 m/g Kollidon CL-M >6 m/g Complex formation Like the soluble grades of Kollidon, the insoluble Kollidon CL-grades form chemica complexes or associates with a large number of drugs and other substances. The formation of the complexes is reversible and no complex formation occurs in alkaline medium. Whether Crospovidone in general forms a complex with a drug depends very much on its chemical structure. Systematic investigations have shown that complexes are formed much more readily with aromatic compounds that contain phenyl and/or carboxyl groups. For most of the drugs that form complexes with Kollidon CL-grades, the degree of complex formation is usually such that the dissolution rate of the drug is accelerated. The ability to form complexes has many uses in pharmaceuticals: to improve the dissolution and bioavailability of drugs, to adsorb and remove polyphenols and tannins from tinctures and herbal extracts and to improve the taste of azithromycin, paracetamol and vitamins.
Infrared spectrum The insoluble Kollidon polymers are mainly physically crosslinked. No differenc: can be seen between the infrared spectra of Kollidon CL (Fig. 2 a) and that o povidone (Kollidon 90 F, Fig. 2 b). Fig. 2 a: Infrared spectrum of Kollidon CL in KBr Fig. 2 b: Infrared spectrum of Kollidon 90 F in KBr
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application General The insoluble Kollidon CL-grades possess a number of useful properties for pharma- ceutical products. Table 6: Functionalities of Kollidon CL, Kollidon CL-F, Kollidon CL-SF and Kollidon CL-M in pharmaceuticals Improvement of tablet disintegration through predictable swelling without gel- formation Swelling properties paired with particle size distribution make the fine Kollidon CL-grades work efficiently in fast disintegrating formulations Narrow particle size distributions in conjunction with a high swelling pressure recommends Kollidon CL-SF as disintegrant for small tablets with low API- concentrations In contrast to other disintegrants the Kollidon grades improve the release and the bioavailability of drugs through complex formation Kollidon grades feature selective adsorption of polyphenols by complex formation Kollidon grades feature selective complex formation with some endotoxins As a hydrophilic polymer Kollidon CL-M stabilizes suspensions Due to its water adsorption properties Kollidon grades act as stabilizers of water sensitive compounds in sold dosage forms, e.g. in vitamin formulations Detailed descriptions of the applications can be found in the books, Polyvinyl- pyrrolidone-Excipients for Pharmaceuticals, published by Springer-Verlag, ISBN 3-540 23412-8 or Kollidon, Polyvinylpyrrolidone for the pharmaceutical industry, published by BASF. Tablet disintegration and dissolution (Kollidon CL, Kollidon CL-F or Kollidon CL-SF) Today Crospovidone is described in the literature as one of the three superdisin- tegrants. A large number of papers have been published that substantiate this in comparisons of the various disintegrants in placebo and active tablets. They come to the conclusion that there is no universal ideal disintegrant and that the best dis- integrant must be determined individually for each application. The usual quantity of Kollidon CL, Kollidon CL-F and Kollidon CL-SF used is a range of 2 8%, as a proportion of the tablet weight. The following formulation for an analgesic tablet has been selected for testing and comparing disintegrants, pro- perties.
Table 7: Comparison of disintegrants in an analgesic tablet 1 Composition Paracetamol cryst. 250 mg Acetylsalicylic acid cryst. 250 mg Caffeine cryst. 50 mg Il Kollidon 30 (dissolved in water) 27.5 mg lll Magnesium stearate 5 mg Disintegrant 16 mg Total tablet weight 598.5 mg Granulate with Il, dry sieve, mix with Ill and compress into tablets. 2 Disintegration times of the tablets (in synthetic gastric juice) Disintegrant Minutes None >70 Kollidon CL 9 Kollidon CL-F 11 Kollidon CL-SF 9 Croscarmellose 24 Sodium carboxy methyl starch 34 Although the disintegration time of a tablet is important, the dissolution rate of the active ingredient is just as important in assessing and comparing disintegrants. To demonstrate this effect, Table 8 below shows the formulation and physical pro- perties of an acetylsalicylic acid tablet that has a very poor dissolution rate withou a disintegrant (Fig. 3). Table 8: Acetylsalicylic acid tablets with different disintegrants (direct compression) (direct compression) 4 Composition Acetylsalicylic acid cryst. 400 g Ludipress 99g Stearic acid 1g Disintegrant 15g 2 Properties (Laboratory rotary tablet press, compression force 8 kN) Without Kollidon Cros- Sodium carboxy- disintegrant CL carmellose methyl starch Weight 503 mg 516mg 522mg 540 mg Hardness 95N 90 N 84N 89 N Disintegration time 22 min 30s 48s 50s (gastric juice) Friability 0.4% 0.4% 0.3% 0.3% Dissolution (USP) see Fig. 3 Sp Eee ee ee 4 Composition Acetylsalicylic acid cryst. 400 g Ludipress 99 g Stearic acid 1g Disintegrant 15g 2 Properties (Laboratory rotary tablet press, compression force 8 kN) & FIOPCrues (LaVOrdalory rOtaly laVICl PIGso, COMIPessiOl lOrece KIN) Without Kollidon Cros- Sodium carboxy- disintegrant CL carmellose methyl starch Weight 503 mg 516mg 522mg 540 mg Hardness 95N 90 N 84N 89 N Disintegration time 22 min 30s 48s 50s (gastric juice) Friability 0.4% 0.4% 0.3% 0.3% Dissolution (USP) see Fig. 3
Fig. 3: Dissolution of the acetylsalicylic acid tablets described in Table 8 (USP method): Rating 1 Smooth 2 small unevenness on the tablet surface 3 small unevenness, rough tablet surface 4 remarkable unevenness, formation of pimples begins 5 slight formation of pimples 6 medium formation of pimples 7 strong formation of pimples 8 strong formation of pimples/tablet fragile and swollen 1 Smooth Storage conditions 23 C, 65% r.h. Disintegrant 65% rel. humidity 65% rel. humidity 65% rel. humidity after 1 day after 3 days after 7 days Kollidon CL 5 5 5 Kollidon CL-SF 2 2 2 Kollidon CL-F 3 4-5 4-5 Kollidon CL-M 1 1 1 Croscarmellose 3 38 on Carboxymethy! 3 3 3 starch sodium
Storage conditions 23 C, 75% r.h. Disintegrant 75% rel. humidity 75% rel. humidity 75% rel. humidity after 1 day after 3 days after 7 days Kollidon CL 6 6 6 Kollidon CL-M 1 1 1 Kollidon CL-F 4 5 5 Kollidon CL-SF 2 3 4 Croscarmellose 3 oF gf Carboxymethyl 3-4 3-4 3 starch sodium tablets show light brown discoloration as of day 1. The color intensifies throughout storage. Moisture-proof packaging is therefore always recommended for tablets and capsules that contain the coarse Kollidon CL-grades. The disintegration effect of Kollidon CL-grades can be used to increase the bio- availability of the active constituent not only in tablets but also in suppositories. In a polyethylene glycol-based suppository, the addition of 1 - 10% of Kollidon CL-grades improve the dissolution rate of the active constituent. Coating Kollidon Cl-, Kollidon CL-F- or Kollidon CL-SF-con- taining tablet cores When tablet cores that contain Kollidon CL as a disintegrant are sugar or film coated, it is necessary to exercise care in selecting a suitable coating pan. This is particularly important if the coating suspension is water-based. In many cases, it is therefore recommended to subcoat the cores before applying the coating proper. A 10% solution of Kollidon VA 64 in isopropanol, ethanol or ethyl acetate provides a good subcoating. It can be sprayed briefly onto the prewarmed tablet cores in the same coating pan before the final aqueous coating is applied (see Technical Information Sheet, Kollidon VA 64). Stabilization of suspensions (Kollidon CL-M) Kollidon CL-M is a hydrophilic polymer that can be used in concentrations of 5 - 12% to physically stabilize oral and topical suspensions. It achieves this effect by increasing the volume of the sediment and reducing its sedimentation rate, and by making it easy to redisperse the sediment by shaking (anticaking effect), practically without increasing the viscosity of the preparation. These properties apply whether the final product is a ready-to-use suspension or an instant drink powder or granulate from which the patient prepares a suspensior before use. It has been found in practice that the increase in sediment volume achieved with Kollidon CL-M in such suspensions can be further enhanced by adding auxiliaries such as sodium citrate as an electrolyte, sugar, Kolliphor P407 or one of the soluble grades of Kollidon, such as Kollidon 90 F. Table 9 presents a formulation for an antibiotic dry syrup as an example of the use of Kollidon CL-M. The formulation has been developed in the laboratory for a number of different active ingredients and can therefore be regarded as a typical standard formulation. Citric acid has been included to give a pH value of 4.9, at which the two active ingredients, ampicillin and amoxicillin trinydrate are most stable in this administration form.
Table 9: Antibiotic dry syrup for children, with Kollidon CL-M Formulation (sales product) Ampicillin or amoxicillin trinydrate 5.0g Sodium citrate 5.0g Citric acid 21g Sodium gluconate 5.0g Sorbitol 40.0 g Kollidon CL-M 6.0g Orange flavouring 1.59 Lime flavouring 0.59 Saccharin sodium 0.4g ce A DOGR. cecsosraisscrore Pincers bec stsee vseoa ti Drink containing 250 mg of active substance per 5 ml: Shake 66 g of the powder mixture with water to give a total volume of 100 ml. Sedimentation is very slow and any sediment that does form can very readily be redispersed even after several weeks. The main applications for Kollidon CL-M are in instant drink granules, ready-to-use suspensions or dry syrups that contain the following types of active ingredient: suspensions or ary syrups that contain the following types of active Ingredient: antibiotics antacids vitamins e analgesics. SN Se ea OSS RE ee a ee > antibiotics > antacids > vitamins > analgesics. A notable property of Kollidon CL-M in suspensions is that, in concentrations of 5 - 10%, it hardly increases the viscosity of the suspension. Kollidon CL-M has also been found to stabilize suspensions in lipophilic mediz such as liquid paraffin. Stabilization of vitamins (Kollidon CL-grades) As with the soluble grades of Kollidon, Kollidon CL-grades are also able to stabilize active ingredients in pharmaceutical products. A typical example is provided by a multivitamin instant drink granulate. The stability of the vitamins in a formulation pre- pared in the laboratory was found to be almost ideal. The effect of Kollidon CL-M on vitamin B1, calcium pantothenate and vitamin C was demonstrated in an accelerated storage test (Table 10). Table 10: Vitamin degradation in multivitamin instant drink granules with and without Kollidon CL-M (30 C/70% relative humidity) Bees eh ce 1 month 2months 3months 5 months Vitamin B,: Without Kollidon CL-M 4% 11% 16% 26% With Kollidon CL-M 0% 1% 7% 10% Vitamin C: Without Kollidon CL-M 17% 18% 40% 49% With Kollidon CL-M 0% 2% 13% 19% Ca-Pantothenate: Without Kollidon CL-M - 8% 21% 50% With Kollidon CL-M = 10% 10% 15%
Improvement of dissolution/bioavailability As with the soluble Kollidon grades, Kollidon CL-grades are capable of forming complexes with active substances and increasing their dissolution rate and bio- availability. Different mixing methods can be used: AVGIADILY., WINE MMAIIG TeUlOOs Call US UsSeO. physical mixture with the active ingredient comilling with the active ingredient coevaporation of a suspension of Kollidon CL in a solution of the active ingredient. All published papers on investigations into the crystalline structure of preparations made by these methods have found that the active ingredient has a stable amorphous forrr and that the dissolution rate and/or the bioavailability is increased. For comilling, Kollidon CL-M or Kollidon CL-SF are preferable to Kollidon CL or Kollidon CL-F, which are coarser. The quantity of Kollidon CL-grades required for this purpose is about 1- to 10-fold the quantity of the active ingredient. In principle, it can be assumed that all active substances whose dissolution rate can be improved with polyvidone (e. g. Kollidon 30) can benefit in the same way from the insoluble Kollidon CL-grades. Absorptive polymer (Kollidon CL) The ability of Crospovidone to form stable complexes with various polyphenols car be used not only in the beverage technology for the stabilization of beer but also in the purification of aqueous or alcoholic herbal extracts and tinctures. Polyphenols are selectively bound by the Kollidon CL-grades which can therefore be used to improve the stability of such phytopharmaceuticals. The Kollidon CL-grades can either be suspended in the extract then filtered off after a certain time, or the extract can be slowly percolated through a bed of Kollidon CL- grades. Under caustic conditions absorbed polyphenols can be released from the polymer and recovered if desired. 5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technic representative. Please refer to Quality & Regulatory Product Information (QRP)). 9. Toxicological data For information on toxicological issues please refer to the tox abstract which car be supplied on request. More/detailed toxicological information for Kollidon grades is available on request under Secrecy Agreement.
10. PRD and Article numbers 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30034964 Kollidon CL 50000695 40 kg Plastic drum 50347948 0.5 kg Plastic pail 30274401 Kollidon CL-F 53216545 30 kg Plastic drums 50539226 0.25 kg Plastic pail 30274400 _ Kollidon CL-SF 52595650 30 kg Plastic drums 50348145 0.25 kg Plastic pail 30444355 Kollidon CL-M Origin Germany 51928647 30 kg Plastic drums 50348144 0.25 kg Plastic pail BASFs commercial product number. Corresponding product sample 11. Publications http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Macrogolglycerol Ricinoleate Ph. Eur. Polyoxyl 35 Castor Oil USP/NF Macrogolglycerol Ricinoleate Ph. Eur., August 2019 Supersedes issue dated October 2018 Last change WF-No. DAWF-2019-0825 = Registered trademark of BASF in many countries.
1. Technical properties Description Kolliphor ELP is a solubilizer, emulsifier and primary surfactant used in a multitude of pharmaceutical formulations, with the primary indication for sensitive APIs and parenteral use. Kolliphor ELP, a purified grade of Kolliphor EL was specifically developed for sensitive active ingredients, as the higher purity was found to improve their stability. Unlike Kolliphor EL, Kolliphor ELP is a white to yellowish paste or cloudy liquid. It exhibits tighter specifications with regard to water content, potassium ions and free fatty acids, in particular, ricinoleic, oleic and palmitic acids. Upon heating, the last solid constituents melt at approximately 26C to yield a clear oily liquid with a weak but characteristic odor. Structural formula Kolliphor ELP is a nonionic solubilizer and emulsifying agent obtained by reacting castor oil with ethylene oxide in a molar ratio of 1:35. The main constituent of Kolliphor ELP is glycerol polyethylene glycol ricinoleate, which, together with fatty esters of polyethylene glycol, this forms the hydrophobic part of the product. The hydrophilic part consists of free polyethylene glycols and ethoxylated glycerol. A diagram of the molecular formula is listed below: The HLB value lies between 12 and 14. CAS-number Solubility Kolliphor ELP forms clear solutions in water. It is also soluble in many organic solvents, e.g. ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethyl acetate, chloroform, carbon tetrachloride, trichloroethylene, toluene and xylene. In contrast to anionic emulsifying agents, Kolliphor ELP becomes less soluble in water at higher temperatures. Thus, aqueous solutions become turbid at a certain temperature. Kolliphor ELP is miscible with all the other Kolliphor grades and, on heating, also with fatty acids, fatty alcohols and certain animal and vegetable oils. It is thus miscible with oleic and stearic acids, dodecyl and octa-decyl alcohols, castor oil, and a number of lipid-soluble substances. Critical micelle concentration The critical micelle concentration (CMC) is 0.02% w/w @ 37 C.
2. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. Dispensing and Sterilization It is recommended that Kolliphor ELP be heated to between 50 and 60 C and lightly agitated prior to use. Kolliphor ELP exhibits complex melting behavior, and phase separation is known to occur depending on the shipping and storage conditions. This is easily overcome via melting and light mixing. In order to ensure product stability during reheating, heat cycling was performed on Kolliphor ELP. Commercial material was heated to 60 C and held for 24 hours, then cooled and held at room temperature for a further 24 hours; this was repeated 20 times in total. The results of this stress test on the stability indicating parameters of Kolliphor ELP are shown below, no significant deviation was noted. Furthermore, as Kolliphor ELP is often used in formulations that are subject to sterilization (e.g. parenterals), a stress test using a single autoclave cycle (121 C, 20 mins) and sterile filtration (0.20 um) were used to study 20% (w/w) solutions of Kolliphor ELP; the consolidated results on stability indicating parameters are shown below. Kolliphor ELP - 20% Solution Blank Filter Autoclave Stress Test pH Value 20% (aq.) 6.03 5.88 4.92 6.1 Viscosity [mPas], 25 C@1000 1/s_ 7.44 7.31 7.06 7.05 Aldehyde [mg/kg] Formaldehyde <1 1 4 2 Acetaldehyde 4 4 3 4 Propionald. <1 <1 <1 <1 Peroxide Value [meq/kg] 5 2 2 1 Hydoxyl Value [mg KOH/kg] 21 18 19 28 lodine Value [g 12/100g] 6.3 6.3 6.5 6.1 Acid Value [mg KOH/g] 0.1 0.1 0.1 <0.1 Note that autoclave sterilization may cause a reduction in pH of Kolliphor ELP, as with other ethoxylated surfactants exposed to higher temperatures.
3. Example application Kolliphor ELP is the industry standard pharmaceutical surfactant used primarily a a solubilizer and emulsifier. Most notably the product is used in the following types of formulations (common concentration show): Softgel Capsules 600 mg per dose Ophthalmics up to 5 % w/w Oral Solutions and Suspensions 0.5 45% Topicals 4% w/w Parenterals approx. 50% w/w Kolliphor ELP is fully miscible in aqueous formulations. Parenteral Administration Kolliphor ELP is a highly purified version of Kolliphor EL, intended for sensitive applications. Below is a comparison of the two products: Ss Parameter Kolliphor ELP Kolliphor EL Appearance almost white paste yellow liquid Viscosity, 25C 600 - 750 mPa:s 700 850 mPa:s Water < 0.5% < 2.8% Potassium < 15 ppm not specified Ricinolic acid < 0.2% not specified Oleic acid <0.1% not specified Palmitinic acid <0.1% not specified Free fatty acids C,,-C,, < 1.0% not specified requirements of Ph.Eur. monograph In addition, endotoxin control and microbial testing on each released batch ensure suitability for use in parenteral applications.
Solubilization In addition to the high purity, Kolliphor ELP exhibits strong solubilization potential in aqueous systems. As an example, several poorly water-soluble drugs are enhanced significantly with the addition of Kolliphor ELP in increasing concentrations. 4. Important note: One possible field of application that can be considered for Kolliphor ELP is ir parenteral dosage forms. Thus Kolliphor ELP is suitable for particularly demanding formulations, which prove not to achieve the desired stability when Kolliphor EL is used. For other injectables, we recommend Kolliphor HS 15 as a solubilizer. For further information, please see the Technical Data Sheets for Kolliphor ELP and Kolliphor HS 15. Kolliphor ELP promotes the penetration of a number of active substances and can exert either activating or inactivating effects on others, e. g. antibiotics. Therefore, before Kolliphor ELP preparations are used in practice, it is advisable to subject them to thorough pharmacological tests. Kolliphor ELP is subjected to thorough quality controls involving comprehensive chemical and physical tests. The individual production batches are not, however, subjected to biological tests. For this reason, producers of preparations that contain Kolliphor ELP must carry out their own tests to check the suitability of the respective material and of the final preparations. Cattle that have been given certain vaccines or medicaments parenterally and have subsequently been injected with preparations containing Kolliphor ELP or similar solubilizers have displayed anaphylactic reactions in isolated cases involving exceptional circumstances. Anaphylactic reactions have occasionally been observed in humans after injections containing Kolliphor ELP. For this reason, the health authorities in the Federal Republic of Germany and the UK, for instance, have laid down that the content of polyethoxylated castor oil in injections for parenteral administration to humans must be declared, and that attention must be drawn to the possibility of side effects in the package insert. This is an aspect to which companies producing pharmaceuticals for human use must pay particular attention. No side effects of this kind have been observed after oral administration of preparations containing Kolliphor ELP.
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technical representative. 8. Toxicological data The toxicological abstracts are available on request. 9. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554034 Kolliphor ELP 50539225 0.5 kg Plastic bottle 50259800 0.5 kg Alu bottle 50251534 60 kg Steel drums 30554034 Kolliphor ELP 10. Publications 50539225 0.5 kg Plastic bottle 50259800 0.5 kg Alu bottle 50251534 60 kg Steel drums BASFs commercial product number. http://pharmaceutical.basf.com/en.html BASFs commercial product number. http://pharmaceutical.basf.com/en.html Inis Gocument, or any answers or intormation provided nerein by BASF, aoes not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELPLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Table of Contents Introduction 6 Ibuprofen 8 Chemical information . wl Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality .. 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Chemical information 20 Product information 20 Chemical and physical properties 21 Particle characterization 21 Regulatory status 21 Specification 21 Medical indication 22 Ibuprofen Sodium Dihydrate 24 Chemical information 24 Product information 24 Storage 25 Regulatory status 25 Specification 25 Medical indication 26 Table of Contents Introduction Ibuprofen 8 Chemical information 8 Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Ibuprofen Racemic Ibuprofen Lysinate (RIBL) Ibuprofen Sodium Dihydrate Ibuprofen Sodium Dihydrate
Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, antipyretic and anti-inflammatory actions, it is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever. Due to its analgesic, antipyretic and anti-inflammatory actions, it is used The common active ingredient dosage in tablets is 200, 400, 600 and 800 mg. The OTC dosage forms are mainly the 200 and 400 mg forms (except for the United States and some other countries, where the 200 mg form is the only OTC form). Other common dosage forms are capsules, syrups, suspensions, suppositories, and topical dosage forms like creams and gels. Pharmacokinetics Orally administered ibuprofen is absorbed rapidly in the Gl tract.? After a single oral dose on an empty stomach, peak plasma levels are reached within 45 to 90 minutes and the apparent plasma volume of distribution is reported to be between 0.1 to 0.2 I/kg.-> Ibuprofen has an extensive protein binding capacity (+98%) and is excreted via the kidneys. The biological half-life is between 2 and 4 hours.? After 24 h, 100% of the active substance is excreted in the urine.
Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as histamine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C. bata Te Ta Tort) U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Gillespie, W. R. et al., Relative Bioavailability of Commercially Available Ibuprofen Oral Dosage Forms in Humans, Journal of Pharmaceutical Sciences, 71:1034-1038, 1982. Verbeeck, R. K., Pathophysiologic Factors Affecting the Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs, Journal of Rheumatology, 15:44-57, 1988. Jamali, F. and D. R. Brocks, Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers, Clinical Pharmacokinetics, 19:197-217, 1990. Vowles, D. T. and B. Marchant, Protein Binding of Ibuprofen and Its Relationship to Drug Interactions, British Journal of Clinical Practice, 1:13-19, 1980. Whitlam, J. B. and K. F. Brown, Ultrafiltration in Serum Protein Binding Determinations, Journal of Pharmaceutical Science: Tio Teel atc oa Rudy, A. C. et al., Stereoselective Metabolism of Ibuprofen in Humans: Administration of R-, S- and Racemic Ibuprofen, Journal of Pharmacology and Experimental Therapeutics, 259:1133-1139, 1991. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(6): 986-1000, 2011.
Ibuprofen (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid Chemical name (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid 15687-27-1 239-784-6 C,,H,,0. 13) 182 206.28 g/mol CAS number EINECS number Molecular formula Molecular weight 3ASF offers 4 grades based on different particle size distributions (see particle charac- erization). Furthermore, a direct compressible grade is offered: Ibuprofen DC 85 W, the somposition of which can be found in chemical and physical properties section below. Product grades (+)-2-[4-(2-methylpropyl)phenyl]propanoic acid; (+)-Benzeneacetic acid, alpha-methyl- 4-(2-methylpropy)); (+)-p-lsobutylhydratropic acid; (+)-2-p-lsobutylphenylpropionic acid Ibuprofen meets the current Ph. Eur., USP, JP and IP monographs. DMFs and CEP are available upon request. Regulatory status Ibuprofen is the racemate of (+)-lbuprofen and (-)-lbuprofen (optical rotation = 0). According to the literature the pharmacologically active form is (+)-lbuprofen. Approximately 30 to 70% of the (-)-lbuprofen is converted to the active form (+)-lbuprofen in the body. This process proceeds solely from the (-)- form to the (+)- form.
Chemical and physical properties Ibuprofen grades 25, 38, 50, 70 Crystalline powder Solubility in phosphate buffer pH 7.2 (37 C) Partition coefficient n-octanol/water The chemical parameters of all pure ibuprofen powder grades are identical. The only difference is the particle size distribution (see particle characteristics).
Particle characterization Ibuprofen 25 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 25 is between 20 um and 33 pm. Ibuprofen 50 Particle Size Distribution Bulk density Tapped density An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 50 is between 45 um and 60 pm. Approximately 0.34 g/ml. Approximately 0.60 g/ml.
Ibuprofen 38 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 38 is between 33 um and 45 pm. ibuprofen 70 Particle Size Distribution Bulk density Approximately 0.38 g/ml. Tapped density Approximately 0.68 g/ml. An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 70 is between 60 pm and 85 pm.
Ibuprofen DC 85 W The ibuprofen used to manufacture Ibuprofen DC 85 W meets the current Ph. Eur., USP, JP and IP monographs. A Technical Package and a US-DMF are available upon request. Granules, free flowing, homogeneous material Appearance SEM photograph
Recommendation for direct compression Today the manufacturing of ibuprofen tablets is often done by direct compression. Using this method, the expensive and time-consuming wet granulation method can be avoided. But in general, ibuprofen has the disadvantage of sticking on the tablet tools so that the process must be interrupted often. Therefore, direct compression formulations with a high content of ibuprofen per tablet are often avoided. Mostly tablets with an ibuprofen content of maximum 60% are compressed. BASF offers a formulated ibuprofen product ideal for direct compression: Ibuprofen DC 85 W. The direct compression (DC) grade ensures that tablet sticking is minimized and allows for excellent tablet engraving. Furthermore, Ibuprofen DC 85 W has a lower angle of repose compared to standard grades, resulting in improved flowability.
General information on processing of Ibuprofen Ibuprofen is used mainly in three (3) different dosage forms: Ibuprofen 50, Ibuprofen 70, Ibuprofen DC 85 W (for direct compression) Recommended grade(s) High concentrations of magnesium stearate as a lubricant are not recommended. For direct compression, the ready-to-use Ibuprofen DC 85 W reduces sticking. For a film coating, Kollicoat IR has a reduced viscosity in aqueous solutions compared to HPMC suspensions, which leads to higher solids content and a faster coating process. Formulation guidance Creams & Gels Recommended grade(s) Recommended grade(s) To stabilize against sedimen- tation, fine particles should be used. The pH of the sus- pension should be in the acid range so that ibuprofen is undissolved, which will reduce bitter taste if any. lbuprofen is dissolved in the ipophilic phase of creams, thus there is no impact of particle size. Propylene glycol or low molecular weight polyethylene glycols are recommended as the oily component. Formulation guidance Formulation guidance
-oomLab - Your Virtual Formulation Assistant Access example formulations and build your own ZoomLab Formulation Wizard identifies suitable excipients and calculates potential formulations depending on the selected dosage form, defined target profile, and properties of the active ingredient. Example formulations include creams, tablets, and more! - Evaluate bioequivalence of your final formulation A WHO biowaiver monograph is available for ibuprofen. The ZoomLab dissolution module can be used to calculate difference and similarity factors (f1, f2) required for showing bioequivalence. ZoomLab provides values for parameters relating to particle size, powder density, flowability, and tabletability. The parameters are scaled from 0 to 10, a risk analysis is run, and an interpretation of results/formulation advice is provided.
Example formulations Production of granules for 200, 400, 600 and 800 mg forms The following ingredients are placed in a high shear mixer and granulated with water: Ibuprofen 50 60.1% w/w Amount of water: approximately 0.2 kg water per 1 kg __ ibuprofen. Wet sieving (4 mm) and drying in a fluid bed Lactose 18% w/w granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following Corn starch 9% w/w additives to form granules suitable for tableting. Kollicoat IR 3.6% w/w Extra granular material Avicel PH 102 3.6% w/w AcDiSol 4.8% w/w Magnesium stearate 0.6% w/w Aerosil 200 0.3% w/w Coating formulations for Ibuprofen tablets oes Fraction with reference to the Fraction with reference Composition atomised suspension [%] to the dry film [%] Polymer Kollicoat IR 16.0 64 Pigments Talc 6.0 24 Sicovit Red 30 3.0 12 Total 25 100 Amount of water: approximately 0.2 kg water per 1 kg ibuprofen. Wet sieving (4 mm) and drying in a fluid bed granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following additives to form granules suitable for tableting. Corn starch Kollicoat IR Extra granular material Magnesium stearate Coating formulations for Ibuprofen tablets
Handling & Safety Product specification The current version of the product specification is avail- able on RegXcellence or from your local BASF sales representative. Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on MyProduct- World or from your local BASF sales representative. Publications Regulatory & Quality Publications including scientific posters are available on: Please refer to the individual document quality & regu- latory product information (QRPI) which is available on RegXcellence and from your local sales representative The QRPI covers all relevant information including retest dates and storage conditions.
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Racemic Ibuprofen Lysinate (RIBL Racemic Ibuprofen Lysinate (RIBL Chemical information Chemical information Ibuprofen Lysinate (+) (+)- (+ (+ -2-[4-(2-methylpropyl)phenyl]propanoic acid lysinate -Benzeneacetic acid, alpha-methyl-4-(2-methylpropyl) lysinate -p-lsobutylhydratropic acid lysinate -2-p-lsobutylphenylpropionic acid lysinate Empirical formula Molecular weight
Chemical and physical properties White to almost white, very fine crystalline powder witt a high volume. In the literature the solubility of Ibuprofen (acid) in distilled water is reported to be less than 0.1%. The solubility of Ibuprofen Lysinate is 1:5, or about 17%. Particle characterization An example particle size distribution is shown below. The median particle size for RIBL is approximately 10 pm Regulatory status No monographs exist. E-DMF is available upon request.
The term RIBL is the acronym for Racemic Ibuprofen Lysinate. Racemic signifies that the ibuprofen drug substance and the lysine anion are both racemic compounds. RIBL differs from the common ibuprofen acid, gen- erally referred to as ibuprofen, in that it is more rapidly absorbed from the intestinal tract and reaches peak plasma levels and t,,., more quickly. After absorption, RIBL is available in the form of pure ibuprofen acid and is therefore to be handled like ibuprofen. Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, anti- pyretic and anti-inflammatory effects, ibuprofen is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever.? For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. Pharmacokinetics RIBL is readily and quickly absorbed from the gastrointestinal tract.!? The peak plasma level of the free acid is reached within 30 to 60 min (with the free acid ibuprofen, t,,,, was measured between 60 and 120 minutes, depending on the dosage form).: After absorption, there is no difference between RIBL and the free acid.
From a pharmacological point of view, there is no difference between RIBL and the free ibuprofen acid because it is the free acid and not the RIBL salt that is the active form. The mode of action of ibuprofen, while not completely understood, is believed to involve reversible inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have among other properties a powerful effect on the smooth muscles. In case of inflammatory stimuli or blood flow disorders, PGs are synthesized in increased amounts, making the tissues sensitive to the action of other agents such as histamine and kinins. As a result, symptoms like pain and inflammation occur. The in- cidence of fever is raised by the influence of the PGs on the heat regulation center in the hypothalamus. There they scale up the normal set point of 37 C. bats CUe Ta Tort) 1 Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration of Ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990. Hermann, T. W. et al., Bioavailability of Racemic Ibuprofen and its Lysinate from Suppositories in Rabbits, Journal of Pharmaceutical Sciences, 82(11):1102-1111, 1993. U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Neupert, W. et al., Effects of lbuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(5): 986-1000, 2011. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration o ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990.
Ibuprofen Sodium Dihydrate Chemical information Ibuprofen Sodium Dihydrate 2-(4-isobutylphenyl)-propionate sodium dihydrate Chemical name Se IS ee ee ee a en re ae ee ee 31121-93-4 C,,H,,0,Na x 2 H,O 228.26 + 36.03 g/mol Empirical formula Molecular weight
Storage Ibuprofen Sodium Dihydrate should be stored in the original, tightly sealed container. It should be placed ina well-ventilated room at ambient temperature and protected from light. The retest period of Ibuprofen Sodium Dihydrate is 60 months for material stored in the original, unopened containe! and according to our recommendations. Regulatory status Currently there are no monographs describing Ibuprofen Sodium Dihydrate in the major Pharmacopoeias (USP, Ph. Eur.. and JP).
According to the literature, ibuprofen sodium dihydrate dissolves more quickly in vitro and is absorbed into blood plasma more quickly than con- ventional ibuprofen, whereas tolerability and safety profiles of the two APIs are comparable.? In an investigation of the dissolution, plasma pharmacokinetics, and safety of ibuprofen sodium dihydrate versus conventional ibuprofen, the following results were reported:? @ buprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 compared to conventional ibuprofen. @ lbuprofen sodium dihydrate reached the t,,,, significantly earlier than conventional ibuprofen. @ lbuprofen sodium dihydrate showed significantly higher c_, compared to conventional ibuprofen. @ buprofen sodium dihydrate was characterized by significantly higher mean plasma concentration (10 min post-dose) compared to conventional ibuprofen. tax iS the necessary time until the maximum plasma concentration of a drug is reached; this is relevant for the drug onset. Generally, reaching the t_ early is of great advantage for analgesic treatment. According to the literature, the first signs of pain relief occurred significantly earlier in ibuprofen sodium dihydrate treated patients, and pain intensity was reduced to half after 30 min for ibuprofen sodium dihydrate compared to 57 min for conventional ibuprofen. In summary, ibuprofen sodium dihydrate causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen.
The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (CO)) which is responsible for the biosynthesis of prostaglandin (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflamma- tory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as hista- mine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C.? c Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandii Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vas FeYToltote CHI (2) Rc) =\ coal O00 Soergel, F. et al. Pharmacokinetics of Ibuprofen Sodium Dihydrate and Gastrointestinal Tolerability of Short-Term Treatment with a Novel, Rapidly Absorbed Formulation, International Journal of Clinical Pharmacology and Therapeutics. 43(8):140-149, 2005. Schleier, P. et al., Ibuprofen Sodium Dihydrate, an Ibuprofen Formulation with Improved Absorption Characteristics, Provides Faster and Greater Pain Relief than Ibuprofen Acid, International Journal of Clinical Pharmacoloay and Therapeutics. 45(2):89-97. 2007. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandir Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997.
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Kollicoat MAE 100-55 Kollicoat MAE 100 P Methacrylic acid/ethyl acrylate copolymers in powder form for enteric coating Methacrylic acid/ethyl acrylate copolymers in powder form for enteric coating
Contents 1. Introduction 1.1 General remarks 1.2 Structural formula 1.3 Commercial form 4A Pharmarnnnaia) citiia 1.2 Structural formula 1.4 Pharmacopoeial situation 2. Specification and properties 2.1 Description 2.2 Specifications 2.3 Solubility 2.1 Description 3. Processsing Notes 3.1 Use of plasticizer 3.1 Use of plasticizer 3.2 Re-dispersion of Kollicoat MAE 100-55 3.3 Re-dispersion of Kollicoat MAE 100 P 4. Applications and typical formulations using Kollicoat MAE 100-55 4.1 Enteric coating of ASS-crystals 4.3 Enteric coating of diclofenac-Na tablets 4.5 Enteric coating of propranolol tablets 5. Applications and typical formulations using Kollicoat MAE 100 P 5.1 Coloured enteric film coatings for tablets 5.1 Coloured enteric film coatings for tablets 5.2 Coloured enteric film coatings for pellets and crystals 5.3 White enteric film coatings for pellets 5.4 Colourless enteric coatings for soft gelatine capsules 5.5 Seal-coating of cores 5.6 Further applications 6. Equipment cleaning recommendations 7. Storage 8. Shelf life 8. Shelf life 9. Product Numbers 10. Packaging
1. Introduction 1.1 General remarks Kollicoat MAE100-55 and Kollicoat MAE 100 P are spray-dried copolymers consisting of methacrylic acid and ethyl acrylate. They are used as film-formers for enteric coatings of solid dosage forms like crystals, multi-particulates, mini-tablets, tablets soft-gel capsules and others. 1.2 Structural formula The monomer ratio in the copolymers is 1:1. The average molecular weight M,, is of the order of 250,000 AMU. Both copolymers have an anionic character. In contrast to Kollicoat MAE 100-55 the copolymer in Kollicoat MAE 100 P is partially neutralized before spray drying. 1.3 Commercial form Both Kollicoat MAE 100-55 and Kollicoat MAE 100 P are white powders with a faint characteristic odour. In order to apply Kollicoat MAE 100-55 the powder has to be re-dispersed in water with the addition of a caustic excipient, preferably sodium hydroxide solution. The pre-neutralized carboxyl groups in the Kollicoat MAE 100 P powder make it easy to re-disperse in water without further excipients added for partial neutralization. 1.4 Pharmacopoeial situation The polymers are listed in the three major pharmacopoeias as follows: Kollicoat MAE 100-55: h.Eur.: = Methacrylic Acid Ethyl Acrylate Copolymer (1:1) Type A ISP/NF: Methacrylic Acid and Ethyl Acrylate Copolymer NF PE: Dried Methacrylic Acid Copolymer LD Kollicoat MAE 100 P: Ph. Eur.: Methacrylic Acid Ethyl Acrylate copolymer (1:1), Type B USP-NF: _ Partially-Neutralized Methacrylic Acid and Ethyl Acrylate copolymer
2. Specifications and properties The Kollicoat MAE grades contain 0.7% sodium lauryl sulfate (USP) and 2.3% Polysorbate 80 (Ph.Eur.) as emulsifying agents. (The percentages refer to the solid substances.) 2.1 Description Polysorbate 80 is manufactured using oil of vegetable origin. The Kollicoat MAE grades are weakly acidic copolymers that dissolve at a pH-value above 5.5. See separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). 2.2 Specification The Kollicoat MAE grades are re-dispersible in water. The achieved dispersions regain their milky white appearance either when using a neutralization medium (Kollicoat MAE 100-55) such as 1 mol/L NaOH or just when mixing it with water (Kollicoat MAE 100 P). When treated with higher quantities of dilute alkalis the Kollicoat MAE powder grades (like the Kollicoat MAE 30 DP dispersion) become soluble and form clear to slightly cloudy solutions of moderate viscosity. Kollicoat MAE 100-55 powder dissolves in alcohols such as methanol, ethanol or i-propanol to yield clear to slightly cloudy solutions Mixing of the re-dispersed aqueous formulations of Kollicoat MAE 100-55 or Kollicoat MAE 100 P with acetone, ethanol or isopropanol in a ratio of 1:5 a faint opalescent or clear, moderately viscous solution is obtained. Upon addition of the organic solvent to the dispersion, the polymer initially precipitates, then re-dissolves as more solvent is added. 3. Processing notes 3.1 Use of plasticizer Plasticizers are essential to improve the flexibility of the films formed. Suitable plasticizers or gloss intensifiers are aN a MI ac oR ce e 1,2-propylene glycol e Triethyl citrate e Polyethylene glycols such as PEG 400 e 1,2-propylene glycol e Triethyl citrate e Polvethviene alvcols such as PEG 4 The recommended amounts of plasticizers range from 10% to 25% relative to the amount of polymer dry matter. The Kollicoat MAE grades are incompatible with magnesium stearate as part of the coating formulation. However, any magnesium stearate present in the cores to be coated does not present problems. 1.2-propylene glycol improves the processibility and barrier properties of the film coatings. A number of factors may cause aqueous dispersions to coagulate during processing, rendering them unusable: SAL PARE ES RENAE Ea AN Addition of finely divided pigments High shear gradients on stirring and grinding Addition of emulsifying agents, stabilizers or wetting agents Changes in pH Cationic additives Organic solvents. Foam formation Foam formation during processing can be prevented by adding a silicone antifoan such as Pharsil 21046. Flat-plate stirrers have proved suitable for the production of spray suspensions.
Spray suspensions with a 15 30% solids content give good results and save time in spraying. recommend to: Dilute the dispersion to a solids content of 15% to 20% Stir the desired auxiliary into the dispersion in the form of a diluted solution. The following excipients can be included in a film-coating formulation: ENS REN Ne RRO ARO EER REE LE OTE Te SUSE Se REA. Fee Re ae OM TGR REE MON NR IR e Talc Syloid Aerosil and Kaolin as release and smoothing agents; e Pigments The Kollicoat MAE grades have a high pigment binding capacity: two to three parts of pigments or other auxiliaries may be added for one part of solid polymer. The proper use of Kollicoat MAE 100-55 comprises of two steps: 1.Re-dispersion of Kollicoat MAE 100-55 powder to form an aqueous latex dispersion 2.Addition of plasticizer To achieve a proper re-dispersion the polymer powder has to be incorporated in water in combination with a caustic compound to achieve the requested degree of neutralization of around 6 mol-percent of the methyacrylic acid moieties in the polymer. This neutralized polymer dispersion can be further processed by adding the required additives such as plasticizer, colorants etc. to generate a coating dispersion of an appropriate concentration. For the re-dispersion step a number of caustic excipients can be used for neutrali- zation. The compounds proposed in the following list are applied in a 1 mol/L aqueous solution if not otherwise stated. Sodium hydroxide (NaOH) is the most recommended compound. Others are SADIE SE FEE LRAR NARONee ET SNA NAS RNS: Nee INES EAS Se Potassium hydroxide (KOH) Ammonia (NH, in water) Ammonium bicarbonate (NH,)HCO, Ammonium carbonate (NH,),CO, (to be applied in a concentration of 0.5 mol/L The following graph shows the viscosity determination for a 20% dispersion of Kollicoat MAE 100 P and the situation for Kollicoat MAE 100-55 after its re- dispersion using a 1 mol/L solution of sodium hydroxide and ammonia, respectively to achieve a 6 mol-% neutralization of the methacrylic acid moiety.
Shortly after the addition of the caustic compound the viscosity of the re-dispersed enteric polymer reaches already its minimum level. Different neutralization media have only little influence on the finally achievable viscosity. The following graph shows the resulting viscosities for the 6 mol-% neutralization of Kolllicoat MAE 100-55 using either a solution of 1 mol/L NaOH, of 1 mol/L ammonia, of 1 mol/L ammonium hydrogen carbonate or of 0.5 mol/L ammonium carbonate solution, respectively. To manufacture 1 kg of a Kollicoat MAE-enteric coating dispersion the following procedure has to be followed: Processing recommendations Instead of adding 100 ml of a 1 mol/L NaOH solution the alternative neutralizing agents mentioned above can be applied. The dry matter content has to be adjusted accordingly. When stirring the powder into water an aqueous dispersion is achieved with pro- cessing properties similar to those of Kollicoat MAE 100-55 or Kollicoat MAE 30 DP-dispersions. Procedure: Add the powder to the specified quantity of water with stirring. During stirring ensure that ensure that e the powder does not form lumps e the powder is immediately wetted e the speed of the stirrer always matches the viscosity not too much foam is being formed. To avoid lump formation and deposits on the stirrer, a stirrer with no horizontal surfaces, e.g. a bar or gate-type should be used. When the powder has been incorporated, the viscosity initially rises and then decreases on further stirring. The dispersion should be stirred for 2 - 4 hours to ensure complete re-dispersion. It must be ensured that not too much air is entrained in the dispersion when it thickens. Acconcentration of 20% has been found to be the optimum. The further steps in the preparation of a suitable dispersion are essentially the same as for Kollicoat MAE 30 DP. It is not necessary to add any other auxiliaries such as alkali to re-disperse Kollicoat MAE 100 P. The powder contains already the necessary percentage of neutralized methacrylic acid groups for easy re-dispersion.
4. Applications and typical formulations using Kollicoat MAE 100-55 For the proper handling of Kollicoat MAE 100-55 it is recommended to follow the instructions given for the re-dispersion of the polymer in section 3.2. Thorough calculation of the dry matter content of the polymer dispersion after addition of the selected neutralisation compound is essential. Formulations with Kollicoat MAE 100-5 The crystals were enteric coated using a Kollicoat MAE 100-55-formulation without pigments. The ASS-crystals were coated in a Glatt WSG fluid-bed coater with a 7 Wurster insert. 4.1 Enteric coated acetyl salicylic acid crystals Acetyl salicylic acid crystals with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendation: in chapter 3.2. An aqueous polymer dispersion containing 600 g of Kollicoat MAE 100-55 with the appropriate amount of triethyl citrate as plasticizer are prepared as follows: Ingredients Parts by weight Composition Ig] [%] Kollicoat MAE 100-55 600.0 18.00 Triethyl citrate 60.0 1.80 (10% relative to polymer weight) NaOH (1 mol/L) 204.0 0.25 Demineralized Water 2460.0 = Total 3224.0 20.10 The polymer powder is stirred into 2200 g of water. The required quantity of NaOH-solution is added and the re-dispersion is performed for 30 minutes under stirring while the triethyl citrate is dispersed in the remaining volume of water in a separate beaker. The plasticizer dispersion is combined with the polymer dispersion and stirred for 2 hours. Coating equipment Glatt GPCG 3.1 with Wurster insert (7 ) Batch size Number of nozzles Nozzle diameter Total applied quantity (for 50% weight gain) Spraying rate Spraying pressure Spraying time Air supply Inlet air temperature Drying time Weight gain kg mm g g/min bar min ms/h C min % 1.0 1 0.8 2750 20.0 1.0 ~ 140 90 ...130 60 8 20 to 50 Coating equipment and process parameters Coating equipment and process parameters
Release testing Kollicoat MAE 100-99 coating eee 20% weight gain === 40% weight gain === 50% weight gain At the recommended minimum coating level of 20% weight gain the release level of acetyl salicylic acid crystals of less than 10% within the 2 h residence time in 0.08N HCl can be achieved. 4.2 Enteric coated acetyl salicylic acid tablets (100 mg/tablet) Composition of the tableting mixture Ingredients Parts by weight Composition Ig] [%] Acetyl salicylic acid 285.7 28.6 Ludipress 704.3 70.4 Stearyl fumarate-Na (Pruv) 10.0 1.0 Total 1000.0 100.0 Processing of the tableting mixture The ingredients except the sodium stearyl fumarate are blended in a Turbula blender for 10 minutes and passed through an 800 ~m-sieve. The lubricant is added and the resulting blend is additionally mixed for 1 minute. Rotary press Tablet shape Tablet weight Tablet diameter Compression force Korsch XL 100 concave 350 mg 9mm 6 kN Tableting equipment
Enteric coating with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Prepare around 1200 g of a dispersion containing around 220 g of Kollicoat MAE 100-55 Ingredients Parts by weight Composition Dry matter Ig] [%] [%] Kollicoat MAE 100-55 218.0 18.2 18.2 Triethyl citrate 21.8 1.8 1.8 (10% relative to polymer weight) NaOH (1 mol/L) 75.2 6.3 0.3 Demineralized Water 887.0 73.7 - Total 1200.0 100.0 20.2 Composition of the coating formulation Around 200 g of the water is used to disperse the triethyl citrate. Kollicoat MAE 100-55 is added to the remaining quantity of water and dispersec after the addition of the required quantity of 1 mol/L NaOH-solution. After 30 minutes of permanent stirring the plasticizer dispersion is added. The resulting coating suspension is stirred for 2 h prior to use. The recommended conditions are shown in the following. The cores were heated to 50 C for 30 minutes before applying the coating formulation. Release testing Kollicoat MAE 100-55 coating levels: Hicoat MAE 1QQ-99 Coating levels: == 3 mg/cm? === 4 mg/cm? === 6 mg/cm? == allowance limit == buffer change
4.3 Enteric coated Diclofenac-Na tablets (50 mg/tablet) Composition of the tableting mixtur Ingredients Parts by weight Composition Ig] [%] Diclofenac-Na 181.8 18.2 Ludipress 738.2 73.8 Kollidon VA 64 Fine 50.9 5.1 Kollidon CL 18.2 1.8 Aerosil 200 3.6 0.4 Magnesium stearate 7.3 0.7 Total 1000.0 100.0 Processing of the tableting mixture The ingredients except the Mg-stearate are blended in a Turbula T2C blender for 10 minutes and passed through an 800 um-sieve. Finally the magnesium stearate is added and the resulting blend is mixed for 1 minute. Rotary press Tablet shape Tablet weight Tablet diameter Compression force Korsch XL 100 concave 275 mg 9mm 15 kN Enteric coating with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Ingredients Parts by weight} Composition Dry matter Ig] [%] [%] Kollicoat MAE 100-55 451.5 18.1 18.1 Triethyl citrate 45.0 1.8 1.8 (10% relative to polymer weight) NaOH (1 mol/L) 153.5 61 2.5 Demineralized Water 1850.0 74.0 - Total 2500.0 100.0 22.3 Composition of the coating formulation Around 200 g of the water is used to disperse the triethyl citrate. Kollicoat MAE 100-55 is added to the remaining quantity and dispersed after the addition of the 1 mol/L NaOH-solution. After 30 minutes of permanent stirring the plasticizer-dispersion is added. The resulting coating suspension is stirred for 2 h prior to use. Coating equipment Manesty Coater XL Lab 01 Batch size kg 4.0 Number of nozzles 1 Nozzle diameter mm 0.8 Spraying rate g/min 20 Application quantity mg/cm? 3-4 Spraying time min 40 Air supply ms/h 400 Inlet air temperature C 55 Drying time min 5 Coating equipment and process parameters
Release testing Kollicoat MAE 100-55 coating levels 4.4 Enteric coated pantoprazol-Na mini-tablets (6.4 mg tablet weight) The mini-tablets were coated using an aqueous solutions of Kollicoat MAE 100-55 in a fluid bed coater. A a sub-coat is applied to prevent the API from degradation caused by interacting with water. Composition of the tableting mixture Ingredients Parts by weight Composition Ig] [%] Pantoprazole Na hydrate 242.4 12.12 Ludipress LCE 1547.6 77.38 Kollidon VA 64 fine 100.0 5.00 Kollidon CL-F 100.0 5.00 Mg-stearate 10.0 0.50 Total 2000.0 100.00 Processing of the tableting mixture Prior to use all ingredients were sieved through an 800um-sieve. After sieving the ingredients with the exception of Mg-stearate were blended in a Turbula T2C blender for 8 minutes. Finally the magnesium stearate was added and the tableting mixture is achieved after 2 minutes additional blending. Korsch XL 100 4 micro punches, no engravings Coating equipment and process parameters ee eee Son an ee in eee Tee ey eR ee ie ee es Tablet diameter Tablet shape Tableting speed Agitator filling shoe Compression force Tablet weight 2mm concave 30 rpm 5 rom 1,5 KN 6.4 mg Around 312,000 mini-tablets were achieved. At a tablet weight of 6.4 mg one tablet contains 0.78 mg of pantoprazole Na.
Enteric coating with Kollicoat MAE 100-55 To prevent the API in the mini-tablets to interact with the aqueous coating formulation a sub-coat consisting either of Kollicoat IR White Il, Kollicoat IR or Kollidon VA 64 can be applied. The latter one has the advantage that the polymer can be applied using an organic solvent e.g. i-propanol. Ingredients Parts by weight Composition Ig] [%] Kollicoat IR White II 199.3 19.9 FD&C Blue No.1 0.7 0.1 Water 800.0 80.0 Total 1000.0 100.0 Glatt GPCG 3.1, Granu 51, Nozzle position 1: top spray Nozzle Mini tablet load Sub-coat dispersion Spray rate Atomization air Air volume rate Inlet air temperature Product temperature mm 9 g g/min bar ms/h C C 0.8 1500 825 20 2.0 206 60 48 Ingredients Parts by weight Composition Ig] [%] Kollicoat IR White II 199.3 19.9 FD&C Blue No.1 0.7 04 Water 800.0 80.0 Total 1000.0 100.0 Ingredients and composition Glatt GPCG 3.1, Granu 51, Nozzle position 1: top spray Coating equipment anc process parameters MIAN APU VT, ATAU Ul, INULEIC PUOIIVUIT I. LUN OMIay Nozzle mm 0.8 Mini tablet load g 1500 Sub-coat dispersion g 825 Spray rate g/min 20 Atomization air bar 2.0 Air volume rate ms/h 206 Inlet air temperature C 60 Product temperature C 48 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Ingredients Parts by weight Composition Ig] [%] Kollicoat MAE 100-55 600.0 18.0 Triethy! citrate 60.0 1.8 (10% relative to polymer weight) NaOH (1 mol/L) 207.0 0.2 Water 2470.0 Total 3337.0 20.0 Ingredients and composition Around 1800 ml of water is used to re-disperse the Kollicoat MAE 100-55 while the 1 mol/L NaOH-solution is added. The mixture is stirred for 30 minutes. In parallel the plasticizer is dispersed in the remaining quantity of water. After adding the dispersed plasticizer to the polymer dispersion this is stirred fo 2 hours. Enteric coating formulation is applied until a coating level of 4.5 mg/cm? was achieved. Coating equipment and process parameters Glatt GPCG 3.1, Granu 51, nozzle position 1: top spray Batch size kg 1.37 Number of nozzles 1 Nozzle diameter mm 0.8 Spraying rate g/min 20 Atomization air bar 2.0 Air supply ms/h 206 Inlet air temperature C 50 Product temperature C 39 Drying time min 5
The coated mini-tablets are filled in hard-gel capsules. To achieve the claimed API concentration of 40 mg per capsule 52 mini-tablets are required. Finished dosage form Release testing Due to the sensitivity of the API release testing with a buffer change is not opportune. The tests at pH 1.2 and pH 6.8 have to be performed separately.
4.5 Enteric Coated Propranolol tablets (30 mg/tablet) Composition of the tableting mixture Ingredients Parts by weight Composition Ig] [%] Propranolol 300.0 16.7 Ludipress LCE 1383.0 76.8 Kollidon VA 64 Fine 54.0 3.0 Kollidon CL-F 54.0 3.0 Magnesium stearate 9.0 0.5 Total 1800.0 100.00 Processing of the tableting mixture The ingredients except the Mg-stearate are blended in a Turbula blender for 10 minutes and passed through an 800 um-sieve. Finally the magnesium stearate is added and the resulting blend is mixed for 1 minute. Coating equipment and process parameters Rotary press Korsch XL 100 Rotary press Korsch XL 100 Tablet shape 7 mm concave, engraved Tableting speed S rpm Tablet weight 180 mg Tablet diameter 7mm Compression force 5 kN Tablet hardness 85-110N Friability 0.02% Enteric coating with Kollicoat MAE 100-55 Re-dispersion of the polymer powder For the preparation of an appropriate polymer dispersion follow the recommendations in chapter 3.2. Ingredients Parts by weight Composition Percentage [gl [%] Kollicoat MAE 100-55 172.0 172.0 17.9 Triethyl citrate TH2 17.2 1.8 NaOH-solution; (1 mol/L) 59.4 2.5 0.3 Water 710.0 - - Total 958.4 191.7 20.0 Coating equipment Manesty XL Lab01 Batch size kg 4.0 Number of nozzles 1 Nozzle diameter mm 0.8 Pan speed rpm 25 Spraying rate g/min 20 Spraying pressure bar 1.8 Air supply ms/h 400 Inlet air temperature C 55 Drying time min. 55 C 5 Composition of the coating formulation Coating equipment and process parameters Coating equipment Manesty XL Lab01 Batch size Number of nozzles Nozzle diameter Pan speed Spraying rate Spraying pressure Air supply Inlet air temperature Drying time kg mm rpm g/min bar ms/h C min. 55 C 4.0 0.8 25 20 1.8 400 55
Release testing Kollicoat MAE 100-55 coating levels: wee 5 mg/cm? === 6 mg/cm? ==== allowance limit ==== buffer change Kollicoat MAE 100-55 coating levels: MCOal WIA 1UU-00 C m= 5 mg/cm? == 6 mg/cm? == allowance limit == buffer change
5. Applications and typical formulations using Kollicoat MAE 100 P 5.1 Coloured enteric film coatings for tablets The formulation below is for 5 kg of propranolol cores coatings for tablets (diameter 9 mm;weight 330 mg) See 3.3 Processing notes Re-dispersion of coating polymer Composition of the spray suspension Polymer suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 148.50 15.00 1,2-propylene glycol 22.28 2.26 Water 665.77 67.25 Pigment suspension Titanium dioxide 4.95 0.5 Sicovit Red 30 4.95 0.5 Talc 36.60 4.0 Water 103.95 10.5 Total 990.00 100.0 Solids content of the spray suspension 22.25% Content of polymer dry substance 15.0% Polymer applied (as solids) 4.0 mg/cm? Total solids applied 5.9 mg/cm? Preparation of the spray suspension Polymer suspension Kollicoat MAE 100 P is dispersed in the specified amount of water. When completely dispersed, the plasticizer is incorporated. Pigment suspension Sicovit Red 30, titanium dioxide and talc are intensively stirred into the specified amount of water and homogenized in a corundum disk mill. Spray suspension The pigment suspension is stirred into the coating suspension. The spray suspension must be stirred during spraying to prevent the solid substances settling out. Coating pan: Size of batch: Air supply temperature: Product temperature: Spraying pressure: Spraying rate: Spraying time: Accela Cota 24 (Manesty) 5 kg 60 C 32 - 35 C 2 bar 40 g/m 25 - 30 min Coating equipment and process parameters
5.2 Coloured enteric film coatings for pellets and crystals Re-dispersion of coating polymer Composition of the spray suspension The following formulation is calculated for 500 g of ASS-crystals spray suspension (diameter 0.3 1.0 mm) Polymer suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 148.5 14.9 1,2-propylene glycol 22.3 2.2 Water 675.8 67.6 Pigment suspension Titanium dioxide 5.0 0.5 Sicovit Red 30 5.0 0.5 Talc 39.6 4.0 Water 104.0 10.4 Total 1000.0 100.0 Solids content of the spray suspension Solid polymer in the spray suspension Solid polymer applied Total solids applied Coating pan: Size of batch: Air supply temperature: Exhaust air temperature: Spraying pressure: Spraying time: WSG Aeromatic Strea 1 500 g 60C 35 C 1 bar 100 min Coating equipment and process parameters Release rates of diclofenac Na and acetylsalicylic acid tablets
5.3 White enteric film coatings for pellets Re-dispersion of coating polymer See 3.3 Processing notes Composition of the spray suspension The following formulation is calculated for 5 kg of pellets (diameter 0.8 1.2 mm) Polymer suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 675.0 15.0 1,2-propylene glycol 67.5 1,5 Water 3.010.0 66.9 Pigment suspension Kollidon 22.5 0.5 Titanium dioxide 45.0 1.0 Talc 180.0 4.0 Water 500.0 1144 Total 4500.0 100.0 Polymer (solids) applied Total solids applied Solids content of the spray suspension 22.0% Polymer (solids) in the spray suspension 15.0% mg/cm? mg/cm? Preparation of the spray suspension Polymer suspension Dissolve Kollidon 100 P in the specified amount of water. Proceed as usual. Pigment suspension Spray suspension See suggested method under 3.3. Coating pan: Size of batch: Air supply temperature: Exhaust air temperature: Spraying rate: Spraying time: Hittlin Kugelcoater HKC 5 TJ 5 kg 60 C 32 - 35 C 45 g/m 100 min Coating equipment and process parameters
5.4 Colourless enteric coatings for soft-gel capsules Re-dispersion of coating polymer The following formulation is intended for 5 kg of soft-gel capsules Composition of the spray Total solids applied 12.0 mg/cm? Coating suspension Parts by weight Composition Ig] [%] Kollicoat MAE 100 P 500.0 21.0 1,2-propylene glycol 100.8 4.2 Water 1,795.2 74.8 Total 2400.0 100.0 Solids content of the spray suspension 25.2% Content of polymer dry substance 21.0% Polymer applied (as solids) 10.0 mg/cm? Polymer suspension Preparation of the spray suspension Polypropylene glycol is first dissolved in the specified amount of water. Then Kollicoat MAE 100 P is stirred in until completely redispered. The blend is stirred for 3 hours. Coating pan: Size of batch: Inlet air temperature: Product temperature: Spraying rate: Spraying time: Accela Cota 24 (Manesty) 5 kg 50 C 30-32 C 30 35 g/min 70 min Coating equipment and process parameters
5.5 Seal-coating of tablet cores Some tablet cores contain a water-sensitive drug or a highly effective tablet disintegrant, e.g. Kollidon CL. Before they can be coated with aqueous solutions a seal coat has to be applied. The same applies if the cores are too soft, or if an aqueous coating will not take to theirsurface. In such cases, heating the cores to about 35 C and spraying them with a 10% solution of Kollidon VA 64, e.g. in isopropanol has given good results. Experience indicates that an adequate sub-coating film is built up when small amounts of Kollidon VA 64 are applied, i.e. approx. 0.4 mg/cm?. Alternatively seal-coating can be performed using Kollicoat IR or even Kollicoat IR White Il. When using aqueous seal-coats a hydrophobic plasticizer can be used. In order to prevent interactions with hydrophilic or water-absorbing components present in the core low spray rates have to be used in the initial stage of the seal-coat application. 5.6 Further applications Coatings levels of 0.5 2.0 mg/cm? can be applied for the following purposes: To mask unpleasant tastes and odours To protect the tablet core against atmospheric humidity As a barrier between incompatible active substances
6. Equipment Cleaning Recommendations Kollicoat MAE 100-55 and Kollicoat 100 become water-soluble after neutralizing the majority of the polymers methacrylic acid moiety. To achieve this level cleaning is thus best performed using dilute NaQH-solutions containing small amounts, e.g. 0.5 - 1% of a surfactant such as sodium lauryl sulfate (SLS). 7. Storage The powder products Kollicoat MAE 100-55 and Kollicoat MAE 100 P should be stored at temperatures below 25 C. In contrast to the Kollicoat MAE 30 DP dispersion the powder grades do not require transportation and storage above 0C. Kollicoat MAE 100-55 and Kollicoat MAE 100 P are stable for at least 18 months in the unopened original drums at room temperature. After re-dispersion to aqueous forms the exposure to heat or frost, as well as foam formation have to be avoided. These effects may cause coagulation and turn the products defective. Once a drum has been opened the contents it is recommended to use the content within a few weeks. Kollicoat MAE 100-55 Kollicoat MAE 100 P 10. Packaging 20 kg polyethylene drums with a PE inner liner. 20 kg polyethylene drums with a PE inner liner. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Table of Contents Introduction 6 Ibuprofen 8 Chemical information . wl Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality .. 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Chemical information 20 Product information 20 Chemical and physical properties 21 Particle characterization 21 Regulatory status 21 Specification 21 Medical indication 22 Ibuprofen Sodium Dihydrate 24 Chemical information 24 Product information 24 Storage 25 Regulatory status 25 Specification 25 Medical indication 26 Table of Contents Introduction Ibuprofen 8 Chemical information 8 Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Ibuprofen Racemic Ibuprofen Lysinate (RIBL) Ibuprofen Sodium Dihydrate Ibuprofen Sodium Dihydrate
Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, antipyretic and anti-inflammatory actions, it is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever. Due to its analgesic, antipyretic and anti-inflammatory actions, it is used The common active ingredient dosage in tablets is 200, 400, 600 and 800 mg. The OTC dosage forms are mainly the 200 and 400 mg forms (except for the United States and some other countries, where the 200 mg form is the only OTC form). Other common dosage forms are capsules, syrups, suspensions, suppositories, and topical dosage forms like creams and gels. Pharmacokinetics Orally administered ibuprofen is absorbed rapidly in the Gl tract.? After a single oral dose on an empty stomach, peak plasma levels are reached within 45 to 90 minutes and the apparent plasma volume of distribution is reported to be between 0.1 to 0.2 I/kg.-> Ibuprofen has an extensive protein binding capacity (+98%) and is excreted via the kidneys. The biological half-life is between 2 and 4 hours.? After 24 h, 100% of the active substance is excreted in the urine.
Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as histamine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C. bata Te Ta Tort) U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Gillespie, W. R. et al., Relative Bioavailability of Commercially Available Ibuprofen Oral Dosage Forms in Humans, Journal of Pharmaceutical Sciences, 71:1034-1038, 1982. Verbeeck, R. K., Pathophysiologic Factors Affecting the Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs, Journal of Rheumatology, 15:44-57, 1988. Jamali, F. and D. R. Brocks, Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers, Clinical Pharmacokinetics, 19:197-217, 1990. Vowles, D. T. and B. Marchant, Protein Binding of Ibuprofen and Its Relationship to Drug Interactions, British Journal of Clinical Practice, 1:13-19, 1980. Whitlam, J. B. and K. F. Brown, Ultrafiltration in Serum Protein Binding Determinations, Journal of Pharmaceutical Science: Tio Teel atc oa Rudy, A. C. et al., Stereoselective Metabolism of Ibuprofen in Humans: Administration of R-, S- and Racemic Ibuprofen, Journal of Pharmacology and Experimental Therapeutics, 259:1133-1139, 1991. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(6): 986-1000, 2011.
Ibuprofen (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid Chemical name (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid 15687-27-1 239-784-6 C,,H,,0. 13) 182 206.28 g/mol CAS number EINECS number Molecular formula Molecular weight 3ASF offers 4 grades based on different particle size distributions (see particle charac- erization). Furthermore, a direct compressible grade is offered: Ibuprofen DC 85 W, the somposition of which can be found in chemical and physical properties section below. Product grades (+)-2-[4-(2-methylpropyl)phenyl]propanoic acid; (+)-Benzeneacetic acid, alpha-methyl- 4-(2-methylpropy)); (+)-p-lsobutylhydratropic acid; (+)-2-p-lsobutylphenylpropionic acid Ibuprofen meets the current Ph. Eur., USP, JP and IP monographs. DMFs and CEP are available upon request. Regulatory status Ibuprofen is the racemate of (+)-lbuprofen and (-)-lbuprofen (optical rotation = 0). According to the literature the pharmacologically active form is (+)-lbuprofen. Approximately 30 to 70% of the (-)-lbuprofen is converted to the active form (+)-lbuprofen in the body. This process proceeds solely from the (-)- form to the (+)- form.
Chemical and physical properties Ibuprofen grades 25, 38, 50, 70 Crystalline powder Solubility in phosphate buffer pH 7.2 (37 C) Partition coefficient n-octanol/water The chemical parameters of all pure ibuprofen powder grades are identical. The only difference is the particle size distribution (see particle characteristics).
Particle characterization Ibuprofen 25 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 25 is between 20 um and 33 pm. Ibuprofen 50 Particle Size Distribution Bulk density Tapped density An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 50 is between 45 um and 60 pm. Approximately 0.34 g/ml. Approximately 0.60 g/ml.
Ibuprofen 38 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 38 is between 33 um and 45 pm. ibuprofen 70 Particle Size Distribution Bulk density Approximately 0.38 g/ml. Tapped density Approximately 0.68 g/ml. An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 70 is between 60 pm and 85 pm.
Ibuprofen DC 85 W The ibuprofen used to manufacture Ibuprofen DC 85 W meets the current Ph. Eur., USP, JP and IP monographs. A Technical Package and a US-DMF are available upon request. Granules, free flowing, homogeneous material Appearance SEM photograph
Recommendation for direct compression Today the manufacturing of ibuprofen tablets is often done by direct compression. Using this method, the expensive and time-consuming wet granulation method can be avoided. But in general, ibuprofen has the disadvantage of sticking on the tablet tools so that the process must be interrupted often. Therefore, direct compression formulations with a high content of ibuprofen per tablet are often avoided. Mostly tablets with an ibuprofen content of maximum 60% are compressed. BASF offers a formulated ibuprofen product ideal for direct compression: Ibuprofen DC 85 W. The direct compression (DC) grade ensures that tablet sticking is minimized and allows for excellent tablet engraving. Furthermore, Ibuprofen DC 85 W has a lower angle of repose compared to standard grades, resulting in improved flowability.
General information on processing of Ibuprofen Ibuprofen is used mainly in three (3) different dosage forms: Ibuprofen 50, Ibuprofen 70, Ibuprofen DC 85 W (for direct compression) Recommended grade(s) High concentrations of magnesium stearate as a lubricant are not recommended. For direct compression, the ready-to-use Ibuprofen DC 85 W reduces sticking. For a film coating, Kollicoat IR has a reduced viscosity in aqueous solutions compared to HPMC suspensions, which leads to higher solids content and a faster coating process. Formulation guidance Creams & Gels Recommended grade(s) Recommended grade(s) To stabilize against sedimen- tation, fine particles should be used. The pH of the sus- pension should be in the acid range so that ibuprofen is undissolved, which will reduce bitter taste if any. lbuprofen is dissolved in the ipophilic phase of creams, thus there is no impact of particle size. Propylene glycol or low molecular weight polyethylene glycols are recommended as the oily component. Formulation guidance Formulation guidance
-oomLab - Your Virtual Formulation Assistant Access example formulations and build your own ZoomLab Formulation Wizard identifies suitable excipients and calculates potential formulations depending on the selected dosage form, defined target profile, and properties of the active ingredient. Example formulations include creams, tablets, and more! - Evaluate bioequivalence of your final formulation A WHO biowaiver monograph is available for ibuprofen. The ZoomLab dissolution module can be used to calculate difference and similarity factors (f1, f2) required for showing bioequivalence. ZoomLab provides values for parameters relating to particle size, powder density, flowability, and tabletability. The parameters are scaled from 0 to 10, a risk analysis is run, and an interpretation of results/formulation advice is provided.
Example formulations Production of granules for 200, 400, 600 and 800 mg forms The following ingredients are placed in a high shear mixer and granulated with water: Ibuprofen 50 60.1% w/w Amount of water: approximately 0.2 kg water per 1 kg __ ibuprofen. Wet sieving (4 mm) and drying in a fluid bed Lactose 18% w/w granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following Corn starch 9% w/w additives to form granules suitable for tableting. Kollicoat IR 3.6% w/w Extra granular material Avicel PH 102 3.6% w/w AcDiSol 4.8% w/w Magnesium stearate 0.6% w/w Aerosil 200 0.3% w/w Coating formulations for Ibuprofen tablets oes Fraction with reference to the Fraction with reference Composition atomised suspension [%] to the dry film [%] Polymer Kollicoat IR 16.0 64 Pigments Talc 6.0 24 Sicovit Red 30 3.0 12 Total 25 100 Amount of water: approximately 0.2 kg water per 1 kg ibuprofen. Wet sieving (4 mm) and drying in a fluid bed granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following additives to form granules suitable for tableting. Corn starch Kollicoat IR Extra granular material Magnesium stearate Coating formulations for Ibuprofen tablets

Handling & Safety Product specification The current version of the product specification is avail- able on RegXcellence or from your local BASF sales representative. Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on MyProduct- World or from your local BASF sales representative. Publications Regulatory & Quality Publications including scientific posters are available on: Please refer to the individual document quality & regu- latory product information (QRPI) which is available on RegXcellence and from your local sales representative The QRPI covers all relevant information including retest dates and storage conditions.
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Racemic Ibuprofen Lysinate (RIBL Racemic Ibuprofen Lysinate (RIBL Chemical information Chemical information Ibuprofen Lysinate (+) (+)- (+ (+ -2-[4-(2-methylpropyl)phenyl]propanoic acid lysinate -Benzeneacetic acid, alpha-methyl-4-(2-methylpropyl) lysinate -p-lsobutylhydratropic acid lysinate -2-p-lsobutylphenylpropionic acid lysinate Empirical formula Molecular weight
Chemical and physical properties White to almost white, very fine crystalline powder witt a high volume. In the literature the solubility of Ibuprofen (acid) in distilled water is reported to be less than 0.1%. The solubility of Ibuprofen Lysinate is 1:5, or about 17%. Particle characterization An example particle size distribution is shown below. The median particle size for RIBL is approximately 10 pm Regulatory status No monographs exist. E-DMF is available upon request.
The term RIBL is the acronym for Racemic Ibuprofen Lysinate. Racemic signifies that the ibuprofen drug substance and the lysine anion are both racemic compounds. RIBL differs from the common ibuprofen acid, gen- erally referred to as ibuprofen, in that it is more rapidly absorbed from the intestinal tract and reaches peak plasma levels and t,,., more quickly. After absorption, RIBL is available in the form of pure ibuprofen acid and is therefore to be handled like ibuprofen. Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, anti- pyretic and anti-inflammatory effects, ibuprofen is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever.? For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. Pharmacokinetics RIBL is readily and quickly absorbed from the gastrointestinal tract.!? The peak plasma level of the free acid is reached within 30 to 60 min (with the free acid ibuprofen, t,,,, was measured between 60 and 120 minutes, depending on the dosage form).: After absorption, there is no difference between RIBL and the free acid.
From a pharmacological point of view, there is no difference between RIBL and the free ibuprofen acid because it is the free acid and not the RIBL salt that is the active form. The mode of action of ibuprofen, while not completely understood, is believed to involve reversible inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have among other properties a powerful effect on the smooth muscles. In case of inflammatory stimuli or blood flow disorders, PGs are synthesized in increased amounts, making the tissues sensitive to the action of other agents such as histamine and kinins. As a result, symptoms like pain and inflammation occur. The in- cidence of fever is raised by the influence of the PGs on the heat regulation center in the hypothalamus. There they scale up the normal set point of 37 C. bats CUe Ta Tort) 1 Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration of Ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990. Hermann, T. W. et al., Bioavailability of Racemic Ibuprofen and its Lysinate from Suppositories in Rabbits, Journal of Pharmaceutical Sciences, 82(11):1102-1111, 1993. U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Neupert, W. et al., Effects of lbuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(5): 986-1000, 2011. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration o ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990.
Ibuprofen Sodium Dihydrate Chemical information Ibuprofen Sodium Dihydrate 2-(4-isobutylphenyl)-propionate sodium dihydrate Chemical name Se IS ee ee ee a en re ae ee ee 31121-93-4 C,,H,,0,Na x 2 H,O 228.26 + 36.03 g/mol Empirical formula Molecular weight
Storage Ibuprofen Sodium Dihydrate should be stored in the original, tightly sealed container. It should be placed ina well-ventilated room at ambient temperature and protected from light. The retest period of Ibuprofen Sodium Dihydrate is 60 months for material stored in the original, unopened containe! and according to our recommendations. Regulatory status Currently there are no monographs describing Ibuprofen Sodium Dihydrate in the major Pharmacopoeias (USP, Ph. Eur.. and JP).
According to the literature, ibuprofen sodium dihydrate dissolves more quickly in vitro and is absorbed into blood plasma more quickly than con- ventional ibuprofen, whereas tolerability and safety profiles of the two APIs are comparable.? In an investigation of the dissolution, plasma pharmacokinetics, and safety of ibuprofen sodium dihydrate versus conventional ibuprofen, the following results were reported:? @ buprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 compared to conventional ibuprofen. @ lbuprofen sodium dihydrate reached the t,,,, significantly earlier than conventional ibuprofen. @ lbuprofen sodium dihydrate showed significantly higher c_, compared to conventional ibuprofen. @ buprofen sodium dihydrate was characterized by significantly higher mean plasma concentration (10 min post-dose) compared to conventional ibuprofen. tax iS the necessary time until the maximum plasma concentration of a drug is reached; this is relevant for the drug onset. Generally, reaching the t_ early is of great advantage for analgesic treatment. According to the literature, the first signs of pain relief occurred significantly earlier in ibuprofen sodium dihydrate treated patients, and pain intensity was reduced to half after 30 min for ibuprofen sodium dihydrate compared to 57 min for conventional ibuprofen. In summary, ibuprofen sodium dihydrate causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen.
The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (CO)) which is responsible for the biosynthesis of prostaglandin (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflamma- tory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as hista- mine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C.? c Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandii Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vas FeYToltote CHI (2) Rc) =\ coal O00 Soergel, F. et al. Pharmacokinetics of Ibuprofen Sodium Dihydrate and Gastrointestinal Tolerability of Short-Term Treatment with a Novel, Rapidly Absorbed Formulation, International Journal of Clinical Pharmacology and Therapeutics. 43(8):140-149, 2005. Schleier, P. et al., Ibuprofen Sodium Dihydrate, an Ibuprofen Formulation with Improved Absorption Characteristics, Provides Faster and Greater Pain Relief than Ibuprofen Acid, International Journal of Clinical Pharmacoloay and Therapeutics. 45(2):89-97. 2007. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandir Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997.
www.pharma.basf.com For sample requests contact us ai pharma-solutions@basf.com Meet your Virtual Pharma Assistants! ZoomLab, RegXcellence, and MyProductWorld, your interactive guides for optimizing drug formulations, navigating quality and regulatory compliance, and browsing ingredients. Learn more and sign up at https://info-mypharma.basf.com/ Inspiring Medicines for Better Lives This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been preparec in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to the extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2021 BASF Corporation. All Rights Reserved.
November 2012 Hard Fat for suppository masses
PRD-No., Article-No. and CAS.-No. PRD-No. Article-No. CAS.-No. Novata B PH 30531224 50209107 67701-26-2 Novata BC PH 30531225 50209108 67701-26-2 Novata BCF PH 30531226 50209109 67701-26-2 Novata BD PH 30531227 50209110 67701-26-2 See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). All Novata PH Grades are complying to the Monograph Hard fat Ph. Eur. Regulatory Status Product characteristics All Novata PH grades are white to slightly yellowish, brittle pellets which are used for the production of suppositories. On account of its mean hydroxyl value range and the melting point, the product can be used as universal suppository mass, alsc in the chemists shop. Typical Properties Novata B PH BC PH BCF PH BD PH Acid value <0.5 <0.5 <0.5 <0.5 lodine value <3.0 $3.0 <3.0 <3.0 Peroxide value <3.0 <3.0 <3.0 <3.0 Alcaline impurities (mL) <0.15 <0.15 <0.15 <0.15 Total ash (%) <0.05 <0.05 <0.05 <0.05 Unsaponifialble (%) <0.6 <0.6 <0.6 <0.6 Hydroxyl value 20-30 30 - 40 20-30 5-15 Saponification value 225 240 225-240 225-240 230-245 Melting point (C) 33.5-35.5 33.0-34.5 35-37 33.5-35.5 Heavy metals as sum <10.0 <10.0 <10.0 <10.0 Pb (ppm)
Application The main application of the Novata PH Grades are suppositories. Suppository is a drug delivery system that is inserted into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository), where it dissolves or melts. Suppositories may be used for patients (e.g. children) in case it may be easier tc administer than tablets or syrups. Suppositories may also be used when a patient has a vomiting tendency, as oral medication can be vomited out. Another benefit of suppositories is, that drugs which often cause stomach upset during oral intake, for example diclofenac sodium are better tolerated in suppository form. Suppositories are made from a greasy or waxy base, containing different Novata PH grades in which the active ingredient and the other excipients are dissolved. The main important point in formulating a suppository, is adjust the melting temperature of the complete formulation to the body temperature. Apart from suppository manufacturing, solid triglycerides (hard fats) are used as carriers in capsule fillings, inlets, ointments and creams and in dental products. In topical formulation they can act as a sensory enhancer, because of their low melting point. All Novata grades are based on vegetable origin. The raw material origin is coconut or palm kernel oil. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreement Toxicology In the original sealed containers all Novata grades can be stored for at least 18 month, protected from moisture at below 30 C. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions c safe and proper handling and disposal. Handling and Disposal Formulations 1. Pain Relief Suppository with Novata B PH Ingredient Tuts Amount (g) Kollisolv MCT 70 Medium Chain Triglycerides 0.200 Phenacetin 0.300 Codeinphosphate 0.010 Acetyl Salicylic Acid 0.500 Soya Lecithin 0.010 Il Novalgin 0.200 Ill Novata B PH Hard Fat ad. 2.000 Remark Tube rise melting point: 34.5 C. Preparation Phase is suspended and triturated with Phase II. Phase Ill is melted on a water bath at 50 C after cooling to 38 C is mixed to a pasty consistency with the additive trithiratinn Ciihean ant ta avan dictrihi tian of all additivee the cammn ind 2 EE EE Phase is suspended and triturated with Phase II. Phase Ill is melted on a water bath at 50 C after cooling to 38 C is mixed to a pasty consistency with the additive trituration. Subsequent to even distribution of all additives, the compound is cast into moulds at 33 C.
2. Suppository with Novata BC PH against Hemorrhoids Ingredient Name Amount (g) Zink Oxide 0.100 Perugen 0.040 Novata BC PH Hard fat ad. 2.000 Witch hazel extract, dest. 0.200 Bismuth Gallate, basic 0.100 Remark Tube rise melting point: 34 C. Preparation Phase is melted 45 C, it is suspended with Phase Il at 45 C. Phase Ill is triturated, added at 40 C to the melt and cast into moulds at 38 C. ai Et RARER ES Phase is melted 45 C, it is suspended with Phase Il at 45 C. Phase Ill is triturated, added at 40 C to the melt and cast into moulds at 38 C. 3. Pain relief suppository 6 ES EEE SAR eee: Ingredient Name Amount (g) Isopropyl Phenazone 0.300 Novata BD PH Hard Fat ad. 2.000 Coffein 0.050 Remark 34.4C Tube rise melting point: an ee er Melt Phase at 50 C on a water bath. At a temperature of 38 C cast the compounc into slightly cooled moulds. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Supersedes issue dated February 2013 Ethylene Glycol and Vinyl Alcohol Graft Copolymer for instant-release coatings and for use as wet-binder
Contents 1. Introduction 1.1 General beh NAMEN 1.2 Structural formul: 1.3 Physical form 1.2 Structural formula 2. Specification and properties 2.1 Chemical nature 2.2 Physicochemical properties 2.3 Specification 2.4 Properties of aqueous solutions 2.5 Peroxide Formation 2.6 Film properties 2.7 Properties as wet-binder 2.2 Physicochemical properties 3. Processing and Application in Film-coatings 3.1 Applications 4. Typical formulations for Instant Release Coating 4.1 Propranolol instant release film-coated tablets 5. Processing and Application as Wet-Binder 5.1 Applications 6. Typical Applications as Wet-Binder 6.1 Acetaminophen instant granules 6.2 Instant-release Ibuprofen tablets: 600mg/tablet 6.3 Instant-release Raloxifen-HCl tablets: 300 mg 7. Storage conditions 8. Stability 9. Toxicology 10. Product Number 11. Packaging
1. Introduction Kollicoat IR is a polyethylene glycol- polyvinyl alcohol graft copolymer that is very readily soluble in water. It iwas initially designed for the application as a polymer for instant-release coating of tablets but in addition to that proofed its functionality as wet binder, too. 1.1 General 1.1 General Due to its property not to form peroxides Kollicaot IR can be posititioned as wet- binder for oxygen-sensitve API solid dosage which is superior to binder polymers of other chemistry. When tested even under accelerated storage conditions in stabililty testing Kollicoat IR in contrast to some of these standard wet-binder polymers does not form detectable levels of peroxides. 1.2 Structural formula Kollicoat IR is a white to faintly yellow, free-flowing, spray-dried powder. 2. Specification and properties The polymer consists of 75% polyvinyl alcohol units and 25% polyethylene glyco units. The product also contains approx. 0.3% colloidal silica to improve its flow properties. 2.1 Chemical nature In contrast to polyvinyl alcohol, the polymer dissolves very fast in acidic, neutral and alkaline aqueous media. Aqueous solutions have a comparatively low viscosity. 2.2 Physicochemical properties Molecular weight Solutions of Kollicoat IR with concentrations of up to 40% can be prepared in water and aqueous systems, e.g. weak acids or alkalis. Solutions of up to 25% can be prepared in a 1:1 ethanol-water mixture. Solubility The polymer is insoluble in organic solvents. The viscosity of a 20% solution is determined according to EN ISO 2555 at 23C and a shear rate of 100 rpm. Film formation An aqueous solution is cast onto a smooth surface. When the water has evaporated, a clear, colourless, flexible film remains. Microbial status
2.3 Specification See separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). 2.4 Properties of aqueous solutions Viscosity Kollicoat IR dissolves rapidly in water. It is though the viscosity of aqueous solutions of Kollicoat IR increases with the polymer concentration, however remains much lower than that of equivalent solutions of, for instance, cellulose derivatives. Viscosity of aqueous Kollicoat IR solutions as a function of polymer concentration: Surface Tension Kollicoat IR reduces the surface tension of water. This makes aqueous solutions easy to spray, and the spray droplets exhibit good wetting behavior on the tablet surface.
2.5 Peroxide Formation Peroxide levels, expressed in meq/kg, are at levels below the detection limit of 1 meq/kg. Even when stored under accelerated storage conditions at 40 C/ 75% rh. the peroxide levels do not exeed 1 meq/kg after 30 months. 0 month <1 3 months <1 6 months <1 12 months 1 18 months 1 30 months 1 2.6 Film properties Kollicoat IR forms clear, colorless films that are enormously flexible and dissolve very rapidly in water. Kollicoat IR films are not tacky, have a high pigment binding capacity and can easily be imprinted. Kollicoat IR has a much higher elongation at break than cellulose derivatives. Elongation at break of various instant release polymers (64% r. h.) elongation at break [%] 120 1007] 80 60 40 204 105 4 Kollocoat IR HPMC 2910 HPMC 2910 type 6 mPas type 3 mPas 2.7 Properties as wet-binder The low viscosity allows even concentrated aqueous solutions to be applied in standard wet-granution equipment such as high-shear blenders or fluid-bed granulators. Alternatively powder blends containing Kollicoat IR can be granu- lated using water as solvent for the binder.
3. Processing and Application in Film-Coatings Kollicoat IR can be used for all applications for which a water-soluble flexible polymer is required. 3.1 Applications Instant release coating - Improves appearance, makes tablets easier to swallow, gives a distincti appearance, protects sensitive active ingredients and protects agains unpleasant taste or odour. Pore former in sustained-release coatings - To control drug release rate Film former in sprays and transdermal therapeutic systems Suspension and emulsion stabiliser Protective colloid The special advantages of Kollicoat IR are reflected in its enormous flexibility, low viscosity and fast dissolution. Kollicoat IR solutions for spraying onto tablets can be applied with a high solids content, which greatly reduces the coating time and minimises costs. 3.2 Processing notes Because of the high flexibility of Kollicoat IR films, it is not necessary to adc a plasticiser. A spray suspension is best prepared as follows: Dissolve Kollicoat IR in water and stir in the previously homogenised pigment suspension. The other water-soluble ingredients can be dissolved together with the Kollicoat IR. The speed of the stirrer should be set such that little ot no foam is produced. As spray suspensions of Kollicoat IR have a lower viscosity than those of other instant release polymers, they can have a much higher concentration. This greatly shortens the spraying and processing time in the manufacture of film-coated tablets. Polymer concentrations of 15 25% can be used, giving a total solids concentration of 20 35%, depending on the quantity of pigments. Since Kollicoat IR has surfactant properties and can act as a protective colloid, it prevents the aggregation of the pigment particles and ensures that the pigment is evenly distributed over the tablet core. The great elasticity of Kollicoat IR ensures that it does not crack on the tablets when they are exposed to different humidity conditions in storage, even when the cores contain powerful swelling agents such as HPMC, xanthan or alginate which are frequently used in sustained release tablets. The coating can be applied in all the usual coaters. e.g. horizontal drum coaters, fluidised bed coaters, immersion sword coaters, and coating pans under the usual conditions for aqueous solutions. The following conditions have been used successfully in numerous trials: Inlet air temperature: 60 - 80 C Outlet air temperature: 30 - 50 C Atomizing pressure: 3-6 bar The product can very easily be cleaned off the equipment with warm or cold water.
4. Typical formulations for Instant Release Coating 4.1 Propranolol instant-release film-coated tablets 40 mg propranolo! HCI; 97.5 mg Ludipress; 12.5 mg Kollidon VA 64; 2.5 mg magnesium stearate; 97.5 mg Avicel PH 102 Composition of the tablets Composition of the spray suspension Composition of the spray suspension The formulation is designed for 250 kg of tablet: (tablet weight 250 mg; diameter 9 mm) Weight [g] Proportion [%] Polymer solution Kollicoat IR 6.080 16.0 Water 24.320 64.0 Pigment suspension Talc 1.710 4.5 Titanium dioxide 1.140 3.0 Sicovit Red 30 570 1.5 Water 4.180 11.0 38.000 100.0 Preparation of the spray suspension Pigment suspension: Spray suspension: eIey Vey tmett. Stir the pigment suspension into the polymer solution. To avoid sedimentation during the spraying process, the mixture must be continuously stirred. Machine parameters Coating equipment Driacoater type 900, perforated drum coater Batch size 250 kg Inlet air temperature 70C Outlet air temperature 48 C Product temperature 50 C A\r flow 4400 m/h Atomizing pressure 6 bar Number of spray nozzles 6 Spraying rate 700 g/min Spraying time 55 min Final drying 60 C/5 min Quantity applied 3.8% Tablet properties Core Film-coated tablet Appearance White Red Hardness 93 N 109 N Friability 0% 0% Disintegration time 5:53 [min:s] 5:47 [min:s] Drug release 10 min: 49% 10 min: 54% 20 min: 98% 20 min: 99%
4.2 Caffeine instant-release tablets 50 mg caffeine; 229 mg Ludipress; 10 mg Kollidon CL; 1 mg magnesium stearate; 40 mg Avicel PH 101 Composition of the tablets Composition of the spray solution The formulation is designed for 5 kg of tablets (weight 330 mg; diameter 9 mm) Weight [g] Proportion [%] Polymer solution Kollicoat IR 108.2 20.8 Water 286.0 55.0 Pigment suspension Talc 40.0 T.70 Titanium dioxide 20.8 4.0 Water 65.0 12.6 520.0 100 Preparation of the spray suspension See, See ee eee Stir the pigment suspension into the polymer solution. To avoid sedimentation during the spraying process, the mixture must be continuously stirred. Machine parameters Accela-Cota 24, perforated drum coater Coater Accla-VCola 24 , permorated aruM Coater Batch size 5 kg Inlet air temperature 60 C Outlet air temperature 39 C Product temperature 35 C Air flow 180 m/h Atomizing pressure 3 bar Number of spray nozzles 1 Spraying rate 30 g/min Spraying time 18 min Final drying 60 C/4 min Quantity applied 3 mg/cm? polymer Tahkilat mernrnarhiiac Tablet properties Uncoated Core Film-coated tablet Appearance White White Hardness 116N 119N Friability 0% 0% Disintegration time 0:58 [min:s] 0:51 [min:s] Drug release 10 min: 93% 10 min: 92% 20 min: 98% 20 min: 98%
5. Processing and Application as Wet-Binder Kollicoat IR can be used for all applications for which a water-soluble binder polymer is required . 5.1 Applications 5.1 Applications The special advantages of Kollicoat IR when used as wet-binder next to its low viscosity, fast dissolution and high binding power in granulation processes is its property that no peroxides become detectale. Due to this propertiy even very oxygen sensitive APIs such as hormones can be formulated with Kollicoat IR in wet binder applications. 5.2 Processing Notes Standard equipment such as high-shear mixer or fluid-bed granulators can be applied. Kollicoat IR can be incorporated into formulations in two ways. Either the blended components are granulated using a Kollicoat IR binder solution of appropriate concentration in order to achieve binder concentrations of 3% to 10%. Alternatively water can be used as granulation fluid in cases where the polymer is already part of the tableting mixture. 6. Typical Applications as Wet-Binder 6.1 Acetaminophen instant granules Composition of the powder mixture 49% oosition of the powder mixture 49% acetaminophen, fine powder; 49% sorbitol; 2% aspartame; 0.06% aroma Composition of the binder solution The formulation is designed for 1 kg of powder mixture Weight [g] Proportion [%] Granulating solution Kollicoat IR 27.0 15.0 Water 153.0 85.0 180.0 100.0 Preparation of the binder solution Kollicoat IR is dissolved in the specified quantity of water under thorough stirring. Mix the components of the powder mixture for 10 min using a Stephan mixer Type UMC 5 Electronic. Apply the Kollicoat IR solution in a fine spray, keeping the mixture in motion. First the moist mass is passed through a 3-mm sieve, then through a 1-mm sieve. Dry the moist granules and repass them through a 1-mm sieve. Mix the components of the powder mixture for 10 min using a Stephan mixer Type UMC 5 Electronic. Apply the Kollicoat IR solution in a fine spray, keeping the mixture in motion. First the moist mass is passed through a 3-mm sieve, then through a 1-mm sieve. Dry the moist granules and repass them through a 1-mm sieve. Manufacture of the granules The granules dissolve in water within 1 min. Properties of the granules
6.2 Instant-release Ibuprofen tablets : 600mg/tablet Composition of the powder mixture Weight [g] Proportion [%] Ibuprofen 700.0 100.0 Composition of the binder solution Weight [g] Proportion [%] Kollicoat IR 35.0 18.9 Water 150.0 81.1 Weight 185.0 100.0 The binder solution is suited for 0.7 kg of Ibuprofen 25 The granulation is performed in a Diosna P1/6 with a 3L Container. The Ibuprofen is mixed for 3 min, the granulation fluid is dosed within 2 minutes. After dosing the binder solution the granulation is performed for additionally 3 minutes with a stirrer speed fo 250 rpm and the chopper set to 2,200 rpm. Manufacture of the granules Wet Sieving Glatt GS 100 screen 1.500 ym sieve grater screen 500 rom with mixer insert # 6 Drying The granules were dried in a Glatt GPCG 3 at 50 C ina 5 L container at an air rate of 66 m/h. Drying time: 16 min Ibuprofen granules 79.50% Avicel PH-102 15.00% Aerosil 200 1.00% Ac-Di-Sol 4.00% Mg-Stearat 0.50% Tableting mixture The components except the Mg-stearate were mixed in a Turbala mixer for 5 minutes and sieved using a 800 ym sieve. Finally the Mg-stearate was added and the blend again Turbula-mixed for 1 minute. Se a a ee a ae as This tableting mixture was compressed on a Korsch XL 100. telease testing for tablets with 5% Kollicoat IR as binder and compressed with 10kN drug release [%] 50ropm 1000mIP.P pH7.2] 30 60 t [min] T 90 1 120
6.3 Instant-release Raloxifen-HCl tablets: 300mg Weight [g] Proportion [%] Raloxifen-HCl 300.0 31.9 Di-calcium phosphate 640.0 64.9 Aerosil 200 20.0 24 Mg-Stearate 10.0 1.4 970.0 100 Composition of the powder mixture The formulation is designed for 0.97 kg of powder mixture Composition of the binder solution Weight [g] Proportion [%] Granulating solution Kollicoat IR 30.0 17.4 Water 145.0 82.9 175.0 100.0 Preparation of the binder solution Kollicoat IR is dissolved in the specified quantity of water under thorough stirring. Manufacture of the granules Mix the components of the powder mixture for 10 min (Stephan mixer Type UMC 5 Electronic). Apply the Kollicoat IR solution in a fine spray, keeping the mixture in motion. The moist mass is passed through a 800 ym sieve. The moist granules are dried in a vaccum-dryer to a final water content of around 1 - 1.2%. Karnavati (India) 8 station rotary press Tableting Parameters Tablet diameter Tablet shape Compression force Hardness Friability mm kg % r circular, concave 900 150 <0.05 When stored under accelerated conditions at 45 C, 75% r.h. the degradation product raloxifen-N-oxide could not be detected after 6 months. Stability Testing
7. Storage conditions At least 2 years in the original sealed containers at room temperature. Comprehensive toxicological studies are compiled in a Tox-Abstract Individual reports are available on request and can be provided under CDy 10. Product Number 10. Product Number 11. Packaging PE-drum, 20 kg capacity with sealed, 0.100 mm PE-inner liner. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. Disclaimer
Technical Information Polyethylene Glycol USP/NF, FCC, Macrogols Ph. Eur., Macrogol 400 JP Liquid polyethylene glycols for the pharmaceutical industry. February 2019 WF-No. 137124 = Registered trademark of BASF in many countries.
1. Technical properties Description Kollisolv PEG 400 is colorless, almost odorless and tasteless liquid at room temperature. The product is manufactured by alkali-catalysed polymerization of ethylene oxide with subsequent neutralization of the catalyst. Structural formula n represents the average number of oxyethylene groups The number in the name of the product indicates its average molecular weight. CAS-number Hygroscopicity At room temperature and 80% r. h. approx. 50% of increase of weight was noted over a period of 42 days. Molecular weight The average molecular weight is 400 g/mol. Solubility Kollisolv@ PEG 400 is readily soluble in water, ethanol, acetone, glycols and chloroform and insoluble in ether, paraffin, oils and fats. Viscosity Figure 1: Dynamic viscosity of Kollisolv? PEG 400 Approximate density At 20 C density is approx. 1.13 g/cm$
2. Handling Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. 3. Example application Softgels Kollisolv PEG 400 and other low molecular weight PEGs are very commonly used hydrophilic Softgel fills. It is critical for this application that the aldehyde level in the PEGs is very low, to prevent to crosslinking of the Gelatin. Nevertheless, these are a potent, low viscosity fill that can be utilized in conjunction with a multitude of surfactants and polymers depending on the application. For example, when intending to increase the solubilization capacity of Kollisolv? PEG 400 in a Softgel fill, it can be used in combination with other BASF solubilizers such as Kolliphor RH 40, Kolliphor EL, Kolliphor HS 15 to enhance the ability to dissolve challenging APIs. Kollisolv PEG 400 LA is manufactured in Geismar, LA, and is stored in steel drums purged with Nitrogen. This packaging configuration and storage condition ensures that oxidation, and the growth of aldehyde levels is kept to an absolute minimum, as required by the Softgel application. Stability data is available upon request. Example formulation: Fenians intial ~~ 95% Kollisolv? PEG 400 LA 5% Kolliphor RH 40 95% Kollisolv? PEG 400 LA 5% Kolliphor HS 15 Furthermore, preventing drug recrystallization is of critical importance for softgel applications. In these examples, low molecular weight polyvinylpyrrolidone (PVP) can be used as a crystallization inhibitor. Example formulation: 95% Kollisolv? PEG 400 LA 5% Kollidon 12 PF 95% Kollisolv? PEG 400 LA 5% Kollidon 17 PF 95% Kollisolv? PEG 400 LA 5% Kollidon 12 PF 95% Kollisolv? PEG 400 LA 5% Kollidon 17 PF
Ointment formulations Kollisolv? PEG ointments can be used as an alternative to traditional petrolatum-based ointment formulations. By pairing different amounts of high and low molecular weight chains, PEG ointments can be tuned for desirable rheological profiles and sensory properties. Phase Ingredients Chemical name Role Mass (Weight%) A Kollisolv PEG 400 Polyethylene Glycol 400 ~ Solvent 50.00 Kollisolv? PEG 3350 Polyethylene Glycol 3350 Solvent 30.00 B Kollisolv PG Propylene Glycol Solvent 20.00 Low molecular weight liquid PEG 400 can be an excellent solvent for substances that do no readily dissolve in water, leaving behind a slightly slick residue. However, stability and solubility vary dramatically with the drug used, so tests should always be performed to ensure the integrity of the API is upheld. Gel formulations - Emulgel At concentrations above 15%, Poloxamers 188 and 407 can be used to make gels and viscous emulsions by both emulsifying and forming phases and networks via the hydrophobic and hydrophilic interactions driven by PPO and PEO segments of the polymer, respectively. SESS BTM EERE SSeS Phase Ingredients Chemical name Role Mass (Weight%) A _ Ethanol 200 Proof Solvent 10 Kollisolv? PEG 400 Polyethylene Glycol 400 Solvent 15 Glycerol Solvent 5 B__ Kolliphor P 407 Poloxamer 407 Gelling agent 18 C Deionized Water Solvent 42 D_ Kollicream 3 C Cocoyl Caprylocaprate Emollient 10 Kolliphor P 407 helps emulsify the Kollicream 3 C in this formulation, resulting in a translucent white gel with a cream-like structure visible underneath the microscope. Both Kolliphor P 407 and Kollicream 3 C have been shown to be very mild, in vitro and in vivo.
4. Safety data sheet Safety data sheets are available on request and are sent with every consignment. Please refer to Quality & Regulatory Product Information (QRP)). 6. Specification For current specification, please speak to your local BASF sales or technical representative. 7. Regulatory status Please refer to Quality & Regulatory Product Information (QRPI). 8. Toxicological data The toxicological abstracts are available on request. 9. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554047 Kollisolv? PEG 400 50259797 0.5 kg Plastic bottle 50263674 1000 kg Composite IBC (81HA1) 50548767 130 kg Plastic drum 50530207 1000 kg Composite IBC (61HA1) 50251480 Plastic drum 130 kg BASFs commercial product number. https://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Fatty acids and alcohols: Consistency factors for topical formulations, and excipients for solid oral dosage forms. Oktober 2021 WF-No. 137189 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes fatty acids and alcohols that can be used as (co-) emulsifiers and consistency factors in topical pharmaceutical applications, but may also function as excipients in solid oral dosage forms, e.g., as matrix formers and lubricants. This document focuses on fatty acids and alcohols of the Kolliwax family. Please refer to the individual technical information sheet for specific information on our two glyceride based grades Kolliwax GMS II and Kolliwax HCO (Glycerol Monostearate, and Hydrogenated Castor Oil, respectively). Trade name Compendial Name Kolliwax CA Ph.Eur.: Cetyl Alcohol USP/NF: Cetyl Alcohol Kolliwax CSA 50 Ph.Eur.: Cetostearyl Alcohol USP/NF: Cetostearyl Alcohol JP: Cetostearyl Alcohol Kolliwax CSA 70 Ph.Eur.: Cetostearyl Alcohol Kolliwax MA USP/NF: Myristyl Alcohol Kolliwax SA Ph.Eur.: Stearyl Alcohol Kolliwax SA Fine USP/NF: Stearyl Alcohol JP: Stearyl Alcohol Kolliwax S Ph.Eur.: Stearic Acid 50 Kolliwax S Fine USP/NF: Stearic Acid 50 llPe Stearic Acid 50 Table 1: Compendial names for fatty alcohols and acids of the Kolliwax family. Description 2. Technical properties Kolliwax grades are white to slightly yellowish, waxy substances derived from natural ressources, namely coconut oil, palm kernel oil, and/or palm stearine. With melting points above room temperature, these products are either supplied as powder, pearls, or pelletts (see table1 and table 2 for details). The numeric part of the name of the two grades of Kolliwax CSA represents the approximate weight percentage of stearyl alcohol. es ene Trade name Chemical nature CAS-No. Melting ranges [cy Kolliwax CA Cetyl Alcohol (C,,) 36653-82-4 46-52 Koliwax CSA S0_ Cety/Stearyl Alcohol 7769 97.9 1666 Kolliwax CSA70_ (Cie/Cra) Kolliwax MA Myristyl Alcohol (C,,) 112-72-1 36-42 Kolliwax SA Stearyl Alcohol (C,,) 112-92-5 57-60 Kolliwax SA Fine Koliwax?S Stearic/Palmitio Acid g 7754 93.05 308 Kolliwax S Fine (Cil/Cy6) Values given for guidance only, see specification sheets for detailed information on melting and/or freezing temperatures. Table 2: Properties of fatty alcohols and acids of the Kolliwax family.
Figure 1: Typical appearance of the Kolliwax grades. The scale in the back is metric, with 1 mm per mark. For detailed information on particle size distributions, please refer to the individual product specification sheets. Scanning electron mircroscopy (SEM) igure 2: SEM images of Kolliwax S, and Kolliwax S Fine. Please refer to the individu: specification sheets for detailed information on particle size distributions.
3. Application Overview The following table 3 gives an overview on the most important applications and functions of the Kolliwax fatty alcohols and acids: while fatty acids and alcohols are generally used as consistency factors, our fine grades of stearic acid and stearyl alcoho (Kolliwax S Fine and Kolliwax SA Fine, respectively) allow to use these substances in the preparation of solid dosage forms, where they can aid as lubricants or matrix formers. Table 3: Application of the Kolliwax grades. Emulsions Exhibiting excellent skin tolerance, the Kolliwax grades can be used for all kinds of topical pharmaceutical applications, such as creams, gels, lotions, and ointments. The typical usage concentration in emulsions is about 1- 5%. All Kolliwax grades will act as consistency factors and co-emulsifiers at the same time. With their amphiphilic structure, they will stabilize the interface between oil and water and will help to enhance the viscosity by building up a liquid crystalline network (lamellar sheet structure). Stabilizing w/o and 0/w emulsions, they also aid in bringing a unique softness and creaminess to the targeted formulation. Lubricants In tableting processes for solid oral dosage forms, lubricants are used to prevent ingredients from clumping to undesired aggregates and from sticking to the tablet punches or capsule filling machine. In addition, lubricants hamper the friction that would hinder tablet formation and ejection. Among inorganic materials (e.g. talc or silica), fat based substances like vegetable stearin, magnesium stearate or stearic acid are commonly used as lubricants in tablets or hard gelatin capsules. Lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. Formulation examples Guideline for the preparation of the model formulations: MaYIGenne 1Or UWle PrepalrauviOrl OF WIE MIOQE! fOMTIUlAvOrls. 1. Heat components of phase A to 80 - 85 C and stir until transformed into a homo- geneous melt. 2. Heat components of phase B to 80 85 C. Under constant stirring, slowly add phase A to phase B, homogenize for 5 min at 5000 rpm. Let cream cool to 35 C while mixing at 200 rpm, and add preservative.
Model formulation Rich Cream: This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as emulsifiers to create avery stiff cream that offers a slow spread and a cushioned feeling when rubbing into the skin. Its high immediate smoothness results from the utilization of Kollicream IPM, a fast spreading oil with broad penetration enhancement properties that can aid as a solubilizer for lipophilic drugs. Ingredient Phase Ph. Eur. name Role Amount [wt.-%] A __ Kolliwax CSA 70 Cetostearyl Alcohol Consistency Factor, 7.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 25 40-55 (Type Il) Co-Emulsifier Kolliphor PS 60 Polysorbate 60 Emulsifier 4.2 Kollisolv@ MCT 70 Medium Chain Emollient 11.5 Triglycerides Kollicream IPM Isopropyl Myristate Emollient 1.3 B Deionized Water 69.2 Solvent _____. Glycerol 3.3 C_ Euxyl PE 9010 Preservative 1.0 Table 4: Model formulation for a rich Cream. Model formulation Light Cream: This formulation is a smooth cream with easy distribution, medium viscosity, and a glossy finish. Due to the difference in HLB values, the blending ratio of Kolliphor CS 12 and Kolliphor CS 20 can be used as a factor to maximize emulsion stability. Phase Ingredient Ph. Eur. name Role Amount [wt.-%] A_ Kolliwax CSA 50 Cetostearyl Alcohol Consistency Factor, 4.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 5.0 40-55 (Type Il) Co-Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Emulsifier 2.0 Ether 20 Kolliphor CS 12 Macrogol Cetostearyl Emollient 0.8 Ether 12 Kollicream CP 15 Cetyl Palmitate 15 Emollient 0.8 Kollicream IPM Isopropyl Myristate Emollient TA B__ Deionized Water 74.0 Solvent Glyerol 5.0) C_ Euxyl PE 9010 Preservative 1.0 in Si Pe Table 5: Model formulation for a light cream. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment.
5. Product specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554718 olliwax CA 50253459 25 kg Plastic film bag 50259499 0.5 kg Plastic bottle 30554719 olliwax CSA 50. 50253501 25 kg Plastic film bag 50259500 0.5 kg Plastic bottle 30554721 olliwax CSA 70 50253504 25 kg Plastic film bag 50259502 0.5 kg Plastic bottle 30554492 olliwax MA 50375472 20 kg Corrugated fiberboard box with PE liner 50259498 0.5 kg Plastic bottle 30554720 olliwax SA 50253503 25 kg Plastic film bag 50259501 0.5 kg Plastic bottle 30563963 olliwax SA Fine 50284249 25 kg Plastic film bag 50372378 0.5 kg Plastic bottle 30554752 olliwax S 50253532 25 kg Plastic film bag 50259521 0.5 kg Plastic bottle 30554750 olliwax S Fine 50253810 25 kg Plastic film bag 50259508 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
PronovaPure 150:500 TC Chemical names of active ingredient Ee Rea ee ee Ae Omega-3 Fatty Acids Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA) CAS-No.  Description PronovaPure 150:500 TG is a pale yellow fish oil concentrate. CUHCSIIU ALG. The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Scombridae and Carangidae). The product is a triglyceride (TG), rich in omega-s fatty acids. The content of EPA (Eicosapentaenoic acid expressed as TG) and DHA (Docosahexaencic acid expressed as TG) is min. 650 mg/g. Articles Country of origin Composition Ingredients in descending order of weight: Fish oil concentrate, tocopherol-rich extract (E 306) Ingredients i in descending order of weight: Fish oil concentrate, tocopherol-rich extract (E 306) mainly derived from soybean (from identity preserved, not genetically modified origin)
Stability, Storage and Handling Solubility age i Practically insoluble in water, very soluble in acetone and heptane, slightly soluble in anhydrous ethanol. Practically insoluble in water, very soluble in acetone and heptane, slightly soluble in anhydrous ethanol. Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 24 months. Specification Specification as triglycerides Ph. Eur. 1352/2.4.29 EPA (Eicosapentaenoic acid) min. 150 mg/g DHA (Docosahexaenoic acid) min. 500 mg/g EPA & DHA (Eicosapentaenoic min. 650 mg/g & Docosahexaenoic acid) Total Omega-3 fatty acids min. 700 mg/g Applications  << PronovaPure 150:500 TG is intended for use in dietary supplements such as in soft gel capsules or in liquid preparations. Note PronovaPure 150:500 TG must be handled in accordance with the Material Safety Data Sheet. For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access) This document, or any answers or information provided herein b BASF, does not constitute a legally binding obligation of BASF. Whil the descriptions, designs, data and information contained herein ar presented in good faith and believed to be accurate, it is provided fo your guidance only. Because many factors may affect processing o application/use, we recommend that you make tests to determine thi suitability of a product for your particular purpose prior to use. It doe not relieve our customers from the obligation to perform a full inspectio of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIEC INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FO! A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCT: DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, Of THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BI USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHT: OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUI TERMS AND CONDITIONS OF SALE. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. Standards Produced under cGMP and HACCP principles. ee povegheeenig, Que sartie serial ater cue mate NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. Monographs and Regulations EF ee NG ETE eS PronovaPure 150: 500 TG meets. the requirements for an omega-3 fatty acid source in most countries. The product complies with the Ph. Eur. monograph on Omega-3-acid triglycerides (1352). Further, the product conforms to the voluntary GOED mono- graph in the current version. Fich oil concentrates are accented for tise in dietary YaVilill tile CUNeHIt VErolorl. Fish oil concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed.
Technical Information Macrogol 15 Hydroxystearate (Ph. Eur.) Polyoxyl 15 Hydrostearate (USP/NF) Macrogol 15 Hydroxystearate (Ph. Eur.) February 2020 Supersedes issue dated January 2019 Last change WF-No. DAWF-2019-0883
1. Introduction Kolliphor HS 15 is a nonionic solubilizer and emulsifying agent obtained by reacting 15 moles of ethylene oxide with 1 mole of 12-hydroxy stearic acid. Description Kollighor HS 15 is a yellowish white paste at room temperature that becomes liquid at approx. 30 C. The hydrophilic-lipophilic balance lies between 14 and 16. 2. Technical properties Structural formula The main components of the lipophilic part have the following chemical structures:  A small part of the 12-hydroxy group can be etherified with polyethylene glycol. CAS number Composition Kolliphor HS 15 consists of polyglycol mono- and di-esters of 12-hydroxystearic acid (= lipophilic part) and of about 30% of free polyethylene glycol (= hydrophilic part). The free polyethylene glycol can be determined by HPLC. Critical micelle concentration The critical micelle concentration (CMC) lies between 0.005 and 0.02%. Micelles are typically in the range of 10-15 nm in diameter (dynamic light scattering) and slightly larger (up to 25 nm) when loaded with API. There is a sharp increase in micelle size at temperatures greater than 60. Solubility Kolliphor HS 15 is soluble in water, ethanol and 2-propanol to form clear solutions. Its solubility in water decreases with increasing temperature. It is insoluble in liquid paraffin.
3. Example application Kolliphor HS 15 is a non-ionic, potent surfactant. Kolliphor HS 15 is now listed in the FDA IID and used in FDA approved parenteral and ophthalmic drugs. Note: prior to sampling, filing or processing Kolliphor HS 15 should be melted and lightly homogenized to ensure a representative sample. A recommended temperature is 50-65C. In order to test the effect of external stress on Kolliphor HS 15, product was testec for applied stress for key applications. As noted, heating and mixing is beyond what is considered normal stability conditions, therefore this was tested independently anc provided as technical data (not intended for regulatory or quality purposes). The product was subjected to 20 heat-cool cycles; each cycle started by heating the product to 65 C and holding for 24 hours, the product was subsequently cooled to 4 C and held for 24 hours prior to repeating the cycle. Key stability indicating parameters were tested. As the product is also routinely sterilized for parenteral applications, key stability indicating parameters were evaluated pre and post sterilization via a 0.20 ym sterile filter (cellulose acetate) and one standard autoclave cycle (20 mins, 121 C). The results of all three stress tests are compared in Table 1. Table 1. Stress Test of Kolliphor HS 15 as original sample, after filter and autoclave sterilization and after a 20 cycle heat stress test. Kolliphor HS 15 - 20% Blank Filter Autoclave Stress Test pH Value 20% (aq.) 6.64 6.62 6.29 5.6 Viscosity [mPas], 25 C@1000 1/s 5.45 5.61 5.28 5.8 Aldehyde [mg/kg] Formaldehyde <1 <1 2 3 Acetaldehyde 4 4 3 4 Propionald. <1 <1 <1 1 Peroxide Value [meq/kg] <2 <2 <2 1 Hydoxyl Value [mg KOH/kg] at 23 23 33 lodine Value [g 12/100g] 0.3 0.4 0.3 0.2 Acid Value [mg KOH/g] 0.1 0.1 0.1 0.2 Gamma sterilization is not recommended for Kolliphor HS 15.
Kolliphor HS 15 is a potent, non-ionic solubilizer specifically designed for poorly water-soluble drugs in parenteral applications. Specifically, this solubilizer has been shown to increase the solubility several orders of magnitude of numerous poorly water-soluble drugs with relevant parenteral applications (see Figure 1.) Figure 1. Several orders of magnitude increase in solubility shown for 10% buffered solutions of Kolliphor HS 15. Kolliphor HS 15 was specifically designed to provide a low immunogenicity during parenteral administration. This is demonstrated by testing haemolytic activity, an assay designed to measure haemolysis (destruction of red blood cells, 100% considered poor). In this assay, Kolliphor HS 15 at low concentrations shows no haemolysis, and at 10% exhibited slightly less, yet comparable results to a standard Polysorbate 80 (common parenteral solubilizer). Next, histamine release is measured in a separate series of experiments, where post- injection, the serum histamine level (beagle dogs) is compared for Kolliphor HS 15 vs. Polysorbate 80 at 0, 15 and 60 minutes. Specifically, the histamine release at 15 minutes post-injection is several orders of magnitude lower indicating an extremely low immunogenicity this effect remains and returns to near baseline values after 6C minutes while lingering effects are noted for Polysorbate 80. All comparative data is shown in Table 2.
4. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 5. Retest date and storage condition Please refer to Quality & Regulatory Product Information (QRPI). 6. Stability Please refer to Quality & Regulatory Product Information (QRPI). 7. Toxicological data The toxicological abstract is available on request. 8. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554050 Kolliphor HS 15 50259817 0.5kg Plastic bottle 50581346 50 kg Steel drums BASFs commercial product number. http://pharmaceutical.basf.com/en.html (1) K. Buszello, S. Harnisch, R. H. Muller, B. W. Muller Eur. J. Pharm. Biopharm 49, 143 (2000) (2) K. Woodburn, E. Sykes, D. Kessel Int. J. Biochem. Cell Biol. 27, 693 (1995) K.-H. Frmming, C. Kraus, W. Mehnert Acta Pharm. Technol. 36, 214 (1990) C. von Corswant, P. Thoren, S. Engstr6m J. Pharm. Sci. 87, 200 (1998) J. S. Coon et al. Cancer Res. 51, 897 (1991) D. B. Smith et al. Br. J. Cancer 57, 623 (1988) (3 (4 5 ) ) ) 6) ( ( This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Maxomega EPA 96 EE Maxomega EPA 97 EE =thyl Ilcosapentate (JP) June 2021 DAWF-2021-0805 = Registered trademark of BASF in many countries.
1. Introduction Maxomega EPA 96 EE and Maxomega EPA 97 EE are oils containing a minimum of 96% of the primary omega-3 acid eicosapentaenoic acid (EPA) in ethy! ester (EE) form. Omega-3 fatty acids, in general, are naturally occurring nutrients that are of high importance for human health. They cannot be synthesized by the human body but are vital for normal metabolism. Omega-3 fatty acids are poly unsaturated fatty acids with a double bound from the 3rd carbon atom from the end (omega). The most abundant omega-3 fatty acids are EPA, docosahexaenoic acid (DHA) and alfa-linoleic acid (ALA). EPA and DHA are long-chain fatty acids found in algal oil and fish. EPA and DHA have been widely studied for medical and nutritional applications. Maxomega EPA 96 EE and Maxomega EPA 97 EE are equivalent products, but with slightly different specifications as they are intended for different markets with different requirements. They are produced the same way from crude fish oil by a transesterification step from a triglyceride to an ethyl ester compound and several concentration and purification steps including liquid chromatography and silica refining. The fish oil is sourced from body oil of wild fatty fish. The only additional ingredient to EPA EE is the antioxidant alfa tocopherol, which is added in a concentration of approximately 0,2%. The minor part (3-4%) that are not EPA EE consists of other naturally occurring fatty acids, including other omega-3 fatty acids. Due to the high amount of unsaturated fatty acids, the product will easily oxidize in contact with air, and needs to be protected from contact with oxygen. The container is therefore flushed with nitrogen prior to, during and after filling. Maxomega EPA 96 EE and Maxomega EPA 97 EE are used as active ingredients in pharmaceutical preparations for oral application after approval by the concerned medicinal authority for a defined indication.
2. Description Name Maxomega EPA 96 EE and Maxomega EPA 97 EE United States Adopted Names (USAN) Icosapent ethyl International nonproprietary name (INN) Icosapent ethyl Pharmacopeia name Chemical names 5Z,8Z,11Z, 14Z, 17Z)-Eicosa-5,8,11,14,17-Pentaenoic Acid Ethyl Ester, Eicosapentaenoic acid etyl ester, Timnodonic acid ethyl ester, Ethyl-EPA Molecular formula Relative Molecular mass Structural formula
3. Physical and chemical properties Appearance Maxomega EPA 96 EE and Maxomega EPA 97 EE are clear, colourless to pale yellow liquid oils. Solubility Maxomega EPA 96 EE and Maxomega EPA 97 EE are practically insoluble in water, very soluble in organic solvents such as hexane, acetone, ethanol, and methanol. Boiling point 417.0 + 34.0 C at 760 Torr Flash point 103.1 + 24.0 C Vapour pressure 3.65E-7 Torr at 25 C Enthalpy of Vaporization 67.04 + 3.0 kJ/mol at 760 Torr
4. Medical information Applications Maxomega EPA 96 EE and Maxomega EPA 97 EE are active pharmaceutical ingredient oils. For application, they are typically filled into soft gelatin capsules as the sole fill ingredient. This dosage form is suitable for EPA EE because it protects the API from oxygen and masks taste and odour. As a consequence, EPA EE is not suitable for liquid multidose formulations as it will readily oxidize in contact with atmospheric oxygen, and also has an unpleasant taste and odour. Therapeutic indication Maxomega EPA 96 EE and Maxomega EPA 97 EE are used as active ingredients for the documented indication in pharmaceutical drug products after approval by the competent authority. The approved indications may be different in different countries. Please refer to the approved indications for finished products containing Ethy! Icosapentate/ Icosapent ethyl in the concerned market. Clinical Pharmacology Mechanism of Action The mechanisms of action for EPA are likely multi-factorial. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Ilcosapentate/ Icosapent ethyl. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Ilcosapentate/ Icosapent ethyl. Pharmacokinetics Absorption: After oral administration, EPA EE is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Icosapentate/ Icosapent ethyl. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Icosapentate/ Icosapent ethyl.
5. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment or can be requested from your BASF sales representative Re-test period & Storage Conditions Please refer to the document Quality & Regulatory Product Information which is available in RegXcellence (RegXcellence (basf.com)). Packaging The commercial product is filled in epoxy phenolic lined mild steel drum. The liner contains iron oxide and titan dioxide pigments and have a golden brown colour. The closure is made of the same material. The product is stored under nitrogen atmosphere to prevent oxidation. The external surface is blue. 6. Product specifications The current version of the product specifications are available at RegXellence (RegXcellence (basf.com)) or from your BASF sales representative. 7. Regulatory & Quality 7. Regulatory & Quality Please refer to the document Quality & Regulatory Product Information which is available in RegXcellence (RegXcellence (basf.com)). PRD and Article numbers PRD-No. Product name Article numbers Packaging 30572258 Maxomega EPA 96 EE 50306243 (sample) 50356278 0,1 kg aluminum bottle 190kg steel drum 30572259 Maxomega EPA 97 EE For the Japanese market only 50306248 (sample) 0,1 kg aluminum bottle 50305109 190kg steel drum BASFs commercial product number. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Macrogolglycerol Hydroxystearate (Ph. Eur.) Polyoxyl 40 Hydrogenated Castor Oil (USP/NF January 2020 Supersedes issue dated February 2019 Last change WF-No. DAWF-2019-0831 = Registered trademark of BASF in many countries.
1. Introduction Kolliphor RH 40 is a solubilizer, emulsifier and primary surfactant used in a multitude of pharmaceutical formulations. 2. Technical properties Description Structural formula Kolliphor RH 40 is a nonionic solubilizer and emulsifying agent obtained by reacting 1 mole of hydrogenated castor oil with 40 moles of ethylene oxide. The main constituent of Kolliphor RH 40 is glycerol polyethylene glycol hydroxy- stearate, which, together with fatty acid glycerol polyglycol esters, forms the hydrophobic part of the product. The hydrophilic part consists of polyethylene glycols and glycerol ethoxylate. A diagram of the molecular formula is listed below: Kolliphor RH 40 is a white to yellowish paste at 20 C. The HLB value lies between 14 and 16. Particular features are that it has very little odor and in aqueous solutions is almost tasteless. Composition The rough composition of the product is as follows: Compound Content Glycerol - Mono-(PEG - 12 - Hydroxystearate) approx. 20% Glycerol - Di-(PEG - 12 - Hydroxystearate) approx. 12% Glycerol -Tri-(PEG - 12 - Hydroxystearate) approx. 6% PEG - 12 - Hydroxystearate approx. 7% PEG approx. 18% Glycerol - PEG approx. 35% CAS number 61788-85-0 Solubility Kolliphor RH 40 forms clear solutions in water, ethanol, 2-propanol, n-propanol, ethyl acetate, chloroform, carbon tetrachloride, toluene and xylene. Solutions become cloudy as the temperature increases. Kolliphor RH 40 can be mixed with all other Kolliphor products. At elevated temperatures it forms clear mixtures with fatty acids and fatty alcohols.
Critical micelle concentration The critical micelle concentration (CMC) is 0.03% w/w @ 37C. Micelles are typically in the range of 10 - 15 nm in diameter (dynamic light scattering) and slightly larger (up to 25 nm) when loaded with API. There is a sharp increase in micelle size at temperatures greater than 60. Stability Pure Kolliphor RH 40 is chemically very stable. Prolonged exposure to elevated temperatures can cause physical separation into a liquid and a solid phase on cooling but the product can be restored to its original form by homogenization. Kolliphor RH 40 is stable in aqueous alcohol and purely aqueous solutions. However, it must be noted that strong bases or acids should not be added, as otherwise the ester components may be saponified. Aqueous Kolliphor RH 40 solutions can be sterilized by heating to 120 C. Allowance must be made for the fact that this can cause a slight decrease in the pH value. The phases may also separate during sterilization, but this can be remedied by agitating the solution, particularly while it is still warm. Preservatives common to the pharmaceuticals industry may be added to the aqueous solutions. The requisite concentrations should be determined in tests. Kolliphor RH 40 is largely insensitive to water hardness. Dispensing It is recommended that Kolliphor RH 40 be heated to between 50 and 60 C and lightly agitated prior to use. Kolliphor RH 40 exhibits complex melting behavior, and phase separation is known to occur depending on the shipping and storage conditions. This is easily overcome via melting and light mixing. In order to ensure product stability during reheating, heat cycling was performed on Kolliphor RH 40. Commercial material was heated to 60 C and held for 24 hours, then cooled and held at room temperature for a further 24 hours; this was repeated 20 times in total. The results of this stress test on the stability indicating parameters of Kolliphor RH 40 are shown below, no significant deviation was noted Stability Indicating Parameter Spec Release Test 1 Test 2 Test 3 Congealing temperature [C] 16 to 26 C 24 25 25 25 Acid value [mg KOH/g] < 0.8 mg KOH/g 0.1 0.3 0.3 0.3 Hydroxylvalue [mg KOH/g] 60 to 75 mg KOH/g 71 2 72 72 lodine value [g 1,/100 g] < 1.0 g I/100g 0.3 0.3 0.3 0.3 Saponication value [mg KOH/g] 50 to 60 mg KOH/g 54 54 54 54 Water [g/ 100g] NA. 1.00 0.80 0.82 0.80 Sulfated ash [g/100g] < 0.259/100g 0.18 0.19 0.18 3. Handling Please refer to the individual Material Safety Data sheet (MSDS) for instructions or safe and proper handling and disposal.
4. Example apllication Solubilization Kolliphor RH 40 is the industry standard pharmaceutical surfactant used primaril as a solubilizer and emulsifier. Most notably the product is used in the following types of formulations (commor concentration show): COMCEHUAUOT! SHOW). Softgel Capsules 400 mg per dose Opthalmics 0.5 % w/w Oral Solutions 0.5 45% Tablets 50 mg Creams 1% w/w In softgel applications, Kolliphor RH 40 is soluble in PEG 400 (Kollisolv@ PEG 400) up to 20% w/w, up to 30% w/w in Medium Chain Triglycerides (Kollisolv? MCT 70), 20% w/w in Propylene Glycol (Kollisolv PG) Kolliphor RH 40 is fully miscible in aqueous formulations. Solubilization and bioavailability enhancement Kolliphor RH 40 may be use very effectively in Lipid-Based Drug Delivery Systems, for example, Self-Emulsifying Drug Delivery Systems (SEDDS). In order to effectively make such formulations, high concentrations of primary surfactant, secondary surfactant, oil and aqueous phase are mixed. The resultant formulations are clear, low-viscosity, isotropic and suitable for encapsulation into softgels, hard shell capsules and other liquid formulations. Once the formulations are released inside the GIT, they emulsify into nanoscale (15 80 nm) droplets, which are further digested and absorbed, significantly increasing bioavailability. In Vivo, it has been shown that Kolliphor RH 40 digests slowly and can retain drug in solution (micelles) for a long period of time allowing for absorption to take place. Note: Water or Ethanol is used as an aqueous phase - this is to account for atmospheric water that is absorbed from the environment or during encapsulation, thus maintaining stability and integrity of the system. Example SEDDS Formulation 1 (High solubility, slow digestion, small droplets). This example shows high concentrations of Kolliphor RH 40, this will result in small droplet sizes upon self-emulsification (20 nm) and slow digestion. Ethanol may be used in place of water to increase drug content. Compound Content Kolliphor RH 40 68 % Kollisolv? MCT 70 10 % Glyceryl Monooleate 12% Water / Ethanol 10 % Example SEDDS Formulation 2 (Faster digestion, larger droplets). This example shows higher oil concentrations, which will result in faster digestion and larger oil droplets (40 nm). Ethanol may be used in place of water to increase drug content. Compound Content Kolliphor RH 40 42.5 % Kollisolv? MCT 70 40.0 % Glyceryl Monooleate 7.5% Water / Ethanol 10.0 %
Miscellaneous solubilizer applications Clear, aqueous solutions of hydrophobic substances other than vitamins can be obtained with Kolliphor RH 40. Examples are essential oils and certain drugs for oral and topical application. A feature of the solutions thus obtained is their good stability. The following substances serve as examples: Hexachlorocyclohexane Miconazole Hexeditine Gramicidin Levomepromazine Eucalyptol Thiopental Azulene Benzocaine Oil of anise Clotrimazole Oil of sage Diazepam Kolliphor RH 40 shows little tendency to foaming, which is particularly importar for solutions in aqueous ethanol. Use as emulsifier Kolliphor RH 40 is also very suitable as an emulsifying agent. It will emulsify a wide range of hydrophobic substances, e. g. fatty acids, fatty alcohols and drugs. Phase Ingredients Description Mass (Weight%) A Kollicream OA Emollient 20.00 Kolliwax GMS II Consistency factor, 2.08 co-emulsifier Kolliphor RH 40 Emulsifier 2.92 B Deionized Water Continuous phase 73.80 Carbopol Ultrez 21 Viscogen 0.20 Cc Triethanolamine Neutralizing Agent Drops to pH = 7 D Euxyl K 350 Preservative 1.00
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 3. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRP)). 7. Specification For current specification, please speak to your local BASF sales or technical representative. 8. Regulatory status Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data 9. Toxicological data For information on toxicological issues please refer to the tox abstract which can be supplied on request. More/detailed toxicological information for Kolliphor RH 40 is available on request under Secrecy Agreement. 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30555082 Kolliphor RH 40 5025981 1 0.5kg Plastic bottle 50581348 60 kg Steel drums BASFs commercial product number. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Table of Contents Introduction 6 Ibuprofen 8 Chemical information . wl Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality .. 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Chemical information 20 Product information 20 Chemical and physical properties 21 Particle characterization 21 Regulatory status 21 Specification 21 Medical indication 22 Ibuprofen Sodium Dihydrate 24 Chemical information 24 Product information 24 Storage 25 Regulatory status 25 Specification 25 Medical indication 26 Table of Contents Introduction Ibuprofen 8 Chemical information 8 Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Ibuprofen Racemic Ibuprofen Lysinate (RIBL) Ibuprofen Sodium Dihydrate Ibuprofen Sodium Dihydrate
Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, antipyretic and anti-inflammatory actions, it is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever. Due to its analgesic, antipyretic and anti-inflammatory actions, it is used The common active ingredient dosage in tablets is 200, 400, 600 and 800 mg. The OTC dosage forms are mainly the 200 and 400 mg forms (except for the United States and some other countries, where the 200 mg form is the only OTC form). Other common dosage forms are capsules, syrups, suspensions, suppositories, and topical dosage forms like creams and gels. Pharmacokinetics Orally administered ibuprofen is absorbed rapidly in the Gl tract.? After a single oral dose on an empty stomach, peak plasma levels are reached within 45 to 90 minutes and the apparent plasma volume of distribution is reported to be between 0.1 to 0.2 I/kg.-> Ibuprofen has an extensive protein binding capacity (+98%) and is excreted via the kidneys. The biological half-life is between 2 and 4 hours.? After 24 h, 100% of the active substance is excreted in the urine.
Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as histamine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C. bata Te Ta Tort) U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Gillespie, W. R. et al., Relative Bioavailability of Commercially Available Ibuprofen Oral Dosage Forms in Humans, Journal of Pharmaceutical Sciences, 71:1034-1038, 1982. Verbeeck, R. K., Pathophysiologic Factors Affecting the Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs, Journal of Rheumatology, 15:44-57, 1988. Jamali, F. and D. R. Brocks, Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers, Clinical Pharmacokinetics, 19:197-217, 1990. Vowles, D. T. and B. Marchant, Protein Binding of Ibuprofen and Its Relationship to Drug Interactions, British Journal of Clinical Practice, 1:13-19, 1980. Whitlam, J. B. and K. F. Brown, Ultrafiltration in Serum Protein Binding Determinations, Journal of Pharmaceutical Science: Tio Teel atc oa Rudy, A. C. et al., Stereoselective Metabolism of Ibuprofen in Humans: Administration of R-, S- and Racemic Ibuprofen, Journal of Pharmacology and Experimental Therapeutics, 259:1133-1139, 1991. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(6): 986-1000, 2011.
Ibuprofen (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid Chemical name (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid 15687-27-1 239-784-6 C,,H,,0. 13) 182 206.28 g/mol CAS number EINECS number Molecular formula Molecular weight 3ASF offers 4 grades based on different particle size distributions (see particle charac- erization). Furthermore, a direct compressible grade is offered: Ibuprofen DC 85 W, the somposition of which can be found in chemical and physical properties section below. Product grades (+)-2-[4-(2-methylpropyl)phenyl]propanoic acid; (+)-Benzeneacetic acid, alpha-methyl- 4-(2-methylpropy)); (+)-p-lsobutylhydratropic acid; (+)-2-p-lsobutylphenylpropionic acid Ibuprofen meets the current Ph. Eur., USP, JP and IP monographs. DMFs and CEP are available upon request. Regulatory status Ibuprofen is the racemate of (+)-lbuprofen and (-)-lbuprofen (optical rotation = 0). According to the literature the pharmacologically active form is (+)-lbuprofen. Approximately 30 to 70% of the (-)-lbuprofen is converted to the active form (+)-lbuprofen in the body. This process proceeds solely from the (-)- form to the (+)- form.
Chemical and physical properties Ibuprofen grades 25, 38, 50, 70 Crystalline powder Solubility in phosphate buffer pH 7.2 (37 C) Partition coefficient n-octanol/water The chemical parameters of all pure ibuprofen powder grades are identical. The only difference is the particle size distribution (see particle characteristics).
Particle characterization Ibuprofen 25 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 25 is between 20 um and 33 pm. Ibuprofen 50 Particle Size Distribution Bulk density Tapped density An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 50 is between 45 um and 60 pm. Approximately 0.34 g/ml. Approximately 0.60 g/ml.
Ibuprofen 38 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 38 is between 33 um and 45 pm. ibuprofen 70 Particle Size Distribution Bulk density Approximately 0.38 g/ml. Tapped density Approximately 0.68 g/ml. An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 70 is between 60 pm and 85 pm.
Ibuprofen DC 85 W The ibuprofen used to manufacture Ibuprofen DC 85 W meets the current Ph. Eur., USP, JP and IP monographs. A Technical Package and a US-DMF are available upon request. Granules, free flowing, homogeneous material Appearance SEM photograph
Recommendation for direct compression Today the manufacturing of ibuprofen tablets is often done by direct compression. Using this method, the expensive and time-consuming wet granulation method can be avoided. But in general, ibuprofen has the disadvantage of sticking on the tablet tools so that the process must be interrupted often. Therefore, direct compression formulations with a high content of ibuprofen per tablet are often avoided. Mostly tablets with an ibuprofen content of maximum 60% are compressed. BASF offers a formulated ibuprofen product ideal for direct compression: Ibuprofen DC 85 W. The direct compression (DC) grade ensures that tablet sticking is minimized and allows for excellent tablet engraving. Furthermore, Ibuprofen DC 85 W has a lower angle of repose compared to standard grades, resulting in improved flowability.
General information on processing of Ibuprofen Ibuprofen is used mainly in three (3) different dosage forms: Ibuprofen 50, Ibuprofen 70, Ibuprofen DC 85 W (for direct compression) Recommended grade(s) High concentrations of magnesium stearate as a lubricant are not recommended. For direct compression, the ready-to-use Ibuprofen DC 85 W reduces sticking. For a film coating, Kollicoat IR has a reduced viscosity in aqueous solutions compared to HPMC suspensions, which leads to higher solids content and a faster coating process. Formulation guidance Creams & Gels Recommended grade(s) Recommended grade(s) To stabilize against sedimen- tation, fine particles should be used. The pH of the sus- pension should be in the acid range so that ibuprofen is undissolved, which will reduce bitter taste if any. lbuprofen is dissolved in the ipophilic phase of creams, thus there is no impact of particle size. Propylene glycol or low molecular weight polyethylene glycols are recommended as the oily component. Formulation guidance Formulation guidance
-oomLab - Your Virtual Formulation Assistant Access example formulations and build your own ZoomLab Formulation Wizard identifies suitable excipients and calculates potential formulations depending on the selected dosage form, defined target profile, and properties of the active ingredient. Example formulations include creams, tablets, and more! - Evaluate bioequivalence of your final formulation A WHO biowaiver monograph is available for ibuprofen. The ZoomLab dissolution module can be used to calculate difference and similarity factors (f1, f2) required for showing bioequivalence. ZoomLab provides values for parameters relating to particle size, powder density, flowability, and tabletability. The parameters are scaled from 0 to 10, a risk analysis is run, and an interpretation of results/formulation advice is provided.
Example formulations Production of granules for 200, 400, 600 and 800 mg forms The following ingredients are placed in a high shear mixer and granulated with water: Ibuprofen 50 60.1% w/w Amount of water: approximately 0.2 kg water per 1 kg __ ibuprofen. Wet sieving (4 mm) and drying in a fluid bed Lactose 18% w/w granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following Corn starch 9% w/w additives to form granules suitable for tableting. Kollicoat IR 3.6% w/w Extra granular material Avicel PH 102 3.6% w/w AcDiSol 4.8% w/w Magnesium stearate 0.6% w/w Aerosil 200 0.3% w/w Coating formulations for Ibuprofen tablets oes Fraction with reference to the Fraction with reference Composition atomised suspension [%] to the dry film [%] Polymer Kollicoat IR 16.0 64 Pigments Talc 6.0 24 Sicovit Red 30 3.0 12 Total 25 100 Amount of water: approximately 0.2 kg water per 1 kg ibuprofen. Wet sieving (4 mm) and drying in a fluid bed granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following additives to form granules suitable for tableting. Corn starch Kollicoat IR Extra granular material Magnesium stearate Coating formulations for Ibuprofen tablets

Handling & Safety Product specification The current version of the product specification is avail- able on RegXcellence or from your local BASF sales representative. Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on MyProduct- World or from your local BASF sales representative. Publications Regulatory & Quality Publications including scientific posters are available on: Please refer to the individual document quality & regu- latory product information (QRPI) which is available on RegXcellence and from your local sales representative The QRPI covers all relevant information including retest dates and storage conditions.
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Racemic Ibuprofen Lysinate (RIBL Racemic Ibuprofen Lysinate (RIBL Chemical information Chemical information Ibuprofen Lysinate (+) (+)- (+ (+ -2-[4-(2-methylpropyl)phenyl]propanoic acid lysinate -Benzeneacetic acid, alpha-methyl-4-(2-methylpropyl) lysinate -p-lsobutylhydratropic acid lysinate -2-p-lsobutylphenylpropionic acid lysinate Empirical formula Molecular weight
Chemical and physical properties White to almost white, very fine crystalline powder witt a high volume. In the literature the solubility of Ibuprofen (acid) in distilled water is reported to be less than 0.1%. The solubility of Ibuprofen Lysinate is 1:5, or about 17%. Particle characterization An example particle size distribution is shown below. The median particle size for RIBL is approximately 10 pm Regulatory status No monographs exist. E-DMF is available upon request.
The term RIBL is the acronym for Racemic Ibuprofen Lysinate. Racemic signifies that the ibuprofen drug substance and the lysine anion are both racemic compounds. RIBL differs from the common ibuprofen acid, gen- erally referred to as ibuprofen, in that it is more rapidly absorbed from the intestinal tract and reaches peak plasma levels and t,,., more quickly. After absorption, RIBL is available in the form of pure ibuprofen acid and is therefore to be handled like ibuprofen. Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, anti- pyretic and anti-inflammatory effects, ibuprofen is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever.? For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. Pharmacokinetics RIBL is readily and quickly absorbed from the gastrointestinal tract.!? The peak plasma level of the free acid is reached within 30 to 60 min (with the free acid ibuprofen, t,,,, was measured between 60 and 120 minutes, depending on the dosage form).: After absorption, there is no difference between RIBL and the free acid.
From a pharmacological point of view, there is no difference between RIBL and the free ibuprofen acid because it is the free acid and not the RIBL salt that is the active form. The mode of action of ibuprofen, while not completely understood, is believed to involve reversible inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have among other properties a powerful effect on the smooth muscles. In case of inflammatory stimuli or blood flow disorders, PGs are synthesized in increased amounts, making the tissues sensitive to the action of other agents such as histamine and kinins. As a result, symptoms like pain and inflammation occur. The in- cidence of fever is raised by the influence of the PGs on the heat regulation center in the hypothalamus. There they scale up the normal set point of 37 C. bats CUe Ta Tort) 1 Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration of Ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990. Hermann, T. W. et al., Bioavailability of Racemic Ibuprofen and its Lysinate from Suppositories in Rabbits, Journal of Pharmaceutical Sciences, 82(11):1102-1111, 1993. U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Neupert, W. et al., Effects of lbuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(5): 986-1000, 2011. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration o ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990.
Ibuprofen Sodium Dihydrate Chemical information Ibuprofen Sodium Dihydrate 2-(4-isobutylphenyl)-propionate sodium dihydrate Chemical name Se IS ee ee ee a en re ae ee ee 31121-93-4 C,,H,,0,Na x 2 H,O 228.26 + 36.03 g/mol Empirical formula Molecular weight
Storage Ibuprofen Sodium Dihydrate should be stored in the original, tightly sealed container. It should be placed ina well-ventilated room at ambient temperature and protected from light. The retest period of Ibuprofen Sodium Dihydrate is 60 months for material stored in the original, unopened containe! and according to our recommendations. Regulatory status Currently there are no monographs describing Ibuprofen Sodium Dihydrate in the major Pharmacopoeias (USP, Ph. Eur.. and JP).
According to the literature, ibuprofen sodium dihydrate dissolves more quickly in vitro and is absorbed into blood plasma more quickly than con- ventional ibuprofen, whereas tolerability and safety profiles of the two APIs are comparable.? In an investigation of the dissolution, plasma pharmacokinetics, and safety of ibuprofen sodium dihydrate versus conventional ibuprofen, the following results were reported:? @ buprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 compared to conventional ibuprofen. @ lbuprofen sodium dihydrate reached the t,,,, significantly earlier than conventional ibuprofen. @ lbuprofen sodium dihydrate showed significantly higher c_, compared to conventional ibuprofen. @ buprofen sodium dihydrate was characterized by significantly higher mean plasma concentration (10 min post-dose) compared to conventional ibuprofen. tax iS the necessary time until the maximum plasma concentration of a drug is reached; this is relevant for the drug onset. Generally, reaching the t_ early is of great advantage for analgesic treatment. According to the literature, the first signs of pain relief occurred significantly earlier in ibuprofen sodium dihydrate treated patients, and pain intensity was reduced to half after 30 min for ibuprofen sodium dihydrate compared to 57 min for conventional ibuprofen. In summary, ibuprofen sodium dihydrate causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen.
The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (CO)) which is responsible for the biosynthesis of prostaglandin (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflamma- tory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as hista- mine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C.? c Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandii Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vas FeYToltote CHI (2) Rc) =\ coal O00 Soergel, F. et al. Pharmacokinetics of Ibuprofen Sodium Dihydrate and Gastrointestinal Tolerability of Short-Term Treatment with a Novel, Rapidly Absorbed Formulation, International Journal of Clinical Pharmacology and Therapeutics. 43(8):140-149, 2005. Schleier, P. et al., Ibuprofen Sodium Dihydrate, an Ibuprofen Formulation with Improved Absorption Characteristics, Provides Faster and Greater Pain Relief than Ibuprofen Acid, International Journal of Clinical Pharmacoloay and Therapeutics. 45(2):89-97. 2007. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandir Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997.
www.pharma.basf.com For sample requests contact us ai pharma-solutions@basf.com Meet your Virtual Pharma Assistants! ZoomLab, RegXcellence, and MyProductWorld, your interactive guides for optimizing drug formulations, navigating quality and regulatory compliance, and browsing ingredients. Learn more and sign up at https://info-mypharma.basf.com/ Inspiring Medicines for Better Lives This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been preparec in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to the extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2021 BASF Corporation. All Rights Reserved.
Technical Information Linear alcohols and esters, medium-chain triglycerides: Emollients for topical applications. February 2019 Supersedes issue dated June 2013 Last change WF-No. 137282 = Registered trademark of BASF in many countries.
1. Introduction While the products cover a wide range of application fields, e.g. oral dosage forms for lipophilic APIs, this technical information sheet is designed to provide an overview on our pharmaceutical-grade emollients for topical pharmaceutical applications. With the inherently low potential for irritation, our petrolatum-free emollients are designed to create mild formulations that are easy to apply even onto large areas, and leave a pleasant feeling on the skin. The products are based on vegetable resources, and manufactured under IPEC-PQG GMP conditions. Trade name Compendial name Highlights for use as an Emollient ollicream 3 C Ph.Eur.: Cocoyl Solubilizer/penetration enhancer Caprylocaprate for some topical APIs ollicream CP 15 Ph.Eur.: Cetyl Palmitate 15 Replacement for spermaceti (from whales); relatively high melting point makes it a viscosity building agent in semi-solid creams, lotions and oils. ollicream DO Ph.Eur.: Decyl Oleate Enhancing skin-penetration of some APIs by disordering stratum corneum lipid domains with its branched C,, chain. ollicream IPM Ph.Eur.: Isopropyl Myristate Skin penetration enhancer for USP/NF: Isopropyl Myristate lipophilic actives. ollicream OA U h.Eur.: Oleyl Alcohol SP/NF: Oleyl Alcohol Cc. Enhancing skin-penetration of some APIs by disordering stratum corneum lipid domains with its branched C,, chain. ollicream OD U h.Eur.: Octyldodecanol ISP/NF: Octyldodecanol Cc Medium spreading, non-ester emollient, therefore inherently stable towards hydrolysis. Rapid plasticizer for com- promised skin. ollisolv? MCT 70 U h.Eur.: Triglycerides, Medium-Chain USP/NF: Medium-Chain Triglycerides Versatile solubilizer for lipophilic drugs, skin protectant through moisture retention. 2. Technical properties Description Kollicream grades are either comprised of esters of fatty acids (8 C, CP 15, DO, IPM), or of natural (OA), as well as naturally derived (OD) long-chain alcohols. Except for CP 15, which is provided in the form of waxy pellets, all other members of the Kollicream family, as well as Kollisolv@ MCT 70, are transparent, colorless liquids at room tempreature. The raw material base is coconut oil, and/or palm kernel oil.
Fatty Acid Fatty Alcohol Molar Weight of Ester [g/mol] ee ee 208 ae 478 478 450 450 450 422 422 304 Kolliwax CP 15 Kollicream 3 C Stearyl (C,,) 422 Cetyl (C,,) 394 Cetyl (C,,) 366 Kollicream 3 C ire 1; Overview on all esters contributing to the products Kollicream CP 15 (top) an Kollicream 3 C (bottom), ordered by molecular weight. The former name is deriv from Cetyl Palmitate, the ester of palmitic acid and cetyl alcohol, which was historic made from Spermaceti, a waxy substance found in the head cavity of sperm wh However, Kollicream CP 15 is, as all our emollients, derived entirely from vegete resources. The name Cocoyl Caprylocaprate (Kollicream 3 C) arises from coconut alcohol, mixture of lauryl (C,,), and myristyl (C,,) alcohol, as well as caprylic (C,) and capric (( acid, which are among the most prevalent fatty acids in the triglycerides of cocoi oll.
Brookfield Viscosities The following graph summarizing the product viscositites is for guidance only: please refer to the individual specification sheets for detailed viscosity information. Brookfield viscosities were measured in a temperature-controlled glass vial of approx. 35 mm inner diameter at 100 rpm using a DV8T device with LV-73 spindle. Figure 2: Brookfield Viscosities (values given in cP), measured at three different temperatures. Due to the relatively high melting point, Kollicream CP 15 could not be measured at the first two temperatures. Spreading The spreading is defined as the surface area (in mm,) of human skin of a test panelist, covered by 4 mg of emollient within 10 min in a room conditioned to 23 C and 60% rel. humidity. Typically, four separate measurements are done with each panelist, whereby a reference oil with known spreading behavior is used Picture 1. In addition to this in vivo method, spreading can also be measured in vitro. Picture 1: Test design to determine spreading of an emollient on human skin.
Emollient Spreading value Emollience [mm] Kollicream 3 C 800 Medium Kollicream CP 15 n/a Rich Kollicream DO 700 Medium Kollicream IPM 1200 Light Kollicream OA 700 Medium Kollicream OD 600 Medium Kollisolv? MCT 70 550 Medium The spreading value of an emollient has an important impact on the skin-feel of the resulting emulsion. Using a high amount of fast spreading emollients in your formulation will result in a smooth feeling on the skin perceived immediately upon application, but disappearing fast. In contrast, slow spreading emollients entail a rather subtle, but long-lasting smoothness. Combining emollients with different spreading behavior allows to tailor formulations towards the desired time profile of smooth skin feel Picture 2. Picture 2: Time profiles of emollients with different spreading behavior. Water Permeability The permeability/occlusivity of a film applied to the skin describes the ability to allow or prevent the passage of water, whereby a highly occlusive material (e.g. petrolatum) retains moisture by creating a barrier that prevents water from evaporating off the skin. Occlusivity is an important consideration for pharmaceutical formulations and the selection of emollients influences the permeability of an emulsion after spreading on the skin. Low permeability films can lead to hydration of the skin, increasing the flexibility of the stratum corneum. Trade name Water permeability Kollicream 3 C medium Kollicream CP 15 low Kollicream DO medium to low Kollicream IPM high Kollicream OA medium Kollicream OD medium Kollisolv@ MCT 70 medium
Solubility Parameters Using Formulating for Efficacy Software (Adaptive Cosmetic Technology Solutions Corp.), Hansen Solubility Parameters (HSP) were computed for the Kollicream products, as well as for light mineral oil. With this set of three parameters, the three major forces that influence the behavior of solute in solvent are considered: polarity (6P), degree of hydrogen bonding (8H), as well as dispersive forces (6D). Solutes and solvents can be mapped in the three-dimensional space that is given by the three parameters. When the HSP of a solute is close to that of a solvent, it is very likely that the solute sanll ARaAviAR A AIA wal dhAilifty In tan anhsant (Cin 9\ Figure 3: Hansen Parameters of some oils shown as a 3D plot.
3. Application Skin Tolerance/Mildness Clinical patch test studies on chronic contact dermatitis sufferers demonstrated that Kollicream 3 C, OD, IPM and CP 15 are very mild. Patch testing is considered to be the standard methodology for evaluating contact dermatitis. A list of standard allergens (70 substances) has been generated and recommended for standard diagnostic testing by the North American Contact Dermatitis Society. Dr. Joseph Fowler, and his team at Forefront Dermatology have been completing patch testing for over 15 years. Test subjects were patients wh have presented with chronic dermatitis with an undetermined cause these were highly sensitive patients. Finn Chambers were used to apply test substances to the backs of patients, per a globally standardized protocol. BASF Kollicream product: were applied at 35% in petrolatum. Patches were removed, and sites evaluated anc scored after 48 72 hours. Study was concluded after 500 patients were treated The following table lists the tested Kollicream grades and the number of patient: that showed no reaction at all to the application. Test material (at 35%) Kollicream 3 C Kollicream IPM Kollicream OD Kollicream CP 15 # of patients (out of 500) with no reaction 500 500 500 500 Effects on API Penetration Through Skin Studies on sodium ibuprofen in 96-well PAMPA system Studies were conducted to determine the effect of the Kollicream products and Kollisolv? MCT 70 on the permeation of Sodium Ibuprofen through a synthetic skin model membrane (Parallel Artificial Membrane Permeation Assay) in a 96 well format (in collaboration with Pion Inc., Billerica, MA, USA). Simple emulsions were prepared with the following composition: 45% w/w% water, 40 w/w% PEG 400 (Kollisolv? PEG 400), 2% Polysorbate 60 (Kolliphor PS 60), 5 w/w% Na-lbuprofen, and 8 w/w% of one of following; Kollicream 3 C, Kollicream OD, Kollicream DO, Kollicream IPM, Kollicream OA or Kollisolv? MCT 70. (The control or blank in this study was the same composition but without any lipophile. Water content was increased to 53 w/w% to compensate.) Figure 4: Cutout of the PAMPA setup for the measurement of AP! penetration through mode membranes. The setup allows 96 parallel measurements. The synthetic skin model membrane was sandwiched between an upper plate and a lower receiver plate. The lower wells were filled with phosphate buffered saline. The test emulsions were applied in the upper wells (6 12 replicates per sample). Both the test emulsions and the receptor solutions were stirred with small magnetic stirrers throughout the test period. The entire set-up was incubated at 37 C for one hour and then the lower plate was removed and sodium ibuprofen concentration (uM) was measured in each well by means of a 96-well UV/VIS spectrophotometer.
The results of the emollient screening indicate that not all lipophilic fluids tested behave in the same way. While Kollicream 3 C and OA, as well as Kollisolv? MCT 70 expressed the greatest impact on sodium ibuprofen permeation through the model membrane during the one-hour incubation period, emulsions with Kollicream IPM, DO, as well as OD were not significantly different from the control experiment. Test substance [Na IBU] (uM) Standard % increase in in receptor Deviation permeation vs (+/-) control Kollicream OD 3602 785 0.3 Kollicream DO 3890 810 8.4 Kollicream IPM 4042 437 12.6 Kollicream OA 4238 280 18.1 Kollisolv? MCT 70 4531 657 26.2 Kollicream 3 C 4700 369 30.0 Control/Blank 3589 280 om Studies of Clotrimazole permeation through Strat-M membrane Studies with 1% Clotrimazole creams were conducted to investigate the effect of different oil phase compositions on the skin permeation of the Clotrimazole. Creams were prepared as in the following table: Ingredient Description Dosage [wt.-%] Kollisolv PG Propylene glycol 8.0 Kolliwax CSA 50 Cetostearyl alcohol 7.0 Variable Lipophilic fluid (oil) 12.0 Kolliphor CS 20 Polyoxyl 20 cetostearyl ether 3.0 Active Ingredient Clotrimazole 1.0 Water -- 68.9 Euxyl 320 Phenoxyethanol 0.1 The lipophilic fluids (oils) subject to test were Kollicreams 3 C, OD, IPM and mineral oil. Clotrimazole permeation through a skin model membrane (Strat-M) was measured using Franz Cells: for each test, the cream was applied to the top surface of the membrane, in the donor compartment, at an infinite dose (= 200 uL). Samples were collected from the receptor phase at 0.5, 1, 2, 4, 6 and 8 hours, and analyzed for Clotrimazole concentration. The flux profile for each formulation is illustrated in the following chart. igure 5: Time profiles of Clotrimazole permeation through a model membrane for different emollients: IPM = Kollicream IPM, MO = Mineral Oil, 3 C = Kollicream 3 C, OD = Kollicream OD.
Note that the different lipophiles had differing influences on Clotrimazole flux rates. In this study the Kollicream IPM-containing cream had the highest flux rate while the Kollicream 3 C-containing cream had the lowest. The mineral oil and Kollicream OD- containing creams had very similar flux rates. Clotrimazole is typically intended to prevent or treat fungal/yeast infections on mucosal membranes, so inhibition of permeation is desirable. In this case the Kollicream 3 C-containing cream had the most desirable performance. Example Formulations The following cream formulations can all be prepared by the same basic procedure: THIS TOWOWITTY Cea lh PONMTUIAUOTIS Call all US PIeValoU VY WIE SGI Udol& VIUCCUUIe. 1. Blend all ingredients in phase A together and heat to 80 C under stirring, until the blend is a clear liquid. 2. Blend all of the ingredients in phase B and heat to 80 C under stirring, until homo: geneous. 3. While strirring phase B vigorously (e.g. by means of a propeller mixer at 500 rpm), pour phase A into phase B and mix until a homogeneous emulsion forms (generally within a few minutes). 4. Transfer the mixture to a high-shear rotor-stator homogenizer and homogenize at approx. 5000 rpm for about ten minutes, making sure that the entire batch is homogenized. 5. Return the mixture to a propeller mixer and stir at 200 rpm whitout heating. After the mixtures has cooled to 45 C, add the preservative. Continue mixing, until homogeneous. 6. Remove from mixer and fill to appropriate packaging, after the cream has cooled to 30 C or below. 1. Cream Formulation with Kolliphor PS 80 This composition yields a medium viscosity cream with a high loading (20 w/w%) of Kollicream 3 C, emulsified by Kolliphor PS 80. The high oil content will allow for solubilization of lipophilic APIs, smooth and pleasing sensory properties, and the benefits of a moisture barrier after application. Phase Ingredient Name Amount [%] A Kollicream 3 C Cocoyl caprylocaprate 20 Kolliphor PS 80 Polysorbate 80 Kolliwax GMS II Glycerol monostearate 40-55 (type Il) Kolliwax CSA 70 Cetostearyl alcohol 5 B Deionized water 68 Preservative Euxyl PE 9010
2. Rich Cream based on Kollisolv MCT 70 and Kollicream IPM This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as consistency factor and emulsifier, respectively, to create a very stiff cream that offers a rich and cushioned feeling when rubbed into the skin. Kollicream IPM is a fast spreading oil for topical semi-solid formulations and a penetration enhancer for some APIs. Phase Ingredient Name Amount [%] A Kolliwax CSA 70 Cetostearyl alcohol 7.0 Kolliwax GMS II Glycerol monostearate 40-55 2.5 (type Il) Kolliphor PS 60 Polysorbate 60 4.2 Kollisolv@ MCT 70 Medium chain triglycerides 11.5 Kollicream IPM Isopropyl myristate 1.3 B Deionized water 69.2 Glycerol 33 Cc Euxyl PE 9010 Phenoxyethanol 1.0 3. Cream based on Kollisolv? MCT 70 Kollisolv? MCT 70 can be a good solvent and carrier for lipophilic APIs, but exhibits rather slow spreading behavior due to its relatively high viscosity. Kollicream IPM was added to reduce the overall viscosity of the oil phase and increase spreading after application. Phase Ingredient Name Amount [%] A Kolliwax CSA 70 Cetostearyl alcohol 7.0 Kolliwax GMS II Glycerol monostearate 40-55 2.5 (type Il) Kolliphor PS 60 Polysorbate 60 4.2 Kollisolv@ MCT 70 Medium chain triglycerides 11.5 Kollicream IPM Isopropyl myristate 1.3 B Deionized water 69.2 Glycerol 3:3 Cc Euxyl PE 9010 Phenoxyethanol 1.0 4. Cream with Kollicream OD and Kolliphor CS 20 Kollicream OD is widely used in creams and lotions and can easily penetrate the skin and aid in the permeation of APIs, while remaining mild and non-irritating. It can also serve as a solvent for lipophilic APIs. It is emulsified by Kolliphor CS 20, an unbranched linear alkyl PEG ether. Both are stable in a wide range of pH values. Creams prepared with Kollicream OD and Kolliphor CS 20 yield a medium viscosity, non-greasy formulation. Phase Ingredient Name Amount [%] A Kollicream OD Octyldodecanol 12.0 Kolliphor CS 20 Polyoxyl-20 cetosteary! ether 3.1 Kolliwax S Stearic acid 0.1 Kolliwax CSA 50 Cetostearyl alcohol 7.5 Kolliwax GMS II Glycerol monostearate 40-55 0.5 (type Il) B Deionized water 15.8 Cc Euxyl PE 9010 1.0
5. Gel Formulation: Emulgel At concentrations above 15%, Poloxamers 188 and 407 can be used to make gel and viscous emulsions by both emulsifying and forming phases and networks via the hydrophobic and hydrophilic interactions driven by PPO and PEO segments of the polymer, respectively. Kolliphor P 407 helps emulsify the Kollicream 3 C in this formulation, resulting in a translucent white gel with a cream-like structure visible underneath the microscope. Both Kolliphor P 407 and Kollicream 3 C have been shown to be very mild, in vitro and in vivo. Phase Ingredient Name Amount [%] A Ethanol 200 Proof 10 Kollisolv@ PEG 400 Polyethylene glycol 400 15 Glycerol 5 B Kolliphor P 407 Poloxamer 407 18 Deionized Water 42 Cc Kollicream 3 C Cocoyl caprylocaprate 10 FLCy 1. Keep mix of components listed under B refrigerated at 5 C for 24 h, or until all Kolliphor P 407 is dissolved. 2. Mix all C and A ingredients to phase A, stir slowly until Kolliphor has gelled. GUO! (WUIU PIUeGoso)s, Preparation (Hot Process): Preparation (Hot Process): 1. Prepare phase B by adding Kolliohor to water preheated to 70 C. Stir this mixture for at least 1h to ensure proper dissolution of the poloxamer. 2. As solution B is cooling down to room temperature, add component mixtures A and C while stirring until a robust gel is formed. 6. Model Foam Formulation: General Aerosol Foams Growing in popularity, topical foams can sometimes be preferred over a cream due to their pleasing sensory application. The four foam formulations below retain their shape upon application onto the skin, spreading easily and drying quickly. Foams made with Kolliphor CS 12 tend to demonstrate a higher viscosity and stiffness than foams formulated with Kolliphor CS 20. Additionally, poloxamers such as Kolliphor P 188 or Kolliphor P 407 can be added to formulations as needed to create richer, creamier foams. This richness is aided by the use of an aerosol. Picture 3: Macrostructures of aerosol foams.
Figure 6: Viscosity profiles of aerosol foams. Phase Ingredient Name Amounts [%] A B Cc OD Kolliwax CSA 50 Cetostearyl alcohol 3 3 3 3 Kolliphor CS 12 Macrogol cetostearyl ether 12 0 0 6 5 Kolliphor CS 20 Macrogol cetostearyl ether 20 5 6 0 0 Kollicream 3 C Cocoyl caprylocaprate 3 3 3 8 Kolliphor P 188 Poloxamer 188 1 0 0 1 Deionized Water 82 82 82 82 A46 Propane/Isobutane 6 6 6 6 Preparation 1. Mix formulation ingredients in a beaker, using slight heat if necessary to ensure uniform distribution of the components. 2. Place the mixture in an aerosol container, charge with desired propellant. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment. 5. Product Specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions.
7. PRD and Article numbers 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554439 ollicream 3 C 50268489 800 kg Composite IBC (31HA1) 50363006 175 kg Steel drum 50259481 0.5 kg Plastic bottle 30554443 ollicream CP 15 50253253 20 kg Plastic film bag 50259485 0.5 kg Plastic bottle 30554441 ollicream DO 50253252 175 kg Steel drum 50259484 0.5 kg Plastic bottle 30554463 ollicream IPM 50264409 850 kg Composite IBC (31HA1) 50253267 175 kg Steel drum 50259491 0.5 kg Plastic bottle 30554462 ollicream OA 50253265 175 kg Steel drum 50259490 0.5 kg Plastic bottle 30554460 ollicream OD 50253259 175 kg Steel drum 50259489 0.5 kg Plastic bottle 30554489 ollisolv? MCT 70 50253413 190 kg Steel drum 50259496 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html Disclaimer This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Fatty acids and alcohols: Consistency factors for topical formulations, and excipients for solid oral dosage forms. Oktober 2021 WF-No. 137189 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes fatty acids and alcohols that can be used as (co-) emulsifiers and consistency factors in topical pharmaceutical applications, but may also function as excipients in solid oral dosage forms, e.g., as matrix formers and lubricants. This document focuses on fatty acids and alcohols of the Kolliwax family. Please refer to the individual technical information sheet for specific information on our two glyceride based grades Kolliwax GMS II and Kolliwax HCO (Glycerol Monostearate, and Hydrogenated Castor Oil, respectively). Trade name Compendial Name Kolliwax CA Ph.Eur.: Cetyl Alcohol USP/NF: Cetyl Alcohol Kolliwax CSA 50 Ph.Eur.: Cetostearyl Alcohol USP/NF: Cetostearyl Alcohol JP: Cetostearyl Alcohol Kolliwax CSA 70 Ph.Eur.: Cetostearyl Alcohol Kolliwax MA USP/NF: Myristyl Alcohol Kolliwax SA Ph.Eur.: Stearyl Alcohol Kolliwax SA Fine USP/NF: Stearyl Alcohol JP: Stearyl Alcohol Kolliwax S Ph.Eur.: Stearic Acid 50 Kolliwax S Fine USP/NF: Stearic Acid 50 llPe Stearic Acid 50 Table 1: Compendial names for fatty alcohols and acids of the Kolliwax family. Description 2. Technical properties Kolliwax grades are white to slightly yellowish, waxy substances derived from natural ressources, namely coconut oil, palm kernel oil, and/or palm stearine. With melting points above room temperature, these products are either supplied as powder, pearls, or pelletts (see table1 and table 2 for details). The numeric part of the name of the two grades of Kolliwax CSA represents the approximate weight percentage of stearyl alcohol. es ene Trade name Chemical nature CAS-No. Melting ranges [cy Kolliwax CA Cetyl Alcohol (C,,) 36653-82-4 46-52 Koliwax CSA S0_ Cety/Stearyl Alcohol 7769 97.9 1666 Kolliwax CSA70_ (Cie/Cra) Kolliwax MA Myristyl Alcohol (C,,) 112-72-1 36-42 Kolliwax SA Stearyl Alcohol (C,,) 112-92-5 57-60 Kolliwax SA Fine Koliwax?S Stearic/Palmitio Acid g 7754 93.05 308 Kolliwax S Fine (Cil/Cy6) Values given for guidance only, see specification sheets for detailed information on melting and/or freezing temperatures. Table 2: Properties of fatty alcohols and acids of the Kolliwax family.
Figure 1: Typical appearance of the Kolliwax grades. The scale in the back is metric, with 1 mm per mark. For detailed information on particle size distributions, please refer to the individual product specification sheets. Scanning electron mircroscopy (SEM) igure 2: SEM images of Kolliwax S, and Kolliwax S Fine. Please refer to the individu: specification sheets for detailed information on particle size distributions.
3. Application Overview The following table 3 gives an overview on the most important applications and functions of the Kolliwax fatty alcohols and acids: while fatty acids and alcohols are generally used as consistency factors, our fine grades of stearic acid and stearyl alcoho (Kolliwax S Fine and Kolliwax SA Fine, respectively) allow to use these substances in the preparation of solid dosage forms, where they can aid as lubricants or matrix formers. Table 3: Application of the Kolliwax grades. Emulsions Exhibiting excellent skin tolerance, the Kolliwax grades can be used for all kinds of topical pharmaceutical applications, such as creams, gels, lotions, and ointments. The typical usage concentration in emulsions is about 1- 5%. All Kolliwax grades will act as consistency factors and co-emulsifiers at the same time. With their amphiphilic structure, they will stabilize the interface between oil and water and will help to enhance the viscosity by building up a liquid crystalline network (lamellar sheet structure). Stabilizing w/o and 0/w emulsions, they also aid in bringing a unique softness and creaminess to the targeted formulation. Lubricants In tableting processes for solid oral dosage forms, lubricants are used to prevent ingredients from clumping to undesired aggregates and from sticking to the tablet punches or capsule filling machine. In addition, lubricants hamper the friction that would hinder tablet formation and ejection. Among inorganic materials (e.g. talc or silica), fat based substances like vegetable stearin, magnesium stearate or stearic acid are commonly used as lubricants in tablets or hard gelatin capsules. Lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. Formulation examples Guideline for the preparation of the model formulations: MaYIGenne 1Or UWle PrepalrauviOrl OF WIE MIOQE! fOMTIUlAvOrls. 1. Heat components of phase A to 80 - 85 C and stir until transformed into a homo- geneous melt. 2. Heat components of phase B to 80 85 C. Under constant stirring, slowly add phase A to phase B, homogenize for 5 min at 5000 rpm. Let cream cool to 35 C while mixing at 200 rpm, and add preservative.
Model formulation Rich Cream: This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as emulsifiers to create avery stiff cream that offers a slow spread and a cushioned feeling when rubbing into the skin. Its high immediate smoothness results from the utilization of Kollicream IPM, a fast spreading oil with broad penetration enhancement properties that can aid as a solubilizer for lipophilic drugs. Ingredient Phase Ph. Eur. name Role Amount [wt.-%] A __ Kolliwax CSA 70 Cetostearyl Alcohol Consistency Factor, 7.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 25 40-55 (Type Il) Co-Emulsifier Kolliphor PS 60 Polysorbate 60 Emulsifier 4.2 Kollisolv@ MCT 70 Medium Chain Emollient 11.5 Triglycerides Kollicream IPM Isopropyl Myristate Emollient 1.3 B Deionized Water 69.2 Solvent _____. Glycerol 3.3 C_ Euxyl PE 9010 Preservative 1.0 Table 4: Model formulation for a rich Cream. Model formulation Light Cream: This formulation is a smooth cream with easy distribution, medium viscosity, and a glossy finish. Due to the difference in HLB values, the blending ratio of Kolliphor CS 12 and Kolliphor CS 20 can be used as a factor to maximize emulsion stability. Phase Ingredient Ph. Eur. name Role Amount [wt.-%] A_ Kolliwax CSA 50 Cetostearyl Alcohol Consistency Factor, 4.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 5.0 40-55 (Type Il) Co-Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Emulsifier 2.0 Ether 20 Kolliphor CS 12 Macrogol Cetostearyl Emollient 0.8 Ether 12 Kollicream CP 15 Cetyl Palmitate 15 Emollient 0.8 Kollicream IPM Isopropyl Myristate Emollient TA B__ Deionized Water 74.0 Solvent Glyerol 5.0) C_ Euxyl PE 9010 Preservative 1.0 in Si Pe Table 5: Model formulation for a light cream. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment.
5. Product specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554718 olliwax CA 50253459 25 kg Plastic film bag 50259499 0.5 kg Plastic bottle 30554719 olliwax CSA 50. 50253501 25 kg Plastic film bag 50259500 0.5 kg Plastic bottle 30554721 olliwax CSA 70 50253504 25 kg Plastic film bag 50259502 0.5 kg Plastic bottle 30554492 olliwax MA 50375472 20 kg Corrugated fiberboard box with PE liner 50259498 0.5 kg Plastic bottle 30554720 olliwax SA 50253503 25 kg Plastic film bag 50259501 0.5 kg Plastic bottle 30563963 olliwax SA Fine 50284249 25 kg Plastic film bag 50372378 0.5 kg Plastic bottle 30554752 olliwax S 50253532 25 kg Plastic film bag 50259521 0.5 kg Plastic bottle 30554750 olliwax S Fine 50253810 25 kg Plastic film bag 50259508 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Kolliphor SLS Fine This technical information gives an overview on the use of Kolliphor SLS and Kolliphor SLS Fine as excipients for solid oral dosage forms.
Rebranding As a result of the integration of former Cognis excipients in the BASF portfolio a rebranding was conducted. The rebranding should increase the reliability and compliance for the supply of pharmaceutical excipients. The following table shows a comparison of old versus new trade names. Table 1: New Tradenames-and former Tradenames Tradename Former Tradename Chemistry Kolliphor SLS Texapon K 12 G PH Sodium Lauryl Sulfate Kolliphor SLS Fine Texapon K 12 P PH Sodium Lauryl Sulfate Tradename Kolliphor SLS Kolliphor SLS Fine Kolliphor SLS Kolliphor SLS Fine Former Tradename Texapon K 12 G PH Texapon K 12 P PH 151-21-3 151-21-3 Chemistry Sodium Lauryl Sulfate Sodium Lauryl Sulfate Table 2: PRD and article numbers of Kolliphor SLS and Kolliphor SLS Fine PRD-No. and Article-No. PRD Article-No. Packaging Kolliphor SLS 30569546 50253852 25 kg 50253851 600 kg Kolliphor SLS Fine 30554762 50253853 15 kg See separate documents: ,Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Table 3 lists all monographs Kolliphor SLS and Kolliphor SLS Fine are meeting. Regulatory Status Table 3: Compendial names Tradename Monographic Names Kolliphor SLS Ph.Eur.: Sodium Laurilsulfate USP/NF: Sodium Lauryl Sulfate JP: Sodium Lauryl Sulfate Kolliphor SLS Fine Ph.Eur.: Sodium Laurilsulfate USP/NF: Sodium Lauryl Sulfate JP: Sodium Lauryl Sulfate Kolliphor SLS Fine has a self-affirmed GRAS status. A kosher certificate is available upon request for both grades. Typical properties Spray-dried sodium alkyl sulfate, based on a natural saturated straight-chain primary fatty alcohol. Production Free flowable powder (Kolliphor SLS Fine) or granules (Kolliphor SLS). Physical Form White to off-white. Faint characteristic odor. Melting point
Solubility information Soluble in hot and cold water, sparingly soluble in ethanol. In high concentrations corrosive to steel. Dust may irritate eyes and respiratory system. Incompatibilities Incompatibilities Figure 1 shows the typical particle size distribution of Kolliphor SLS Fine measured by laser diffraction with a powder module. Particle size distribution Figure 1: Typical Particle size distribution of Kolliphor SLS Fine measured by laser diffraction. Tapped density Picture 1 shows a scanning electron microscopic (SEM) pictures of Kolliphor SLS Fine in two different magnitudes. SEM Picture Picture 1: SEM Picture of Kolliphor SLS Fine.
Application Kolliphor SLS and Kolliphor SLS Fine can be used as solubilizers to enhance the solubility of poorly soluble APIs in both solid and liquid oral dosage forms. Kolliphor SLS grades are also suitable for semi solid dosage form like creams, lotions and gels. Sodium lauryl! sulfate is also very broadly used in oral care formulations. The typical usage concentration as a solubilizer or emulsifier is 0.5-2.5 wt%. Solubilizer Wetting agent in tableting Kolliphor SLS and Kolliphor SLS Fine can reduce tablet disintegration time due to improved wettability of the tablet. Some micronized active drugs require a wetting agent to improve drug dissolution rate if compressed into tablets or filled into hard capsules. As wetting agent the typical usage concentration is 0.5-5 wt%. For this application Kolliphor SLS Fine is often more suitable than Kolliphor SLS. Kolliphor SLS and Kolliphor SLS Fine can be used as tablet lubricant if standard lubricants (magnesium stearate 0.5%) are incompatible with the formulation. Since sodium lauryl sulfate can also increase drug dissolution rate, magnesium stearate cannot be replaced one to one by Kolliphor SLS fine. Kolliphor SLS fine offers a combination of good lubrication effect together with improved tablet/capsule disintegration properties and facilitates manufacturing of modern solid dosage forms. As lubricant the typical usage concentration of Kolliphor SLS or Kolliphor SLS Fine is 2%. Example for use as lubricant ina direct compressible formulation Magnesium stearate is known to form eutectics with the drug substance ibuprofen. During tableting, product can adhere on the punch tips (Roberts et al. 2004) and cause problems in the manufacturing process of ibuprofen tablets. The following example demonstrates how magnesium stearate can be successfully exchanged for Kolliphor SLS Fine as an alternative lubricant and tablet disintegration aid. Table 4: Formulation of a direct compression Ibuprofen tablet Ingredient Name mg per tablet Ibuprofen Ibuprofen 400 Tablettose 80 Lactose monohydrate 350 Vivapur 102 Microcrystalline cellulose 175 Kollidon 30 Polyvinylpyrrolidone K 30 50 Kolliphor SLS Fine Sodium lauryl sulfate 20 Aerosil Fumed silica 5 The present direct compressible tablet formulation is intended as technical example only and does not contain additional tablet disintegrants that facilitate tablet disintegration. All components (except the lubricant) are sieved and blended in a double cone blender for 15 minutes. Kolliphor SLS Fine or alternatively magnesium stearate 0.5% (5 mg per tablet, Microcrystalline cellulose is used for mass correction) are added to the blend and blended for another 5 minutes. Tableting is carried out on an eccentric tablet press equipped with a 18 mm diameter flat faced punch. A concentration of 2% Kolliphor SLS Fine is sufficient to obtain good lubrication results. Tablet breaking force was comparable to magnesium stearate but shows a lower standard deviation indicating homogeneous blending (Figure 2).
Tablet disintegration according to Ph. Eur. in 0.1 N HCl solution indicates shorter disintegration times for tablets lubricated with Kolliphor SLS Fine. Even the time difference between the first and the last tablet disintegrated was shorter for Kolliphor SLS Fine (Figure 3). Ibuprofen drug dissolution experiments have been performed according to USP 33 method <711>, Kolliphor SLS Fine can improve dissolution results of the model drug substance ibuprofen. Although the tablet formulation is not optimized for high drug dissolution rates (absence of additional disintegrants in the formulation) the data can clearly demonstrate the benefit of Kolliphor SLS Fine compared to standard lubricant magnesium stearate in this application. Figure 2: Breaking force and disintegration time of Ibuprofen tablets with Mc stearate compared to Kolliphor SLS Fine. Figure 3: Dissolution of Ibuprofen tablets over time.
Raw material origin Kolliphor SLS and Kolliphor SLS fine are based on vegetable and synthetic raw materials. The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreement. Stability and storage In original sealed containers Kolliphor SLS and Kolliphor SLS Fine can be stored for at least two years. It is important that they are protected from moisture and stored at less than 30 C. Handling and Disposal Please refer to the individual Material Safety Data Sheet (MSDS) for instruction on safe and proper handling and disposal. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Poloxamer Ph. Eur., Poloxamer USP/N Poloxamer for Pharmaceutical Use Poloxamer Ph. Eur., Poloxamer USP/I Poloxamer for Pharmaceutical Use March 2020 WF-No. DAWF-2019-0813 = Registered trademark of BASF in many countries.
1. Introduction BASFs Kolliphor P grade poloxamers are white, coarse- grained powders with a waxy consistency. They contain an appropriate quantity of the antioxidant BHT. Poloxamers are ABA-type co-polymers of poly (ethylene oxide) (PEO=A) and poly (propylene oxide) (PPO=B). The approximate relative amount of PEO and the average molecular weight of the PPO are indicated in the name of the poloxamer. For example, P8338 succeeding the word Kolliphor indicates a poloxamer with ca. 80% m/m PEO (P338; 8x10= 80%) and approximately average molecular weight of PPO of 3300 (P3838; 33x100= 3300). 2. Technical properties Structural formula Kolliphor P 338 Geismar is a block copolymer that is a synthetic copolymer of ethylene oxide and propylene oxide represented by the following chemical structure: CH, HO - CH,- CH,- OH CH,- CH- OL} CH,-CH,-O+ H Where the a and b blocks have the following values: a=141,b=44 Appearance Kolliphor P 338 Geismar is produced as a white to almost white prill/powder. CAS Number 9003-11-6 Molecular Weight The average molecular weight for Kolliphor P 338 Geismar is 12700 to 17400 g/mol. The product contains nominally 135 to 145 ethylene oxide units and 40 50 propylene oxide units, with a rough concentration of oxyethylene of 81.4 84.8 % based on the current monograph specification. An example of the molecular weight distribution for Kolliphor P 338 Geismar is shown below in Figure 1. Figure 1:The above graph was generated using size exclusion chromatography (SEC), note that the smaller peak to the left represents diblock polymers.
Viscosity Poloxamers, and Kolliphor P 338 Geismar exhibits a thermoreversible gelling behavior that occurs as a function of temperature. At low concentrations, aqueous concentrations exhibit Newtonian flow properties and negligible viscosity alterations to that of water, however, at higher temperatures, the solutions begin to exhibit non-Newtonian flow behavior. An example of the viscosity curve is evident in Figure 2 below with the gel points indicated by the sharp increase in viscosity for a 20% w/w solution. Figure 2: HLB The HLB value of Kolliphor P 338 Geismar is approximately 27. Critical Micelle Concentration (CMC) The critical micelle concentration for Kolliphor P 338 Geismar is published as 2.2 - 10-5 mol/L @ 37 C. Note that the CMC value decreases significantly as the temperature increases. Furthermore, due to the linear structure of the poloxamer, the value is difficult to ascertain as an inflection point using standard methods (such as Wilhelmy Plate Method). Solubility Kolliphor P 338 Geismar is highly soluble in water. Note that Kolliphor P 338 Geismar is significantly faster to dissolve in cold water Kolliphor P 338 Geismar is highly soluble in water. Ringn thet Velinhnce DOOR.
Particle size Kolliphor P 338 Geismar exhibits spherical prill particles of a mean diameter of approximately 600 um in size. An example of the size and morphology of these particles is shown in the scanning electron microscope image (SEM) show below in Figure X. Cloud point The cloud point for Kolliphor P 338 Geismar is >100C for a 1% and a 10% aqueous solution. BHT Poloxamers, and specifically Kolliphor P 338 Geismar utilize 50 - 125 ppm BHT as an antioxidant the protects the quality and performance of the P 338 Geismar in the multitude of pharmaceutical applications. The primary degradation mechanism is oxidation, and is typically monitored via the pH, hydroxyl value and molecular weight o the poloxamer. 3. Example application Poloxamers are a widely used pharmaceutical ingredient in multitude of applications, most notably, as a dispersing agent, emulsifier, solubilizer, tablet and capsule lubricant, wetting agent, stabilizer for oral and topical suspensions, gelling agent in topical formulations. Example Use Levels Indication Concentration (w/w%) Gelling agent 15 to 50 Suspension stabilizer 0.1 to 5 Tableting 1 to 10 Wetting Agent 0.01 to5 Emulsifier 1to5 Foaming agent 1to3 Plasticizer (matrix) 5 to 15 Solubilization Kolliphor P 338 Geismar can be used in a multitude of solubilization examples more specifically the product may be a liquid solution, suspension or solid tablet Given the low critical micelle concentration (CMC) stabilizing and solubilizing occurs at concentrations 1 to 2 orders of magnitude lower than for standard ethoxylatec surfactants.
Skin delivery Poloxamers as Gelling agents Poloxamers can be used as gelling agents to build structure in a topical aqueous solution. Gels using Kolliphor P 338 Geismar can exhibit thermoreversible behavior; they form gels which are liquids at room temperature but solidify upon contact with skin. Phase Ingredients Chemical name _ Description Mass (Weight%) A Ethanol 200 Proof Solvent 10 Kollisolv PG Propylene Glycol Solvent 10 Kollicream IPM Isopropylmyristate Tack reducer 2 Glycerol Solvent 5 B Kolliphor P 338 Geismar Poloxamer 338 Gelling agent 15 20 Deionized Water Solvent 53 58 Gelling is a function of temperature, structure, and concentration of a given poloxamer. At high enough concentrations, poloxamers form multimolecular aggregates and micelles that aid in gelling. Notably, an increase in the amount of ethanol used in a formulation increases the gelling temperature of a given formulation. Kollicream IPM reduces tackiness, resulting in an improved sensory experience. Emulgel At concentrations above 15%, Poloxamers 188 and 338 can be used to make gels and viscous emulsions by both emulsifying and forming phases and networks via the hydrophobic and hydrophilic interactions driven by PPO and PEO segments of the polymer, respectively. Phase Ingredients Chemical name Description Mass (Weight%) A Ethanol 200 Proof Solvent 10 Kollisolv? PEG 400 Polyethylene Glycol 400 Solvent 15 Glycerol Solvent 5 B Kolliphor P 338 Poloxamer 338 Gelling agent 18 Geismar Cc Deionized Water Solvent 42 D Kollicream 3 C Cocoyl Caprylocaprate Emollient 10 Kolliphor P 338 Geismar helps emulsify the Kollicream 3 C in this formulation, resulting in a translucent white gel with a cream-like structure visible underneath the microscope. Both Kolliphor P 338 Geismar and Kollicream 3 C have been shown to be very mild, in vitro and in vivo.
4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on BASF WorldAccount or from your local BASF sales representative. The current version of the product specification is available on BASF WorldAccount or from your local BASF sales representative. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI) which is available on BASF WorldAccount and from your local sales representative. aR Se Eee The QRPIc covers 5 all relevant information including retest dates and storage conditions. 7. Toxicology The toxicological abstract is available on request. 8. PRD and Article numbers 8. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30631059 Kolliphor P 338 Geismar 50424591 0.5 kg Plastic bottle 50423936 80 kg Fibre drum BASFs commercial product number. 9. Publications Publications including scientific posters are available on http://pharmaceutical.basf.com/en.htm Disclaimer This document. or any answers or information provided herein by BASF. does not PRD-No. Product name Article numbers Packaging 30631059 Kolliphor P 338 Geismar 50424591 0.5 kg Plastic bottle 50423936 80 kg Fibre drum This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information isoluble Kollidon grades Crospovidone Ph. Eur., USP and JP Crospovidone as excipient for the pharmaceutical industry Crospovidone as excipient for the pharmaceutical industry January 2019 Supersedes issue dated September 2011 Last change WF-No. 136636 = Registered trademark of BASF in many countries
1. Introduction The insoluble grades of Kollidon are widely used in the pharmaceuticals industry because of their swelling properties. They are thus predominantly used as disintegrants in solid oral dosage forms such as tablets. Furthermore their application as pharmaceutical excipients is triggered by their ability to hydrophilize insoluble drugs, to stabilize suspensions and to form complexes. 2. Technical properties Description The insoluble Kollidon grades are supplied as fine white or almost white powders. They have a slight characteristic odor and are practically tasteless. They are insoluble in all of the usual solvents. The insoluble grades of Kollidon (Crospovidone) are manufactured by a polymerization process that yields crosslinked insoluble polyvinylpyrrolidone in the form of a popcorn polymer. The polymerisation is performed using an aqueous system. Neither organic solvents nor radical starters are involved at any stage. The crosslinking is of chemical and physical nature. The latter one, mainly achieved by entanglement of the polymer chains, dominates the product properties. This is supported by comparisons of the infrared spectra of the soluble and insoluble grades of polyvinylpyrrolidone which do not reveal any differences. In contrast, the infrared spectrum of chemically crosslinked insoluble vinylpyrrolidone polymer prepared in the laboratory is quite different. Details that are beyond the scope of this brochure can be found in the books, Kollidon, Polyvinylpyrrolidone for the pharmaceutical industry, published by BASF or Polyvinylpyrrolidone-Excipients for Pharmaceuticals, published by Springer-Verlag, ISBN 3-540 23412-8 Synonyms Crospovidone, crospovidonum, insoluble polyvinylpyrrolidone, crosslinked PVP. Product range Due to the fact that Crospovidone is completely insoluble the corresponding products cannot be named according to a K-value or a molecular weight. The product differentiation is done mainly by the particle size distribution. The followinc products are available: Kollidon CL Kollidon CL-F Kollidon CL-SF Kollidon CL-M The products differ not only in their particle size distributions but in other physical pro- perties, too, such as in their bulk density and their swelling behavior. CAS-number 9003-39-08
Picture 1: Crospovidone Hygroscopicity The hygroscopic properties of the Kollidon grades are important in many applications. There is hardly any difference between the individual grades so that they can all be represented by a single curve (Fig. 1). The curve shows the amount of water absorbed after seven days exposure to different conditions of relative humidity. Fig. 1: Hygroscopicity of the Kollidon CL-grades
Swelling and hydration properties One of the most important properties of the insoluble Kollidon CL-grades used as tablet disintegrants is their property to swell very fast and predictably without forming a gel. A number of methods are described in the literature for measuring swelling properties in aqueous media. The data for the swelling pressure shown in table 1 were measured with a powder mass of 0.3 g and a punch diameter of 25 mm. The swelling pressure of Kollidon CL powder in water is much higher than that one of Kollidon CL-M, Kollidon CL-SF and Kollidon CL-F. The pressure increase per time depends on the particle size distribution and is highest for Kollidon CL, followed by Kollidon CL-F and Kollidon CL-SF. The relative high swelling pressure of Kollidon CL-M is achieved after a comparably long swelling time. Table 1: Swelling pressure [kpa] and time to reach 90% of the maximum swelling pressure [s] of the insoluble Kollidon grades (typical values) VJ eve! varus] Kollidon Kollidon Kollidon Kollidon CL CL-F CL-SF CL-M Swelling pressure, kPa approx. 170 approx. 30 approx. 25 approx. 70 Time to reach 90% of <10 <15 <35 > 100 the maximum swelling pressure, S Swelling can also be measured in terms of the adsorption of water, or hydration. It is determined as follows: Weigh 2.0 g of Kollidon CL into a 100 ml centrifuge tube, add 40 ml of water and shake vigorously until the powder is suspended. Re-suspend after 5 and again after 10 minutes. Then centrifuge for 15 minutes at 2000 rpm. Decant the supernatant liquid, then weigh again. The hydration capacity is calculated as the quotient of the weight after hydration and the initial weight. The hydration capacity is shown in Table 2. Table 2: Hydration capacity of the insoluble Kollidon grades (typical values) Kollidon Kollidon Kollidon Kollidon CL CL-F CL-SF CL-M g water/g polymer 3.5 -5.5 5.0 - 6.6 7.0-8.5 3.0-4.5 Particle size distribution (PSD) The particle size distribution of the solid ingredients must be taken into account when formulating tablets, particularly if they are to be made by direct compression. The following table gives some typical values for particle size distributions, determined using an air jet sieve after 5 min at 20 mbar: Table 3: Particle sizes of the insoluble Kollidon grades (typical values) Kollidon Kollidon Kollidon Kollidon CL CL-F CL-SF CL-M <15 um - - - = 90% >50 um max. 80% max. 60% max. 30% = >100 um max. 60% max. 20% max. 10% a For the determination of the PSD of Kollidon CL-M laser diffraction is applied.
Bulk density, tap density Table 4 gives typical values for the bulk and tap densities after 500 taps of the insoluble Kollidon grades. One of the major differences between Kollidon CL and Kollidon CL-M lies in their bulk densities, and this affects their applications. Table 4: Bulk and tap densities of the insoluble Kollidon grades (typical values) Bulk density Tap density (500 taps) Kollidon CL 0.30 - 0.40 g/ml 0.40 0.50 g/ml Kollidon CL-F 0.18 - 0.28 g/ml 0.25 0.35 g/ml Kollidon CL-SF 0.10 -0.16 g/ml 0.18 - 0.25 g/ml Kollidon CL-M 0.15 - 0.25 g/ml 0.25 - 0.35 g/ml Specific surface area The insoluble grades of Kollidon have different specific surface areas, as can be seen from Table 5. Table 5: Specific surface areas of the insoluble Kollidon grades determined according to DIN 66131-132 (typical values) GClCrnea aCCOoraing lO VIN OD lol loe (lypiCdl Values) Product Specific surface area (N2-BET) Kollidon CL <1 m%/g Kollidon CL-F approx. 1.5 m/g Kollidon CL-SF approx. 3 m/g Kollidon CL-M >6 m/g Complex formation Like the soluble grades of Kollidon, the insoluble Kollidon CL-grades form chemica complexes or associates with a large number of drugs and other substances. The formation of the complexes is reversible and no complex formation occurs in alkaline medium. Whether Crospovidone in general forms a complex with a drug depends very much on its chemical structure. Systematic investigations have shown that complexes are formed much more readily with aromatic compounds that contain phenyl and/or carboxyl groups. For most of the drugs that form complexes with Kollidon CL-grades, the degree of complex formation is usually such that the dissolution rate of the drug is accelerated. The ability to form complexes has many uses in pharmaceuticals: to improve the dissolution and bioavailability of drugs, to adsorb and remove polyphenols and tannins from tinctures and herbal extracts and to improve the taste of azithromycin, paracetamol and vitamins.
Infrared spectrum The insoluble Kollidon polymers are mainly physically crosslinked. No differenc: can be seen between the infrared spectra of Kollidon CL (Fig. 2 a) and that o povidone (Kollidon 90 F, Fig. 2 b). Fig. 2 a: Infrared spectrum of Kollidon CL in KBr Fig. 2 b: Infrared spectrum of Kollidon 90 F in KBr
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application General The insoluble Kollidon CL-grades possess a number of useful properties for pharma- ceutical products. Table 6: Functionalities of Kollidon CL, Kollidon CL-F, Kollidon CL-SF and Kollidon CL-M in pharmaceuticals Improvement of tablet disintegration through predictable swelling without gel- formation Swelling properties paired with particle size distribution make the fine Kollidon CL-grades work efficiently in fast disintegrating formulations Narrow particle size distributions in conjunction with a high swelling pressure recommends Kollidon CL-SF as disintegrant for small tablets with low API- concentrations In contrast to other disintegrants the Kollidon grades improve the release and the bioavailability of drugs through complex formation Kollidon grades feature selective adsorption of polyphenols by complex formation Kollidon grades feature selective complex formation with some endotoxins As a hydrophilic polymer Kollidon CL-M stabilizes suspensions Due to its water adsorption properties Kollidon grades act as stabilizers of water sensitive compounds in sold dosage forms, e.g. in vitamin formulations Detailed descriptions of the applications can be found in the books, Polyvinyl- pyrrolidone-Excipients for Pharmaceuticals, published by Springer-Verlag, ISBN 3-540 23412-8 or Kollidon, Polyvinylpyrrolidone for the pharmaceutical industry, published by BASF. Tablet disintegration and dissolution (Kollidon CL, Kollidon CL-F or Kollidon CL-SF) Today Crospovidone is described in the literature as one of the three superdisin- tegrants. A large number of papers have been published that substantiate this in comparisons of the various disintegrants in placebo and active tablets. They come to the conclusion that there is no universal ideal disintegrant and that the best dis- integrant must be determined individually for each application. The usual quantity of Kollidon CL, Kollidon CL-F and Kollidon CL-SF used is a range of 2 8%, as a proportion of the tablet weight. The following formulation for an analgesic tablet has been selected for testing and comparing disintegrants, pro- perties.
Table 7: Comparison of disintegrants in an analgesic tablet 1 Composition Paracetamol cryst. 250 mg Acetylsalicylic acid cryst. 250 mg Caffeine cryst. 50 mg Il Kollidon 30 (dissolved in water) 27.5 mg lll Magnesium stearate 5 mg Disintegrant 16 mg Total tablet weight 598.5 mg Granulate with Il, dry sieve, mix with Ill and compress into tablets. 2 Disintegration times of the tablets (in synthetic gastric juice) Disintegrant Minutes None >70 Kollidon CL 9 Kollidon CL-F 11 Kollidon CL-SF 9 Croscarmellose 24 Sodium carboxy methyl starch 34 Although the disintegration time of a tablet is important, the dissolution rate of the active ingredient is just as important in assessing and comparing disintegrants. To demonstrate this effect, Table 8 below shows the formulation and physical pro- perties of an acetylsalicylic acid tablet that has a very poor dissolution rate withou a disintegrant (Fig. 3). Table 8: Acetylsalicylic acid tablets with different disintegrants (direct compression) (direct compression) 4 Composition Acetylsalicylic acid cryst. 400 g Ludipress 99g Stearic acid 1g Disintegrant 15g 2 Properties (Laboratory rotary tablet press, compression force 8 kN) Without Kollidon Cros- Sodium carboxy- disintegrant CL carmellose methyl starch Weight 503 mg 516mg 522mg 540 mg Hardness 95N 90 N 84N 89 N Disintegration time 22 min 30s 48s 50s (gastric juice) Friability 0.4% 0.4% 0.3% 0.3% Dissolution (USP) see Fig. 3 Sp Eee ee ee 4 Composition Acetylsalicylic acid cryst. 400 g Ludipress 99 g Stearic acid 1g Disintegrant 15g 2 Properties (Laboratory rotary tablet press, compression force 8 kN) & FIOPCrues (LaVOrdalory rOtaly laVICl PIGso, COMIPessiOl lOrece KIN) Without Kollidon Cros- Sodium carboxy- disintegrant CL carmellose methyl starch Weight 503 mg 516mg 522mg 540 mg Hardness 95N 90 N 84N 89 N Disintegration time 22 min 30s 48s 50s (gastric juice) Friability 0.4% 0.4% 0.3% 0.3% Dissolution (USP) see Fig. 3
Fig. 3: Dissolution of the acetylsalicylic acid tablets described in Table 8 (USP method): Rating 1 Smooth 2 small unevenness on the tablet surface 3 small unevenness, rough tablet surface 4 remarkable unevenness, formation of pimples begins 5 slight formation of pimples 6 medium formation of pimples 7 strong formation of pimples 8 strong formation of pimples/tablet fragile and swollen 1 Smooth Storage conditions 23 C, 65% r.h. Disintegrant 65% rel. humidity 65% rel. humidity 65% rel. humidity after 1 day after 3 days after 7 days Kollidon CL 5 5 5 Kollidon CL-SF 2 2 2 Kollidon CL-F 3 4-5 4-5 Kollidon CL-M 1 1 1 Croscarmellose 3 38 on Carboxymethy! 3 3 3 starch sodium
Storage conditions 23 C, 75% r.h. Disintegrant 75% rel. humidity 75% rel. humidity 75% rel. humidity after 1 day after 3 days after 7 days Kollidon CL 6 6 6 Kollidon CL-M 1 1 1 Kollidon CL-F 4 5 5 Kollidon CL-SF 2 3 4 Croscarmellose 3 oF gf Carboxymethyl 3-4 3-4 3 starch sodium tablets show light brown discoloration as of day 1. The color intensifies throughout storage. Moisture-proof packaging is therefore always recommended for tablets and capsules that contain the coarse Kollidon CL-grades. The disintegration effect of Kollidon CL-grades can be used to increase the bio- availability of the active constituent not only in tablets but also in suppositories. In a polyethylene glycol-based suppository, the addition of 1 - 10% of Kollidon CL-grades improve the dissolution rate of the active constituent. Coating Kollidon Cl-, Kollidon CL-F- or Kollidon CL-SF-con- taining tablet cores When tablet cores that contain Kollidon CL as a disintegrant are sugar or film coated, it is necessary to exercise care in selecting a suitable coating pan. This is particularly important if the coating suspension is water-based. In many cases, it is therefore recommended to subcoat the cores before applying the coating proper. A 10% solution of Kollidon VA 64 in isopropanol, ethanol or ethyl acetate provides a good subcoating. It can be sprayed briefly onto the prewarmed tablet cores in the same coating pan before the final aqueous coating is applied (see Technical Information Sheet, Kollidon VA 64). Stabilization of suspensions (Kollidon CL-M) Kollidon CL-M is a hydrophilic polymer that can be used in concentrations of 5 - 12% to physically stabilize oral and topical suspensions. It achieves this effect by increasing the volume of the sediment and reducing its sedimentation rate, and by making it easy to redisperse the sediment by shaking (anticaking effect), practically without increasing the viscosity of the preparation. These properties apply whether the final product is a ready-to-use suspension or an instant drink powder or granulate from which the patient prepares a suspensior before use. It has been found in practice that the increase in sediment volume achieved with Kollidon CL-M in such suspensions can be further enhanced by adding auxiliaries such as sodium citrate as an electrolyte, sugar, Kolliphor P407 or one of the soluble grades of Kollidon, such as Kollidon 90 F. Table 9 presents a formulation for an antibiotic dry syrup as an example of the use of Kollidon CL-M. The formulation has been developed in the laboratory for a number of different active ingredients and can therefore be regarded as a typical standard formulation. Citric acid has been included to give a pH value of 4.9, at which the two active ingredients, ampicillin and amoxicillin trinydrate are most stable in this administration form.
Table 9: Antibiotic dry syrup for children, with Kollidon CL-M Formulation (sales product) Ampicillin or amoxicillin trinydrate 5.0g Sodium citrate 5.0g Citric acid 21g Sodium gluconate 5.0g Sorbitol 40.0 g Kollidon CL-M 6.0g Orange flavouring 1.59 Lime flavouring 0.59 Saccharin sodium 0.4g ce A DOGR. cecsosraisscrore Pincers bec stsee vseoa ti Drink containing 250 mg of active substance per 5 ml: Shake 66 g of the powder mixture with water to give a total volume of 100 ml. Sedimentation is very slow and any sediment that does form can very readily be redispersed even after several weeks. The main applications for Kollidon CL-M are in instant drink granules, ready-to-use suspensions or dry syrups that contain the following types of active ingredient: suspensions or ary syrups that contain the following types of active Ingredient: antibiotics antacids vitamins e analgesics. SN Se ea OSS RE ee a ee > antibiotics > antacids > vitamins > analgesics. A notable property of Kollidon CL-M in suspensions is that, in concentrations of 5 - 10%, it hardly increases the viscosity of the suspension. Kollidon CL-M has also been found to stabilize suspensions in lipophilic mediz such as liquid paraffin. Stabilization of vitamins (Kollidon CL-grades) As with the soluble grades of Kollidon, Kollidon CL-grades are also able to stabilize active ingredients in pharmaceutical products. A typical example is provided by a multivitamin instant drink granulate. The stability of the vitamins in a formulation pre- pared in the laboratory was found to be almost ideal. The effect of Kollidon CL-M on vitamin B1, calcium pantothenate and vitamin C was demonstrated in an accelerated storage test (Table 10). Table 10: Vitamin degradation in multivitamin instant drink granules with and without Kollidon CL-M (30 C/70% relative humidity) Bees eh ce 1 month 2months 3months 5 months Vitamin B,: Without Kollidon CL-M 4% 11% 16% 26% With Kollidon CL-M 0% 1% 7% 10% Vitamin C: Without Kollidon CL-M 17% 18% 40% 49% With Kollidon CL-M 0% 2% 13% 19% Ca-Pantothenate: Without Kollidon CL-M - 8% 21% 50% With Kollidon CL-M = 10% 10% 15%
Improvement of dissolution/bioavailability As with the soluble Kollidon grades, Kollidon CL-grades are capable of forming complexes with active substances and increasing their dissolution rate and bio- availability. Different mixing methods can be used: AVGIADILY., WINE MMAIIG TeUlOOs Call US UsSeO. physical mixture with the active ingredient comilling with the active ingredient coevaporation of a suspension of Kollidon CL in a solution of the active ingredient. All published papers on investigations into the crystalline structure of preparations made by these methods have found that the active ingredient has a stable amorphous forrr and that the dissolution rate and/or the bioavailability is increased. For comilling, Kollidon CL-M or Kollidon CL-SF are preferable to Kollidon CL or Kollidon CL-F, which are coarser. The quantity of Kollidon CL-grades required for this purpose is about 1- to 10-fold the quantity of the active ingredient. In principle, it can be assumed that all active substances whose dissolution rate can be improved with polyvidone (e. g. Kollidon 30) can benefit in the same way from the insoluble Kollidon CL-grades. Absorptive polymer (Kollidon CL) The ability of Crospovidone to form stable complexes with various polyphenols car be used not only in the beverage technology for the stabilization of beer but also in the purification of aqueous or alcoholic herbal extracts and tinctures. Polyphenols are selectively bound by the Kollidon CL-grades which can therefore be used to improve the stability of such phytopharmaceuticals. The Kollidon CL-grades can either be suspended in the extract then filtered off after a certain time, or the extract can be slowly percolated through a bed of Kollidon CL- grades. Under caustic conditions absorbed polyphenols can be released from the polymer and recovered if desired. 5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technic representative. Please refer to Quality & Regulatory Product Information (QRP)). 9. Toxicological data For information on toxicological issues please refer to the tox abstract which car be supplied on request. More/detailed toxicological information for Kollidon grades is available on request under Secrecy Agreement.
10. PRD and Article numbers 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30034964 Kollidon CL 50000695 40 kg Plastic drum 50347948 0.5 kg Plastic pail 30274401 Kollidon CL-F 53216545 30 kg Plastic drums 50539226 0.25 kg Plastic pail 30274400 _ Kollidon CL-SF 52595650 30 kg Plastic drums 50348145 0.25 kg Plastic pail 30444355 Kollidon CL-M Origin Germany 51928647 30 kg Plastic drums 50348144 0.25 kg Plastic pail BASFs commercial product number. Corresponding product sample 11. Publications http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Poloxamer Ph. Eur., Poloxamer USP/NF, Polyoxyethylene (160) Polyoxypropylene (30) Glycol JPE Poloxamer Ph. Eur., Poloxamer USP/NF, Polyoxyethylene (160) Polyoxypropylene (30) Glycol JPE Poloxamer for Pharmaceutical Use June 2021 DAWF-2021-0779 = Registered trademark of BASF in many countries.
1. Introduction Surface Tension BASFs Kolliphor P grade poloxamers are white, coarse - grained powders with a waxy consistency. They contain an appropriate quantity of the antioxidant BHT. The static surface tension measured by the pendant drop method at 37 C stabilizes after ca. 2 g/L. Poloxamers are ABA-type co-polymers of poly (ethylene oxide) (PEO=A) and poly (propylene oxide) (PPO=B). The approximate relative amount of PEO and the average molecular weight of the PPO are indicated in the name of the poloxamer. For example, P 188 succeeding the word Kolliphor indicates a poloxamer with ca. 80% m/m PEO (P 188; 8x10= 70%) and approximately average molecular weight of PPO of 1800 (P 188; 18x100= 1800). Kolliphor P 188 Bio is designed for protection against shear stress in biologic drug manufacturing processes. It is also suitable as an excipient for parenteral formulations. Improvements in the manufacturing process and a validated RP-HPLC assay ensures the highest quality product for consistent performance and less variability versus other poloxamer 188 grades. 2. Technical properties Structural formula The Kolliphor P 188 Bio is a block copolymer that is a synthetic copolymer of ethylene oxide and propylene oxide represented by the following chemical structure: Figure 2: Surface tension as a function of concentratior Molecular Weight The average molecular weight for Kolliphor P 188 Bio is 7680 to 9510 g/mol. The product contains nominally 75 to 85 ethylene oxide units split between the two chains and 25 to 30 propylene oxide units, with a rough concentration of oxyethylene of 79.9 to 83.7 % based on the current monograph specification. An example of the molecular weight distribution for Kolliphor P 188 Bio is shown below in Figure 3. Where in a and b blocks have the following values: Kolliphor Poloxamer Kolliphor P 188 Bio 188 80 27 Ire 3: Size Exclusion Chromatogram of Kolliphor P188 Bio The above graph was generated using size exclusion chromatography (SEC), note that the smaller peak to the left represents diblock polymers. Solubility in water at 25 C measured gravimetrically is between 35-45 wt.%.
The micelle size is approximately 5 - 10 nm in diameter; this is shown in Figure 6 as determined via laser diffraction: Viscosity Poloxamers, and Kolliphor P 188 Bio exhibits a thermoreversible gelling behavior that occurs as a function of temperature. At low concentrations, aqueous concentrations exhibit Newtonian flow properties and negligible viscosity alterations to that of water, however, at higher temperatures, the solutions begin to exhibit non- Newtonian flow behavior. An example of the viscosity curve is evident in Figure 4 with the gel points clearly noted by the sharp increase in viscosity: Figure 6: Micelle size as measured by laser diffraction Particle Size Kolliphor P 188 Bio exhibits spherical prill particles of a mean diameter of approximately 500 uum in size. An example of the size and morphology of these particles is shown in the scanning electron microscope image (SEM). Figure 4: Viscosity changes of Kolliphor P188 Bio solutions as function of temperature HLB The HLB value of Kolliphor P 188 Bio is approximately 29. The HLB value of Kolliphor P 188 Bio is approximately 29 Critical Micelle Concentration (CMC) The critical micelle concentration for Kolliphor P 188 Bio is ca. 4.8 - 10% mol/L @ 37 C (4.1 g/L). Note that the CMC value decreases significantly as the temperature increases. Furthermore, due to the linear structure of the poloxamer, the value is difficult to ascertain as an inflection point using standard methods (such as Wilhelmy Plate Method). An example of the surface tension for Kolliphor P 188 Bio as a function of concentration at 37 C is shown in Figure 5. A closer image of the particles is shown below at a higher magnification: Figure 7: SEM images of Kolliphor P188 Bio Cloud point The cloud point for Kolliphor P 188 Bio is >100C for a 1% and a 10% aqueous solution. Density The bulk density of Kolliphor P 188 Bio is approximately 0.56 g/cm Figure 5: Surface tension as function of concentration
5. Safety data sheet Moisture sorption Safety data sheets are available on request and are sent with every consignment. The uptake of moisture for Kolliphor P 188 Bio is dependent on the relative humidity of the environment, at moisture levels above 80% (RH) significant moisture uptake is possible and shown in Figure 8. 36 months when stored in tightly closed containers at ambient conditions. Please refer to Quality & Regulatory Product Information (QRP)) for further details. 7. Stability Please refer to Quality & Regulatory Product Information (QRP)). 8. Toxicological data The toxicological abstract is available on request. 9. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30631540 Kolliphor P 188 Bio 50424596 0.5 kg Plastic bottle 50519572 25 kg Plastic drums 50519573 50519927 102 kg Plastic drums 12.5 kg Platic pail 50519924 5 kg Plastic pail OU0S1OSU FRONIPNOr 100 DIO DYUS2549OI0 VY. KY PidslG DOWE 50519572 25 kg Plastic drums 50519573 102 kg Plastic drums 50519927 12.5 kg Platic pail 50519924 5 kg Plastic pail 10. Publications BASFs commercial product number. http://pharmaceutical.basf.com/en.html Disclaimer This document, or any answers or information provided herein by BASF, does no constitute a legally binding obligation of BASF. While the descriptions, designs, date and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affec processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upor delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBEL OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED / PART OF OUR TERMS AND CONDITIONS OF SALE. June 2021 BASFs commercial product number. Figure 8: Moisture uptake as a function of relative humidity BHT Kolliphor P 188 Bio utilizes 50 - 125 ppm BHT as an antioxidant this protects the quality and performance of the P 188 in the litany of pharmaceutical applications. The primary degradation mechanism is oxidation, and is typically monitored via the pH, hydroxyl value and molecular weight of the poloxamer. 3. Handling Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application aimer This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. Three indipendent lots of Kolliphor P 188 Bio were tested. RP-HPLC assay shows no hydrophobic peak at retention time of 4 mL (left). The cell culture assay shows cumulative CHO cell count on day four as exepted for lots with good performance BASF Nutrition & Health - www.pharma-ingredients.basf.com
Table of Contents Introduction 6 Ibuprofen 8 Chemical information . wl Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality .. 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Chemical information 20 Product information 20 Chemical and physical properties 21 Particle characterization 21 Regulatory status 21 Specification 21 Medical indication 22 Ibuprofen Sodium Dihydrate 24 Chemical information 24 Product information 24 Storage 25 Regulatory status 25 Specification 25 Medical indication 26 Table of Contents Introduction Ibuprofen 8 Chemical information 8 Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Ibuprofen Racemic Ibuprofen Lysinate (RIBL) Ibuprofen Sodium Dihydrate Ibuprofen Sodium Dihydrate
Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, antipyretic and anti-inflammatory actions, it is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever. Due to its analgesic, antipyretic and anti-inflammatory actions, it is used The common active ingredient dosage in tablets is 200, 400, 600 and 800 mg. The OTC dosage forms are mainly the 200 and 400 mg forms (except for the United States and some other countries, where the 200 mg form is the only OTC form). Other common dosage forms are capsules, syrups, suspensions, suppositories, and topical dosage forms like creams and gels. Pharmacokinetics Orally administered ibuprofen is absorbed rapidly in the Gl tract.? After a single oral dose on an empty stomach, peak plasma levels are reached within 45 to 90 minutes and the apparent plasma volume of distribution is reported to be between 0.1 to 0.2 I/kg.-> Ibuprofen has an extensive protein binding capacity (+98%) and is excreted via the kidneys. The biological half-life is between 2 and 4 hours.? After 24 h, 100% of the active substance is excreted in the urine.
Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as histamine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C. bata Te Ta Tort) U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Gillespie, W. R. et al., Relative Bioavailability of Commercially Available Ibuprofen Oral Dosage Forms in Humans, Journal of Pharmaceutical Sciences, 71:1034-1038, 1982. Verbeeck, R. K., Pathophysiologic Factors Affecting the Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs, Journal of Rheumatology, 15:44-57, 1988. Jamali, F. and D. R. Brocks, Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers, Clinical Pharmacokinetics, 19:197-217, 1990. Vowles, D. T. and B. Marchant, Protein Binding of Ibuprofen and Its Relationship to Drug Interactions, British Journal of Clinical Practice, 1:13-19, 1980. Whitlam, J. B. and K. F. Brown, Ultrafiltration in Serum Protein Binding Determinations, Journal of Pharmaceutical Science: Tio Teel atc oa Rudy, A. C. et al., Stereoselective Metabolism of Ibuprofen in Humans: Administration of R-, S- and Racemic Ibuprofen, Journal of Pharmacology and Experimental Therapeutics, 259:1133-1139, 1991. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(6): 986-1000, 2011.
Ibuprofen (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid Chemical name (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid 15687-27-1 239-784-6 C,,H,,0. 13) 182 206.28 g/mol CAS number EINECS number Molecular formula Molecular weight 3ASF offers 4 grades based on different particle size distributions (see particle charac- erization). Furthermore, a direct compressible grade is offered: Ibuprofen DC 85 W, the somposition of which can be found in chemical and physical properties section below. Product grades (+)-2-[4-(2-methylpropyl)phenyl]propanoic acid; (+)-Benzeneacetic acid, alpha-methyl- 4-(2-methylpropy)); (+)-p-lsobutylhydratropic acid; (+)-2-p-lsobutylphenylpropionic acid Ibuprofen meets the current Ph. Eur., USP, JP and IP monographs. DMFs and CEP are available upon request. Regulatory status Ibuprofen is the racemate of (+)-lbuprofen and (-)-lbuprofen (optical rotation = 0). According to the literature the pharmacologically active form is (+)-lbuprofen. Approximately 30 to 70% of the (-)-lbuprofen is converted to the active form (+)-lbuprofen in the body. This process proceeds solely from the (-)- form to the (+)- form.
Chemical and physical properties Ibuprofen grades 25, 38, 50, 70 Crystalline powder Solubility in phosphate buffer pH 7.2 (37 C) Partition coefficient n-octanol/water The chemical parameters of all pure ibuprofen powder grades are identical. The only difference is the particle size distribution (see particle characteristics).
Particle characterization Ibuprofen 25 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 25 is between 20 um and 33 pm. Ibuprofen 50 Particle Size Distribution Bulk density Tapped density An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 50 is between 45 um and 60 pm. Approximately 0.34 g/ml. Approximately 0.60 g/ml.
Ibuprofen 38 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 38 is between 33 um and 45 pm. ibuprofen 70 Particle Size Distribution Bulk density Approximately 0.38 g/ml. Tapped density Approximately 0.68 g/ml. An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 70 is between 60 pm and 85 pm.
Ibuprofen DC 85 W The ibuprofen used to manufacture Ibuprofen DC 85 W meets the current Ph. Eur., USP, JP and IP monographs. A Technical Package and a US-DMF are available upon request. Granules, free flowing, homogeneous material Appearance SEM photograph
Recommendation for direct compression Today the manufacturing of ibuprofen tablets is often done by direct compression. Using this method, the expensive and time-consuming wet granulation method can be avoided. But in general, ibuprofen has the disadvantage of sticking on the tablet tools so that the process must be interrupted often. Therefore, direct compression formulations with a high content of ibuprofen per tablet are often avoided. Mostly tablets with an ibuprofen content of maximum 60% are compressed. BASF offers a formulated ibuprofen product ideal for direct compression: Ibuprofen DC 85 W. The direct compression (DC) grade ensures that tablet sticking is minimized and allows for excellent tablet engraving. Furthermore, Ibuprofen DC 85 W has a lower angle of repose compared to standard grades, resulting in improved flowability.
General information on processing of Ibuprofen Ibuprofen is used mainly in three (3) different dosage forms: Ibuprofen 50, Ibuprofen 70, Ibuprofen DC 85 W (for direct compression) Recommended grade(s) High concentrations of magnesium stearate as a lubricant are not recommended. For direct compression, the ready-to-use Ibuprofen DC 85 W reduces sticking. For a film coating, Kollicoat IR has a reduced viscosity in aqueous solutions compared to HPMC suspensions, which leads to higher solids content and a faster coating process. Formulation guidance Creams & Gels Recommended grade(s) Recommended grade(s) To stabilize against sedimen- tation, fine particles should be used. The pH of the sus- pension should be in the acid range so that ibuprofen is undissolved, which will reduce bitter taste if any. lbuprofen is dissolved in the ipophilic phase of creams, thus there is no impact of particle size. Propylene glycol or low molecular weight polyethylene glycols are recommended as the oily component. Formulation guidance Formulation guidance
-oomLab - Your Virtual Formulation Assistant Access example formulations and build your own ZoomLab Formulation Wizard identifies suitable excipients and calculates potential formulations depending on the selected dosage form, defined target profile, and properties of the active ingredient. Example formulations include creams, tablets, and more! - Evaluate bioequivalence of your final formulation A WHO biowaiver monograph is available for ibuprofen. The ZoomLab dissolution module can be used to calculate difference and similarity factors (f1, f2) required for showing bioequivalence. ZoomLab provides values for parameters relating to particle size, powder density, flowability, and tabletability. The parameters are scaled from 0 to 10, a risk analysis is run, and an interpretation of results/formulation advice is provided.
Example formulations Production of granules for 200, 400, 600 and 800 mg forms The following ingredients are placed in a high shear mixer and granulated with water: Ibuprofen 50 60.1% w/w Amount of water: approximately 0.2 kg water per 1 kg __ ibuprofen. Wet sieving (4 mm) and drying in a fluid bed Lactose 18% w/w granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following Corn starch 9% w/w additives to form granules suitable for tableting. Kollicoat IR 3.6% w/w Extra granular material Avicel PH 102 3.6% w/w AcDiSol 4.8% w/w Magnesium stearate 0.6% w/w Aerosil 200 0.3% w/w Coating formulations for Ibuprofen tablets oes Fraction with reference to the Fraction with reference Composition atomised suspension [%] to the dry film [%] Polymer Kollicoat IR 16.0 64 Pigments Talc 6.0 24 Sicovit Red 30 3.0 12 Total 25 100 Amount of water: approximately 0.2 kg water per 1 kg ibuprofen. Wet sieving (4 mm) and drying in a fluid bed granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following additives to form granules suitable for tableting. Corn starch Kollicoat IR Extra granular material Magnesium stearate Coating formulations for Ibuprofen tablets

Handling & Safety Product specification The current version of the product specification is avail- able on RegXcellence or from your local BASF sales representative. Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on MyProduct- World or from your local BASF sales representative. Publications Regulatory & Quality Publications including scientific posters are available on: Please refer to the individual document quality & regu- latory product information (QRPI) which is available on RegXcellence and from your local sales representative The QRPI covers all relevant information including retest dates and storage conditions.
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Racemic Ibuprofen Lysinate (RIBL Racemic Ibuprofen Lysinate (RIBL Chemical information Chemical information Ibuprofen Lysinate (+) (+)- (+ (+ -2-[4-(2-methylpropyl)phenyl]propanoic acid lysinate -Benzeneacetic acid, alpha-methyl-4-(2-methylpropyl) lysinate -p-lsobutylhydratropic acid lysinate -2-p-lsobutylphenylpropionic acid lysinate Empirical formula Molecular weight
Chemical and physical properties White to almost white, very fine crystalline powder witt a high volume. In the literature the solubility of Ibuprofen (acid) in distilled water is reported to be less than 0.1%. The solubility of Ibuprofen Lysinate is 1:5, or about 17%. Particle characterization An example particle size distribution is shown below. The median particle size for RIBL is approximately 10 pm Regulatory status No monographs exist. E-DMF is available upon request.
The term RIBL is the acronym for Racemic Ibuprofen Lysinate. Racemic signifies that the ibuprofen drug substance and the lysine anion are both racemic compounds. RIBL differs from the common ibuprofen acid, gen- erally referred to as ibuprofen, in that it is more rapidly absorbed from the intestinal tract and reaches peak plasma levels and t,,., more quickly. After absorption, RIBL is available in the form of pure ibuprofen acid and is therefore to be handled like ibuprofen. Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, anti- pyretic and anti-inflammatory effects, ibuprofen is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever.? For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. Pharmacokinetics RIBL is readily and quickly absorbed from the gastrointestinal tract.!? The peak plasma level of the free acid is reached within 30 to 60 min (with the free acid ibuprofen, t,,,, was measured between 60 and 120 minutes, depending on the dosage form).: After absorption, there is no difference between RIBL and the free acid.
From a pharmacological point of view, there is no difference between RIBL and the free ibuprofen acid because it is the free acid and not the RIBL salt that is the active form. The mode of action of ibuprofen, while not completely understood, is believed to involve reversible inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have among other properties a powerful effect on the smooth muscles. In case of inflammatory stimuli or blood flow disorders, PGs are synthesized in increased amounts, making the tissues sensitive to the action of other agents such as histamine and kinins. As a result, symptoms like pain and inflammation occur. The in- cidence of fever is raised by the influence of the PGs on the heat regulation center in the hypothalamus. There they scale up the normal set point of 37 C. bats CUe Ta Tort) 1 Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration of Ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990. Hermann, T. W. et al., Bioavailability of Racemic Ibuprofen and its Lysinate from Suppositories in Rabbits, Journal of Pharmaceutical Sciences, 82(11):1102-1111, 1993. U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Neupert, W. et al., Effects of lbuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(5): 986-1000, 2011. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration o ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990.
Ibuprofen Sodium Dihydrate Chemical information Ibuprofen Sodium Dihydrate 2-(4-isobutylphenyl)-propionate sodium dihydrate Chemical name Se IS ee ee ee a en re ae ee ee 31121-93-4 C,,H,,0,Na x 2 H,O 228.26 + 36.03 g/mol Empirical formula Molecular weight
Storage Ibuprofen Sodium Dihydrate should be stored in the original, tightly sealed container. It should be placed ina well-ventilated room at ambient temperature and protected from light. The retest period of Ibuprofen Sodium Dihydrate is 60 months for material stored in the original, unopened containe! and according to our recommendations. Regulatory status Currently there are no monographs describing Ibuprofen Sodium Dihydrate in the major Pharmacopoeias (USP, Ph. Eur.. and JP).
According to the literature, ibuprofen sodium dihydrate dissolves more quickly in vitro and is absorbed into blood plasma more quickly than con- ventional ibuprofen, whereas tolerability and safety profiles of the two APIs are comparable.? In an investigation of the dissolution, plasma pharmacokinetics, and safety of ibuprofen sodium dihydrate versus conventional ibuprofen, the following results were reported:? @ buprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 compared to conventional ibuprofen. @ lbuprofen sodium dihydrate reached the t,,,, significantly earlier than conventional ibuprofen. @ lbuprofen sodium dihydrate showed significantly higher c_, compared to conventional ibuprofen. @ buprofen sodium dihydrate was characterized by significantly higher mean plasma concentration (10 min post-dose) compared to conventional ibuprofen. tax iS the necessary time until the maximum plasma concentration of a drug is reached; this is relevant for the drug onset. Generally, reaching the t_ early is of great advantage for analgesic treatment. According to the literature, the first signs of pain relief occurred significantly earlier in ibuprofen sodium dihydrate treated patients, and pain intensity was reduced to half after 30 min for ibuprofen sodium dihydrate compared to 57 min for conventional ibuprofen. In summary, ibuprofen sodium dihydrate causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen.
The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (CO)) which is responsible for the biosynthesis of prostaglandin (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflamma- tory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as hista- mine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C.? c Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandii Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vas FeYToltote CHI (2) Rc) =\ coal O00 Soergel, F. et al. Pharmacokinetics of Ibuprofen Sodium Dihydrate and Gastrointestinal Tolerability of Short-Term Treatment with a Novel, Rapidly Absorbed Formulation, International Journal of Clinical Pharmacology and Therapeutics. 43(8):140-149, 2005. Schleier, P. et al., Ibuprofen Sodium Dihydrate, an Ibuprofen Formulation with Improved Absorption Characteristics, Provides Faster and Greater Pain Relief than Ibuprofen Acid, International Journal of Clinical Pharmacoloay and Therapeutics. 45(2):89-97. 2007. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandir Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997.
www.pharma.basf.com For sample requests contact us ai pharma-solutions@basf.com Meet your Virtual Pharma Assistants! ZoomLab, RegXcellence, and MyProductWorld, your interactive guides for optimizing drug formulations, navigating quality and regulatory compliance, and browsing ingredients. Learn more and sign up at https://info-mypharma.basf.com/ Inspiring Medicines for Better Lives This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been preparec in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to the extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2021 BASF Corporation. All Rights Reserved.
Technical Information Omega-3 acid triglycerides (Ph.Eur., 1352) September 2021 DAWF-2020-0732 = Registered trademark of BASF in many countries.
1. Introduction CN 600 TG is an Omega-3-acid triglyceride oil comprised of minimum 60% omega-< acids and minimum 45% of the primary omega-3 acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA). CN 600 TG meets the standards to be used as ingredient in formulated and sterilized clinical nutrition products to be given by parenteral administration. The product complies with the following compendial names (please refer to the quality & regulatory product information for details): e Omega-3-acid triglycerides (Ph.Eur. 1352) 2. Technical properties Description CN 600 TG is a clear, pale yellow liquid oil. It is practically insoluble in water, very soluble in acetone and in heptane, and slightly soluble in ethanol. The product is a hydrophobic solution, not soluble in water so pH is not applicable. 3. Medical information Therapeutic indication CN 600 TG is intended for use in preparations for parenteral nutrition supplementation with long chain omega-3-fatty acids, especially EPA and DHA, when oral or enteral administration way for nutrition is impossible, insufficient or contraindicated. Pharmacokinetics The distribution of Omega-s fatty acids after parenteral administration will depend upon the specific formulation. The intrinsic pharmacokinetic properties of Omega-c fatty acids are similar to other fats regarding distribution, metabolism and elimination. Following distribution after parenteral administration, there are three main pathways for the metabolism of the omega-3 fatty acids: - The fatty acids are first transported to the liver where they are incorporated into various categories of lipoproteins and then channeled to the peripheral lipid stores; The cell membrane phospholipids are replaced by lipoprotein phospholipids and the fatty acids can then act as precursors for various eicosanoids; The majority is oxidized to meet energy requirements. The concentration of omega-3 acids, EPA and DHA, in the plasma phospholipids corresponds to the EPA and DHA incorporated into the cell membranes. Pharmacodynamics The omega-s fatty acids are essential fatty acids, i.e. they cannot be synthesized in the body, and need to be provided via dietary or other intake. The omega-3 fatty acids EPA and DHA provide numerous health benefits. CN 600 TG contains these essential fatty acids in the form of triglycerides. CN 600 TG is constituted mainly of the two main Omega-s fatty acids; EPA and DHA. EPA and DHA are used as a source of energy, incorporated into tissue lipids, ot used in eicosanoid synthesis. DHA is a component of membrane structural lipids, especially of phospholipids in the nervous tissue and the retina. EPA can be transformed to eicosanoids, group of biologically active substances including prostaglandins, prostacyclins anc leukotrienes which participate in the regulation of blood pressure, renal function, blood coagulation, inflammatory and immunological reactions and other functions in tissues. CN 600 TG is intended for use as active ingredient in parenteral nutrition formulations that shall undergo formulation and a final sterilization process before it is presented as a Finished Product for parenteral use. 4. Applications
5. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions or safe and proper handling and disposal. Material safety data sheets are sent with every consignment. When stored below 25 C and protected from freezing in its original container blanketec with nitrogen, the re-test period is 48 months. 6. Product specification The current version of the product specification is available from your local BASI sales representative. CN 600 TG complies with the European Pharmacopeia monograph for Omega-3 acid triglycerides (1352). A Certificate of Suitability (CEP) from EDQM is available CEP 2017-298. 8. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30607326 CN600TG 50380683 190 kg steel drum 50413334 28 kg steel drum 50380685 0.1 kg aluminum bottle 9. Publications Publications including scientific posters are available on http://omega3.basf.com This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information August 2019 Supersedes issue dated September 2015 Last change DAWF-2019-0893 = Registered trademark of BASF in many countries.
1. Introduction Soluplus is a polymeric solubilizer with an amphiphilic chemical structure, which was particularly developed for solid solutions. Due to its bifunctional character, it is able to act as a matrix polymer for solid solutions on the one hand, and, on the other hand, it is capable of solubilizing poorly soluble drugs in aqueous media. Furthermore, Soluplus can increase the bioavailability of poorly soluble drugs. Description Soluplus is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-poly- mer. It is a free flowing white to slightly yellowish granule with a faint characteristic odor. 2. Technical properties Structural formula PEG 6000 / vinylcaprolactam / vinyl acetate 13/57/30 Appearance White to yellowish free flowing granules CAS number CAS number 402932-23-4
Molecular weight The average molecular weight determined by gel permeation chromatography is approximately 118,000 g/mol (nominally in the range of 90 000 140 000 g/mol). A representative molecular weight distribution is shown in Figure 1. Figure 1: Gel Permeation Chromatography; Reference: PMMA Critical Micelle Concentration 7.6 mg/L (surface tension curve shown in Figure 2) Micelles are typically 70 to 100 nm in diameter (pH 7 buffer Figure 2 Approximately ~14 K-value 31-41 (1% in ethanol)
Solubility Soluplus is soluble in water. Furthermore, it is soluble in acetone (up to 50%), methanol (up to 45%), ethanol (up to 25%), dimethylformamide (up to 50%) and in mixtures of (1:1 m/m) methanol/ acetone (up to 50%) and (1:1 m/m) ethanol/acetone (up to 45%). Higher polymer concentration may result in a cloudy or turbid aqueous solution. This is due to formation of colloidal Soluplus micelles. Solubility of Soluplus in common solvents shown in Figure 3. Figure 3 This phenomenon is more pronounced at elevated temperature (~40 C), which is a lower critical solution temperature (LCST). Thus, when the polymer solution is heated at or above its LCST, a clear polymer solution turns cloudy or turbid due to formation of larger micelles. This process is reversible upon cooling the polymer solution. Soluplus is not soluble in medium-chain triglyceride Kollisolv? MCT and is not soluble in poloxamer grade Kollisolv P124. In Kollisolv? PEG 400 Soluplus is soluble up to 25% (w/w). The data shown in Figure 4 show the viscosity of a Soluplus-in-PEG 400 solution and are obtained at 60 C on a HAAKE Rotovisco with coaxial cylinder DG 43 and a plate-plate PP 60 geometry for a shear rate of 100 1/s. Figure 4: Viscosity of Soluplus-in-Kollisolv? PEG 400 solution
In Kollisolv PG (propylene glycol) Soluplus is soluble up to 2.5% (w/w). The data shown in Figure 5 show the viscosity of a Soluplus-in-PG solution and are obtainec at 60 C on a HAAKE Rotovisco with coaxial cylinder DG 48 and a plate-plate PP 6( geometry for a shear rate of 100 1/s. Figure 5: Viscosity of Soluplus-in-Propylene Glycole solution Solution Viscosity Viscosity of Soluplus is shown in Figure 6 at four distinct temperatures. Figure 6: Cone-plate viscosimeter, 100 s
Melt Viscosity The values shown in Figure 7 were obtained on a capillary rheometer. Figure 7 Specific Heat Capacity The following graph shows the specific heat capacity and the heat enthalpy for Soluplus in dependency from temperatur. Figure 8 Density The Density of Soluplus was determined at room temperature using a helium pycno- meter with 1.082 g/cm. Angle of Repose The angle of repose for Soluplus batch 21819647G0 was determined with the method according to Dr. Pfrengle with 27.5 .
Particle Size Soluplus Granulates are approximately 340 microns in diameter (determined by laser diffraction); images of the granules are shown in Figure 9. 3. Application and processing Solubilization A potential affinity between Soluplus and a poorly soluble drug can be pretested by means of various methods. The solubilization capacity of the amphiphilic polymer is tested by determination of the saturation solubility of a poorly soluble drug in a polymer solution. Phosphate buffer as solvent (e. g. DH 7.0) assures comparable conditions when testing ionic solubilizers or drugs. Thus, solubility effects due to PH shifts can be avoided.  A 10% polymer solution in phosphate buffer is oversaturated with a discrete drug and stirred for 72 h at room temperature. The resulting suspension is filtered through 0.45 um filter and the content of solubilized drug in the filtrate is determined by UV spectroscopy. Figure 10 shows the results of the solubility enhancement of Soluplus for various drugs in comparison to the API solubilities in phosphate buffer pH 7.0: Figure 10: Phosphate buffer 0H 7.0; 10% solubilizer solution, saturation solubility detected after 72h stirring
Capacity for Amorphous Solid Solutions Soluplus was designed for solubilizing high concentrations of poorly water-soluble APIs in amorphous solid dispersions (ASDs) these can be produced using a multitude of technologies including, but not limited to: Hot Melt Extrusion, Spray Drying, and Drug-Polymer Layering. In order to screen for effectiveness, the following procedure is recommended: Choose an appropriate solvent that dissolves the API and also Soluplus (e. g. ethanol, methanol, acetone, dimethylformamide). Dissolve both substances with gentle stirring, then cast the solution on a glass plate as a thin film. It is recommended to utilize a scraper that leads to a film of approximately 120 um. The thin film (thickness of the dry film < 120 um) enables fast drying and avoids a recrystallization of the poorly soluble drug. Subsequent drying should be performed in a vacuum drying cabinet (50 C, 10 mbar, 30 min) to ensure a fast and complete drying of the film. Test several concentration ratios of drug to polymer in incremental steps. (e. g. 20, 30, 40 and 50%). Samples should be viewed using polarized light (recommended) or optical microscopy; crystalline API should be visible in ranges beyond the solubility limit. This can be then used as a starting point for designing the formulation. Additional solubilizers (e.g. Kolliphor RH 40) or plasticizers (e.g. Kollisolv? PEG 1450) can also be incorporated into the solution to test the effect on the solid solution as desired. Hot Melt Extrusion Soluplus exhibits a glass transition temperature of approximately 70 C and is well extrudable within standard hot melt extrusion devices. As an example, in a standard 16mm twin-screw extruder, temperatures from 120 C to 220 C are possible. The polymer shows no chemical degradation even after extrusion at 220 C. Incorporation of a drug can lead to lower temperatures than 120 C in dependence on the drug melting point. The relatively low glass transition temperature for Soluplus allows for lower temperatures during extrusion processes, resulting in less thermal stress to APIs. A comparison of the Tg against other extrudable polymers is shown in Figure 11.
The ability to extrude Soluplus is further shown by observing the melt rheology of the polymer melt, which is shown to be comparatively low vs. well known extrudable polymers such as Kollidon VA 64. The comparison is shown in Figure 12. Figure 12: Rotary viscosimeter, plate-plate method, angular frequency: 1.6 rad/s A solid solution of Fenofibrate (melting point ~77 C) at 20% drug content was prepared as an example at 100 C. This was prepared using a twin screw co-rotating extruder with a 16 mm diameter at 200 rpm and 1 kg/h. In vitro release from USP II (50 rom, 700 mL 0.8 M HCl) is shown in Figure 13. Figure 13
It is important to note that the API does not need to be melted during extrusion in order to produce an amorphous solid dispersion. For example, Itraconazole (melting point ~166 C) was extruded at 150 C notably lower than the melting point of the API in vitro drug release results are shown in Figure 14. Figure 14 Spray Drying Soluplus has a high solubility in common volatile organic solvents used in spray drying, while maintaining also a low viscosity that is needed to process (see sectior 2 for viscosity). Recommended solvents include methanol, ethanol and acetone. Optimal concentrations for spraying range from 5 to 30% w/w depending on solvent, viscosity, API load and other spray dryer conditions. An example formulation of 20% poorly water-soluble drug Ritonavir at 20% w/w in Soluplus is shown in Figure 15.
Drug Polymer Layering Soluplus can effectively be layered over beads, spheres, mini-tablets or other fluidized granules using a conventional fluid bed coater. Similar to spray drying, Soluplus should first be dissolved together with poorly water-soluble API in a mutually effective solvent (e.g. ethanol, methanol, acetone). Care should be taken to allow coating of the substrate prior to evaporation rather than spray drying of the solution. This is typically controlled with solvent type, solids concentration and temperature profile in the bed. In the following example, poorly water-soluble drug Carbamazepine was spray coated using Soluplus from an ethanol solution (ratio 1:2 Soluplus: Ethanol). The mass gain was approximately 10%. Figure 16: Dissolution rate of carbamazepine Capsule formulation Once an amorphous solid dispersion is formed, it can be loaded into a hard gelatin capsule. It is recommended to mill the ASDs down to an appropriate and desired size, mixed with a disintegrant (e.g. Kollidon CL) at a concentration of 10-15% w/w and any non-soluble filler may also be used (e.g. microcrystalline cellulose). An example formulation is shown below: Capsule formulation: Solid solution 70% Kollidon CL 15% Microcrystalline cellulose 15% Capsule formulation: Tablet formulation Using a preformed ASD from hot melt extrusion or spray drying, the formulation may be compressed into tablets. It is typically recommended to include 5-10% disintegrant (e.g. Kollidon CL), lubricant, flowability aid and insoluble filler such as microcrystalline cellulose. An example formulation is shown below: Tablet formulation: Solid solution 60% Microcrystalline cellulose (Avicel PH 102) 29% Kollidon CL 10% Magnesium stearate 0.5% Aerosil 200 0.5%
Case Study - Bioavailability Three poorly water-soluble APIs were used as a case study for Soluplus bioavailability enhancement. These drugs were administered to Beagle dogs in a fasted state (n=5). The APIs and dose were as follows: Itraconazole (10 mg/kg bw), Danazol (30 mg/kg bw), and Fenofibrate (10 mg/kg bw). Formulations were compared in three configurations: > Crystalline API: 95% API + 5% disintegrant Physical Mixture: 15% API + 80% Soluplus + 5% disintegrant Amorphous Solid Dispersion: 95% ASD + 5% disintegrant All formulations were produced using a 16 mm twin screw co-rotating extruder. Itraconazole ASDs were produced at 1kg/hr, 200 rom and 150 C - the results are shown in Figure 17 where a clear increase in bioavailability is only evident for the ASD. Figure 17: Blood concentration of itraconazole Danazol formulations were extruded at 0.9 kg/h, 200 rpm, and 140 C the results also show a significant increase in bioavailability vs. the crystalline API or the physical mixture (Figure 18): Figure 18: Blood concentration of danazole
Fenofibrate ASDs were extruded at 0.7 kg/h, 200 rpm and 95 C; in this case both the ASD formulation as well as the physical mixture exhibited large increases in bioavailability this is due to the ability of Soluplus to increase drug solubility in aqueous environments. This effect is known for some APIs and may be tested using similar means. Figure 19: Blood concentration of fenofibrate
4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on BASF WorldAccount or from your local BASF sales representative. 5. Product Specification The current version of the product specification is available on BASF WorldAccount or from your local BASF sales representative. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI) which is available on BASF WorldAccount and from your local sales representative. WETTIG QVGHOAMIG UI DP\OT VYUTUPIGUUUEIL GUI HUTT YUU MUU OAIGS TOMICOULILALNVG. The QRPI covers all relevant information including retest dates, and storage conditions. Toxicological studies are available on request. For detailed information and individual reports a secrecy agreement has to be signed in advance. 8. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30446233 Soluplus 50539897 0.5kg Plastic bottle 50101050 2.5 kg Plastic jerricans 50477909 12.5kg Plastic drums 52155222 25 kg Fibreboard boxes BASFs commercial product number. Publications including scientific posters are available or http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Table of Contents Introduction 6 Ibuprofen 8 Chemical information . wl Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality .. 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Chemical information 20 Product information 20 Chemical and physical properties 21 Particle characterization 21 Regulatory status 21 Specification 21 Medical indication 22 Ibuprofen Sodium Dihydrate 24 Chemical information 24 Product information 24 Storage 25 Regulatory status 25 Specification 25 Medical indication 26 Table of Contents Introduction Ibuprofen 8 Chemical information 8 Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Ibuprofen Racemic Ibuprofen Lysinate (RIBL) Ibuprofen Sodium Dihydrate Ibuprofen Sodium Dihydrate
Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, antipyretic and anti-inflammatory actions, it is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever. Due to its analgesic, antipyretic and anti-inflammatory actions, it is used The common active ingredient dosage in tablets is 200, 400, 600 and 800 mg. The OTC dosage forms are mainly the 200 and 400 mg forms (except for the United States and some other countries, where the 200 mg form is the only OTC form). Other common dosage forms are capsules, syrups, suspensions, suppositories, and topical dosage forms like creams and gels. Pharmacokinetics Orally administered ibuprofen is absorbed rapidly in the Gl tract.? After a single oral dose on an empty stomach, peak plasma levels are reached within 45 to 90 minutes and the apparent plasma volume of distribution is reported to be between 0.1 to 0.2 I/kg.-> Ibuprofen has an extensive protein binding capacity (+98%) and is excreted via the kidneys. The biological half-life is between 2 and 4 hours.? After 24 h, 100% of the active substance is excreted in the urine.
Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as histamine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C. bata Te Ta Tort) U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Gillespie, W. R. et al., Relative Bioavailability of Commercially Available Ibuprofen Oral Dosage Forms in Humans, Journal of Pharmaceutical Sciences, 71:1034-1038, 1982. Verbeeck, R. K., Pathophysiologic Factors Affecting the Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs, Journal of Rheumatology, 15:44-57, 1988. Jamali, F. and D. R. Brocks, Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers, Clinical Pharmacokinetics, 19:197-217, 1990. Vowles, D. T. and B. Marchant, Protein Binding of Ibuprofen and Its Relationship to Drug Interactions, British Journal of Clinical Practice, 1:13-19, 1980. Whitlam, J. B. and K. F. Brown, Ultrafiltration in Serum Protein Binding Determinations, Journal of Pharmaceutical Science: Tio Teel atc oa Rudy, A. C. et al., Stereoselective Metabolism of Ibuprofen in Humans: Administration of R-, S- and Racemic Ibuprofen, Journal of Pharmacology and Experimental Therapeutics, 259:1133-1139, 1991. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(6): 986-1000, 2011.
Ibuprofen (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid Chemical name (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid 15687-27-1 239-784-6 C,,H,,0. 13) 182 206.28 g/mol CAS number EINECS number Molecular formula Molecular weight 3ASF offers 4 grades based on different particle size distributions (see particle charac- erization). Furthermore, a direct compressible grade is offered: Ibuprofen DC 85 W, the somposition of which can be found in chemical and physical properties section below. Product grades (+)-2-[4-(2-methylpropyl)phenyl]propanoic acid; (+)-Benzeneacetic acid, alpha-methyl- 4-(2-methylpropy)); (+)-p-lsobutylhydratropic acid; (+)-2-p-lsobutylphenylpropionic acid Ibuprofen meets the current Ph. Eur., USP, JP and IP monographs. DMFs and CEP are available upon request. Regulatory status Ibuprofen is the racemate of (+)-lbuprofen and (-)-lbuprofen (optical rotation = 0). According to the literature the pharmacologically active form is (+)-lbuprofen. Approximately 30 to 70% of the (-)-lbuprofen is converted to the active form (+)-lbuprofen in the body. This process proceeds solely from the (-)- form to the (+)- form.
Chemical and physical properties Ibuprofen grades 25, 38, 50, 70 Crystalline powder Solubility in phosphate buffer pH 7.2 (37 C) Partition coefficient n-octanol/water The chemical parameters of all pure ibuprofen powder grades are identical. The only difference is the particle size distribution (see particle characteristics).
Particle characterization Ibuprofen 25 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 25 is between 20 um and 33 pm. Ibuprofen 50 Particle Size Distribution Bulk density Tapped density An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 50 is between 45 um and 60 pm. Approximately 0.34 g/ml. Approximately 0.60 g/ml.
Ibuprofen 38 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 38 is between 33 um and 45 pm. ibuprofen 70 Particle Size Distribution Bulk density Approximately 0.38 g/ml. Tapped density Approximately 0.68 g/ml. An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 70 is between 60 pm and 85 pm.
Ibuprofen DC 85 W The ibuprofen used to manufacture Ibuprofen DC 85 W meets the current Ph. Eur., USP, JP and IP monographs. A Technical Package and a US-DMF are available upon request. Granules, free flowing, homogeneous material Appearance SEM photograph
Recommendation for direct compression Today the manufacturing of ibuprofen tablets is often done by direct compression. Using this method, the expensive and time-consuming wet granulation method can be avoided. But in general, ibuprofen has the disadvantage of sticking on the tablet tools so that the process must be interrupted often. Therefore, direct compression formulations with a high content of ibuprofen per tablet are often avoided. Mostly tablets with an ibuprofen content of maximum 60% are compressed. BASF offers a formulated ibuprofen product ideal for direct compression: Ibuprofen DC 85 W. The direct compression (DC) grade ensures that tablet sticking is minimized and allows for excellent tablet engraving. Furthermore, Ibuprofen DC 85 W has a lower angle of repose compared to standard grades, resulting in improved flowability.
General information on processing of Ibuprofen Ibuprofen is used mainly in three (3) different dosage forms: Ibuprofen 50, Ibuprofen 70, Ibuprofen DC 85 W (for direct compression) Recommended grade(s) High concentrations of magnesium stearate as a lubricant are not recommended. For direct compression, the ready-to-use Ibuprofen DC 85 W reduces sticking. For a film coating, Kollicoat IR has a reduced viscosity in aqueous solutions compared to HPMC suspensions, which leads to higher solids content and a faster coating process. Formulation guidance Creams & Gels Recommended grade(s) Recommended grade(s) To stabilize against sedimen- tation, fine particles should be used. The pH of the sus- pension should be in the acid range so that ibuprofen is undissolved, which will reduce bitter taste if any. lbuprofen is dissolved in the ipophilic phase of creams, thus there is no impact of particle size. Propylene glycol or low molecular weight polyethylene glycols are recommended as the oily component. Formulation guidance Formulation guidance
-oomLab - Your Virtual Formulation Assistant Access example formulations and build your own ZoomLab Formulation Wizard identifies suitable excipients and calculates potential formulations depending on the selected dosage form, defined target profile, and properties of the active ingredient. Example formulations include creams, tablets, and more! - Evaluate bioequivalence of your final formulation A WHO biowaiver monograph is available for ibuprofen. The ZoomLab dissolution module can be used to calculate difference and similarity factors (f1, f2) required for showing bioequivalence. ZoomLab provides values for parameters relating to particle size, powder density, flowability, and tabletability. The parameters are scaled from 0 to 10, a risk analysis is run, and an interpretation of results/formulation advice is provided.
Example formulations Production of granules for 200, 400, 600 and 800 mg forms The following ingredients are placed in a high shear mixer and granulated with water: Ibuprofen 50 60.1% w/w Amount of water: approximately 0.2 kg water per 1 kg __ ibuprofen. Wet sieving (4 mm) and drying in a fluid bed Lactose 18% w/w granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following Corn starch 9% w/w additives to form granules suitable for tableting. Kollicoat IR 3.6% w/w Extra granular material Avicel PH 102 3.6% w/w AcDiSol 4.8% w/w Magnesium stearate 0.6% w/w Aerosil 200 0.3% w/w Coating formulations for Ibuprofen tablets oes Fraction with reference to the Fraction with reference Composition atomised suspension [%] to the dry film [%] Polymer Kollicoat IR 16.0 64 Pigments Talc 6.0 24 Sicovit Red 30 3.0 12 Total 25 100 Amount of water: approximately 0.2 kg water per 1 kg ibuprofen. Wet sieving (4 mm) and drying in a fluid bed granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following additives to form granules suitable for tableting. Corn starch Kollicoat IR Extra granular material Magnesium stearate Coating formulations for Ibuprofen tablets

Handling & Safety Product specification The current version of the product specification is avail- able on RegXcellence or from your local BASF sales representative. Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on MyProduct- World or from your local BASF sales representative. Publications Regulatory & Quality Publications including scientific posters are available on: Please refer to the individual document quality & regu- latory product information (QRPI) which is available on RegXcellence and from your local sales representative The QRPI covers all relevant information including retest dates and storage conditions.
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Racemic Ibuprofen Lysinate (RIBL Racemic Ibuprofen Lysinate (RIBL Chemical information Chemical information Ibuprofen Lysinate (+) (+)- (+ (+ -2-[4-(2-methylpropyl)phenyl]propanoic acid lysinate -Benzeneacetic acid, alpha-methyl-4-(2-methylpropyl) lysinate -p-lsobutylhydratropic acid lysinate -2-p-lsobutylphenylpropionic acid lysinate Empirical formula Molecular weight
Chemical and physical properties White to almost white, very fine crystalline powder witt a high volume. In the literature the solubility of Ibuprofen (acid) in distilled water is reported to be less than 0.1%. The solubility of Ibuprofen Lysinate is 1:5, or about 17%. Particle characterization An example particle size distribution is shown below. The median particle size for RIBL is approximately 10 pm Regulatory status No monographs exist. E-DMF is available upon request.
The term RIBL is the acronym for Racemic Ibuprofen Lysinate. Racemic signifies that the ibuprofen drug substance and the lysine anion are both racemic compounds. RIBL differs from the common ibuprofen acid, gen- erally referred to as ibuprofen, in that it is more rapidly absorbed from the intestinal tract and reaches peak plasma levels and t,,., more quickly. After absorption, RIBL is available in the form of pure ibuprofen acid and is therefore to be handled like ibuprofen. Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, anti- pyretic and anti-inflammatory effects, ibuprofen is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever.? For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. Pharmacokinetics RIBL is readily and quickly absorbed from the gastrointestinal tract.!? The peak plasma level of the free acid is reached within 30 to 60 min (with the free acid ibuprofen, t,,,, was measured between 60 and 120 minutes, depending on the dosage form).: After absorption, there is no difference between RIBL and the free acid.
From a pharmacological point of view, there is no difference between RIBL and the free ibuprofen acid because it is the free acid and not the RIBL salt that is the active form. The mode of action of ibuprofen, while not completely understood, is believed to involve reversible inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have among other properties a powerful effect on the smooth muscles. In case of inflammatory stimuli or blood flow disorders, PGs are synthesized in increased amounts, making the tissues sensitive to the action of other agents such as histamine and kinins. As a result, symptoms like pain and inflammation occur. The in- cidence of fever is raised by the influence of the PGs on the heat regulation center in the hypothalamus. There they scale up the normal set point of 37 C. bats CUe Ta Tort) 1 Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration of Ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990. Hermann, T. W. et al., Bioavailability of Racemic Ibuprofen and its Lysinate from Suppositories in Rabbits, Journal of Pharmaceutical Sciences, 82(11):1102-1111, 1993. U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Neupert, W. et al., Effects of lbuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(5): 986-1000, 2011. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration o ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990.
Ibuprofen Sodium Dihydrate Chemical information Ibuprofen Sodium Dihydrate 2-(4-isobutylphenyl)-propionate sodium dihydrate Chemical name Se IS ee ee ee a en re ae ee ee 31121-93-4 C,,H,,0,Na x 2 H,O 228.26 + 36.03 g/mol Empirical formula Molecular weight
Storage Ibuprofen Sodium Dihydrate should be stored in the original, tightly sealed container. It should be placed ina well-ventilated room at ambient temperature and protected from light. The retest period of Ibuprofen Sodium Dihydrate is 60 months for material stored in the original, unopened containe! and according to our recommendations. Regulatory status Currently there are no monographs describing Ibuprofen Sodium Dihydrate in the major Pharmacopoeias (USP, Ph. Eur.. and JP).
According to the literature, ibuprofen sodium dihydrate dissolves more quickly in vitro and is absorbed into blood plasma more quickly than con- ventional ibuprofen, whereas tolerability and safety profiles of the two APIs are comparable.? In an investigation of the dissolution, plasma pharmacokinetics, and safety of ibuprofen sodium dihydrate versus conventional ibuprofen, the following results were reported:? @ buprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 compared to conventional ibuprofen. @ lbuprofen sodium dihydrate reached the t,,,, significantly earlier than conventional ibuprofen. @ lbuprofen sodium dihydrate showed significantly higher c_, compared to conventional ibuprofen. @ buprofen sodium dihydrate was characterized by significantly higher mean plasma concentration (10 min post-dose) compared to conventional ibuprofen. tax iS the necessary time until the maximum plasma concentration of a drug is reached; this is relevant for the drug onset. Generally, reaching the t_ early is of great advantage for analgesic treatment. According to the literature, the first signs of pain relief occurred significantly earlier in ibuprofen sodium dihydrate treated patients, and pain intensity was reduced to half after 30 min for ibuprofen sodium dihydrate compared to 57 min for conventional ibuprofen. In summary, ibuprofen sodium dihydrate causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen.
The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (CO)) which is responsible for the biosynthesis of prostaglandin (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflamma- tory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as hista- mine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C.? c Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandii Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vas FeYToltote CHI (2) Rc) =\ coal O00 Soergel, F. et al. Pharmacokinetics of Ibuprofen Sodium Dihydrate and Gastrointestinal Tolerability of Short-Term Treatment with a Novel, Rapidly Absorbed Formulation, International Journal of Clinical Pharmacology and Therapeutics. 43(8):140-149, 2005. Schleier, P. et al., Ibuprofen Sodium Dihydrate, an Ibuprofen Formulation with Improved Absorption Characteristics, Provides Faster and Greater Pain Relief than Ibuprofen Acid, International Journal of Clinical Pharmacoloay and Therapeutics. 45(2):89-97. 2007. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandir Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997.
www.pharma.basf.com For sample requests contact us ai pharma-solutions@basf.com Meet your Virtual Pharma Assistants! ZoomLab, RegXcellence, and MyProductWorld, your interactive guides for optimizing drug formulations, navigating quality and regulatory compliance, and browsing ingredients. Learn more and sign up at https://info-mypharma.basf.com/ Inspiring Medicines for Better Lives This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been preparec in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to the extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2021 BASF Corporation. All Rights Reserved.
Technical Information Poloxamer Ph. Eur., Poloxamer USP/NF Poloxamer for Pharmaceutical Use March 2020 WF-No. DAWF-2019-0839 = Registered trademark of BASF in many countries.
1. Introduction BASFs Kolliphor P grade poloxamers are white, coarse- grained powders with a waxy consistency. They contain an appropriate quantity of the antioxidant BHT. Poloxamers are ABA-type co-polymers of poly (ethylene oxide) (PEO=A) and poly (propylene oxide) (PPO=B). The approximate relative amount of PEO and the average molecular weight of the PPO are indicated in the name of the poloxamer. For example. P 188 succeeding the word Kolliphor indicates a poloxamer with ca. 80% m/m PEC (P 188; 8x10= 80%) and approximately average molecular weight of PPO of 180C (P 188; 18x100= 1800) 2. Technical properties Structural formula Kolliphor P 188 Geismar is a block copolymer that is a synthetic copolymer of ethylene oxide and propylene oxide represented by the following chemical structure: Where in a and b blocks have the following values: Kolliphor Poloxamer P 188 188 80 27 Appearance Appearance Kolliphor P 188 Geismar is produced as a white to almost white prill/powdel Kolliphor P 188 Geismar is produced as a white to almost white prill/oowder. CAS Number Molecular Weight The average molecular weight for Kolliphor P 188 Geismar is 7680 to 9510 g/mol. The product contains nominally 75 to 85 ethylene oxide units split between the two chains and 25 to 30 propylene oxide units, with a rough concentration of oxyethylene of 79.9 to 83.7 % based on the current monograph specification. An example of the molecular weight distribution for Kolliphor P 188 Geismar is shown below in Figure 1. The above graph was generated using size exclusion chromatography (SEC), note that the smaller peak to the left represents diblock polymers.
Viscosity Poloxamers, and Kolliphor P 188 Geismar exhibits a thermoreversible gelling behavior that occurs as a function of temperature. At low concentrations, aqueous concentrations exhibit Newtonian flow properties and negligible viscosity alterations to that of water, however, at higher temperatures, the solutions begin to exhibit non- Newtonian flow behavior. An example of the viscosity curve is evident in Figure 2 below with the gel points clearly noted by the sharp increase in viscosity: HLB The HLB value of Kolliphor P 188 Geismar is approximately 29. Critical Micelle Concentration (CMC) The critical micelle concentration for Kolliphor P 188 Geismar is published as 4.8- 10% mol/L @ 37 C (4.1 g/L). Note that the CMC value decreases significantly as the temperature increases. Furthermore, due to the linear structure of the poloxamer, the value is difficult to ascertain as an inflection point using standard methods (such as Wilhelmy Plate Method) an example of the surface tension for Kolliphor P 188 Geismar as a function of concentration is shown below in Figure 3 (37 C).
The micelle size is approximately 5 10 nm in diameter; this is shown in Figure 4 below as determined via laser diffraction: Solubility Kolliphor P 188 Geismar is highly soluble in water. Particle Size Kolliphor P 188 Geismar exhibits spherical prill particles of a mean diameter of approximately 500 ym in size. An example of the size and morphology of these particles is shown in the scanning electron microscope image (SEM) show below in Figure 5.
A closer image of the particles is shown below in Figure 6 at a higher magnification: Cloud point The cloud point for Kolliphor P 188 Geismar is >100C for a 1% and a 10% aqueous solution. Density The true density of Kolliphor P 188 Geismar is approximately 1.06 g/cm. The bulk density of Kolliphor P 188 Geismar is approximately 0.56 g/cm?. The tapped density of Kolliphor P 188 Geismar is approximately 0.61 g/cm.
Moisture sorption The uptake of moisture for Kolliphor P 188 Geismar is dependent on the relative humidity of the environment, at moisture levels above 80% (RH) significant moisture uptake is possible and shown in Figure 7 below: BHT Poloxamers, and specifically Kolliphor P 188 Geismar utilize 50 125 ppm BHT as an antioxidant the protects the quality and performance of the P 188 in the litany of pharmaceutical applications. The primary degradation mechanism is oxidation, and is typically monitored via the pH, hydroxyl value and molecular weight of the poloxamer. 3. Handling Please refer to the individual Material Safety Data sheet (MSDS) for instructions on safe and proper handling and disposal.
4. Example application Poloxamers are a widely used pharmaceutical ingredient in multitude of applications, most notably, as a dispersing agent, emulsifier, solubilizer, tablet and capsule lubricant, wetting agent, stabilizer for oral and topical suspensions, gelling agent in topical formulations and shear protectant (for cell culture applications please see Kolliphor P 188 Bio). Example use levels Indication Concentration (w/w%) Gelling agent 15 to 50 Suspension stabilizer 0.1 to5 Tableting 1 to 10 Wetting Agent 0.01 to 5 Emulsifier 1to5 Foaming agent 1to3 Plasticizer (matrix) 5to 15 Solubilization Kolliphor P 188 Geismar can be used in a multitude of solubilization examples more specifically the product may be a liquid solution, suspension or solid tablet. Given the low critical micelle concentration (CMC) stabilizing and solubilizing occurs at concentrations 1 to 2 orders of magnitude lower than for standard ethoxylated surfactants. In solid solutions, such as amorphous solid dispersions (ASDs) produced via hot melt extrusion (HME) and spray drying, Kolliphor P 188 Geismar may be used as a plasticizing agent and/or solubilizer to further increase poorly water drug solubility in the matrix. As a plasticizer, it lowers the Tg of many polymers and allows foi processing at lower shear rates and/or temperatures. An example of the processing temperature reduction is shown below in Figure 8. Extrusion temperature [C] 30 60 70 60 $0 160 110 120 180 140 10 160 170 160 190 200 210 280 250 240 VME YA) Kollidon 17 PF Pure Polymer (_] 410% Kolliphor P 188 NY
Skin Delivery Aerosol Foams Growing in popularity, topical foams can sometimes be preferred over a cream due to their pleasing sensory application. The four foam formulations below retain their shape upon application onto the skin, spreading easily and drying quickly. Ingredients Chemical name Role A B Cc OD (Weight%) Kolliwax CSA 50 Cetostearyl Alcohol Foam Stabilizer 3 3 3 3 Kolliphor CS 12 Macrogol Cetostearyl Foaming Agent/ o oOo 6 6 Ether 12 Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Foaming Agent/ 5 6 0 0 Ether 20 Emulsifier Kollicream 3C Cocoyl Caprylocaprate Emollient/ 3 3 3 3 Solubilizer Kolliphor P 188 Poloxamer 188 Foaming Agent 1 Qo. 00 1 Geismar Deionized Water Solvent 82 82 82 82 A46 Propane/Isobutane Propellant/Solvent 6 6 6 6 Foams made with Kolliphor CS 12 tend to demonstrate a higher viscosity and stiffness than foams formulated with Kolliphor CS 20. Additionally, poloxamers such as Kolliphor P 188 Geismar or Kolliphor P 407 Geismar can be added to formulations as needed to create richer, creamier foams. This richness is aided by the use of an aerosol. Povidone-lodine Foams Kolliphor P 188 Geismar acts as an effective emulsifier in the formation of non-aerosol foams for topical use. Foams of varying strengths can be created by altering the mass percent of API. Phase _ Ingredients Chemical name Role Mass (Weight%) A PVP lodine 30 Povidone-iodine API 5-10 Deionized Water Solvent 87 -92 Kolliphor P 188 Geismar Poloxamer 188 Emulsifier 3
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage condition Please refer to Quality & Regulatory Product Information (QRPI). 7. Stability Please refer to Quality & Regulatory Product Information (QRPI). 8. Toxicological data The toxicological abstract is available on request. 9. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30631536 Kolliphor P 188 Geismar 50424518 0.5 kg IP23 50498319 25 kg Fibre drums 50424307 102 kg Fibre drums BASFs commercial product number. 10. Publications http://pharmaceutical.basf.com/en.html This document, or any answers or Information proviaed nerein by BAorF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information = Registered trademark of BASF in many countries.
1. Introduction Historical aspects of polyvinylpyrrolidone The modern acetylene chemistry was developed at BASF in the 1930s by Reppe. One of the many products that emerged from this work are the soluble polyvinyl- pyrrolidone grades, obtained by radical polymerization of the monomer unit N-vinyl pyrrolidone. The polymerization can be performed either in water or in organic solutions. Triggered by organic or inorganic radical starters, the polymers span a wide range of molecular weights. Because of its solubility in water and in many organic solvents, its high binding power and its ability to form complexes, soluble polyvinylpyrrolidones are very valuable synthetic polymers for the pharmaceutical industry. Separate Technical Information Sheets are available for the Povidones with low molecular weights, for the insoluble Kollidon grades (Crospovidone) and for Kollidon VA 64, the copolymer consisting of N-vinylpyrrolidone and vinyl acetate (Copovidone). More information on Kollidon grades may be found in the book, Kollidon, Poly- vinylpyrrolidone for the Pharmaceutical Industry. 2. Technical properties Description The range of medium and high molecular weight Povidones comprises of the grades Kollidon 25, Kollidon 30, Kollidon 30 LP, which are of medium molecular weight and are polymerized in aqueous solution and spray dried. In addition, the high mole- cular weight grade Kollidon 90 F, after being polymerized in water achieving a very highly viscous polymer solution, is finally dried using a drum dryer. The product range comes as white powders with faint, characteristic odor. Structural formula Trivial names Soluble polyvinylpyrrolidone is also known as povidon(e), povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone) and PVP. CAS number 9003-39-8
Product range and molecular weights The product range of the medium and high molecular weight Povidones comprises of 4 different products which are, product dependent, manufactured in the production sites in Ludwigshafen, Geismar and/or Shanghai. The molecular weight of polymers can be expressed in three different forms, as weight average molecular weight, as number average molecular weight and as viscosity average molecular weight. The molecular weight of povidone is usually expressed as the K-value, from whict it is possible to calculate the viscosity average molecular weight (M,). However, the weight average molecular weight (M,,) is found more frequently in the literature. The following M,, values were determined for different grades of Kollidon in recent measurements. In contrast to former determinations SEC was performed using a detection system not requiring reference standards anymore. Nominal Compendial range M,, K-Value for K-value [g/mol] Kollidon 25 25 24-27 28000 - 34000 Kollidon 30 30 28 - 32 44000 - 54000 Kollidon 30 LP 30 28 - 32 44000 - 54000 Kollidon 90 F 90 85 - 95 900000 1200000 Table1 Solubility The solubility of Kollidon varies considerably from one solvent to another. In Table 2 below, soluble signifies that a solution of at least 10% can be prepared, and insoluble signifies that the solubility is less than 1%. Soluble in: chloroform n-butanol cyclohexanol n-propanol ethanol abs. polyethylene glycol 300 glycerol polyethylene glycol 400 isopropanol propylene glycol methanol triethanolamine methylene chloride water Insoluble in: cyclohexane pentane diethyl ether carbon tetrachloride ethyl acetate toluene liquid paraffin xylene Table 2: Solubility of Kollidon Grades
Particle size When analyzed the particle size distribution using a sieving method, particle size distributions of the various polymers can be described with the following ranges. Product <50 um >250 um Kollidon 25 max. 40% max. 5% Kollidon 30 max. 40% max. 5% Kollidon 30 LP max. 20% max. 5% Kollidon 90 F max. 10% max. 15% Table 3 Bulk density Bulk density of Kollidon is determined according to Ph. Eur. current edition, method 2.9.34. Product Bulk density Kollidon 25/30/30 LP 400 600 g/L Kollidon 90 F 400 550 g/L Table 4: Bulk density of the Kollidon grades Particle size distribution and bulk density are considered characteristic values. They are not part of any specifications. Particle size distribution and bulk density are considered characteristic values. They are not part of any specifications. Glass transition temperature Tg, Product Tg, [C] Kollidon 25 165 Kollidon 30 171 Kollidon 30 LP 171 Kollidon 90 F 177 The glass transition temperature was determined by DSC as Tg,, after having eliminated water by heating and finally cooling the dried polymer to room temperature for a second cycle.
Viscosity Fig. 1 shows the relationship between the viscosity of aqueous solutions of the different grades of Kollidon and their concentration. Fig. 1: Viscosity of Kollidon solutions (Ubbelohde viscometer, 25 C) Complexation, chemical interactions Povidone can form fairly stable association compounds or complexes with a number of active substances. The best known example is PVP-iodine which is the subject of a separate leaflet. The ability of Kollidon to form a water-soluble complex with insoluble active substances can be used in pharmaceuticals to improve the release rate and solubility of drugs. There are a few substances such as the polyphenols that form stronger complexes that can precipitate in neutral or acidic media. It must be noted that if povidone is combined with strongly alkaline substances such as lithium carbonate or sodium hydroxide it can crosslink and become insoluble, particularly at elevated temperatures. In extreme cases, this can increase the viscosity of liquid presentation forms and delay bioavailability in solid presentation forms.
3. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. 4. Example application The main applications of the soluble Kollidon grades are summarized in Table 6. Binder Tablets, capsules, granules Bioavailability enhancement Tablets, capsules, granules, pellets, suppositories, transdermal systems Film formation Opthalmic solutions, tablets, medical plastics Solubilization Oral, parenteral and topical solutions Lyophilising agent Injection preparations, oral lyophilisates Stabilisation of suspensions Oral and parenteral suspensions Oral instant beverage powders and granules for redispersion Viscosity modifier Ophthalmic formulations Adhesives Transdermal systems, adhesive gels Drug stabilisation Enzymes in diagnostics Table 6: Main applications of the soluble Kollidon grades of medium and high molecular weight The adhesive, film-forming, dispersing and thickening properties of the soluble Kollidon grades are used in the various modifications of granulation technologies for tablet production, film coating and in the preparation of other dosage forms. The improvement in the solubility of active ingredients brought about by complexatior or association, and the thickening effect find use mainly in the manufacture of liquid presentation forms. The grade of Kollidon that is selected depends mainly on its molecular weight, as this dictates the viscosity, binding effect, the complexation capacity and how readily it is eliminated from the body. A detailed description of the applications is to be found in the book, Kollidon, poly- vinylpyrrolidone for the Pharmaceutical Industry. Tablet binding Kollidon 25, Kollidon 30, Kollidon 30 LP and Kollidon 90 F When applied for granulation in high shear mixers or fluid-bed granulators the resultinc granules with Kollidon 25, Kollidon 30 and Kollidon 90 F are hard, free flowing with a low proportion of fines. Binding strength is excellent to achieve hard and stable tablets. Kollidon 25 and Kollidon 30 require binder quantities of 2% and 5% related to the tablet weight. As Kollidon 90 F has a higher binding capacity the required quantities are 2% or even less. The high viscosity of binder solutions of Kollidon 90 F sometimes requires precautions to ensure the granules to be evenly wetted. Kollidon 25, 30 and 90 F are also suitable for the direct compression of tablets without granulation. This technique requires a certain relative humidity, as the powder mixture must have a certain moisture content to bind properly. If Kollidon is used in addition to microcrystalline cellulose, it not only makes the tablets harder but also gives them stronger edges. For best results in direct compression, all the excipients should have acertain moisture content. This applies to starch, micro- crystalline cellulose and lactose monohydrate as fillers. It can be seen from Fig. 2 that there is hardly any difference in the hardness of lactose placebo tablets made with Kollidon 25 and Kollidon 30. However, the same quantity (3% of the tablet weight) of Kollidon 90 F almost doubles the hardness, compared with Kollidon 25.
Fig. 2: Lactose monohyarate tablets with 3% Kollidon (wet granulation) Kollidon is also suitable as a binder in fluidized-bed granulation processes. Thanks to their relatively low viscosity, solutions of Kollidon 25 and Kollidon 30 can be prepared relatively quickly, and sprayed easily, to quickly give stable granules. Co-precipitation, co-milling Kollidon 25, 30 The dissolution rate and therefore the absorption rate of drugs that do not dissolve readily in water can be greatly improved by co-milling or coprecipitation with Kollidon 25 or Kollidon 30, as the complex formed is, in effect, a solid solution of the drug in the Kollidon. This requires an excess of Kollidon to maintain the (partially) amorphous form of the active substance. Suitable processes include mixing, co-milling or melt extrusion of the Kollidon-drug mixture, or coprecipitation, granulation onto a carrier or spray-drying a solution containing the drug and Kollidon. The literature contains hundreds of publications on this application. The most frequently tested active substance mentioned is probably nifedipine. Stabilizers of suspensions Kollidon 25, 30, 90 F These grades can be used to stabilize oral and topical suspensions with a wide range of active ingredients, e.g. acyclovir, ibuprofen, magaldrate, nystatin, phenytoin, trimethoprim, sulfonamides and antibiotics, as well as sugar-coating suspensions. Combinations of Kollidon 90 F with Kollidon CL-M have often given very good results. Thickener Kollidon 90 F Because of its good solubility in water and alcohol, Kollidon 90 F can be used as a thickener for aqueous or aqueous-alcoholic solutions for oral application (viscosity curve, see Figure 1).
5. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 6. Retest date and storage condition: 6. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). 7. Specification For current specification, please speak to your local BASF sales or technica representative. Please refer to Quality & Regulatory Product Information (QRPI). 9. Toxicological data For information on toxicological issues please refer to the tox abstract which can be supplied on request. More/detailed toxicological information for Kollidon grades is available on request under Secrecy Agreement.
10. PRD and Article numbers 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30034967 _ Kollidon 25 57254799 25 kg Cardboard boxes 50348143 0.5 kg Plastic pail 30697299 Kollidon 25 50574244 50 kg Plastic drums 50574245 0.5 kg Plastic pail 30034974 Kollidon 30 Origin Germany 57254693 25 kg Cardboard boxes 50347950 0.5 kg Plastic pail 30525451 Kollidon 30 Origin Germany 50022331 50 kg Plastic drums 50347978 0.5 kg Plastic pail 30403404 Kollidon 30 Origin USA 55238758 1 kg PE-Bottle 55087337 50 kg PE-Drum, removable head 30660388 Kollidon 30 Origin China 50486018 50 kg Plastic drums 50498559 0.5 kg Plastic pail 30255812 Kollidon 30 LP 50347979 0.5 kg Plastic pail 50796353 25 kg Cardboard boxes 30034978 Kollidon 90 F 50347976 0.5 kg Plastic pail 51031936 25 kg Cardboard boxes BASFs commercial product number. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Kolliphor PS grades - Polysorbates eae ae Supersedes issue dated May 2013 ) = Registered trademark of BASF in many countries.
PRD-No., Article-No. and CAS.-No. Tradename PRD-No. Article-No. CAS.-No. Kolliphor PS 20 30554436 50253857 9005-64-5 Kolliphor PS 60 30554490 50253808 9005-67-8 Kolliphor PS 80 30554437 50253859 9005-65-6 Table 1: PRD, Article and CAS numbers of the Kolliphor PS grades In table 2 you can find all the monographs for the Kolliphor PS grades Regulatory Status Kolliphor PS 20 Ph. Eur.: Polysorbate 20 USP/NF: Polysorbate 20 Kolliphor PS 60 Ph. Eur.: Polysorbate 60 USP/NF: Polysorbate 60 JPE : Polysorbate 60 Kolliphor PS 80 Ph. Eur.: Polysorbate 80 USP/NF: Polysorbate 80 Table 3: Compendial names Polysorbates are non-ionic surfactants and emulsifiers for pharmaceutical application, derived from polyethoxylated sorbitan and fatty acids. Polysorbates Chemical structure

Chemical characterization Chemical characterization Appearance Oily, yellow or brownish- yellow, clear slightly opalescent liquid Yellowish- brown gelatinous mass, clear liquid at temperatures above 25 C Oily, colorless or brownish-yellow, clear or slightly opalescent liquid Composition of fatty acids C6, < 1.0% C 18, 40.0 - 60.0% C14, < 5.0% C8,C 10 < 10.0% C16 +C 18 > 90.0% C16, <16.0% C12, 40.0 to 60.0% C16:1 < 8.0% C 14, 14.0 to 25.0% C18, < 6.0% C 16, 7.0 to 15.0% C 18:1, 258.0% C 18, < 7.0% C 18:2, < 18.0% C181 <11.0% C 18:3, < 4.0% C18:2 < 3.0% Acid value < 2.0 < 2.0 < 2.0 Hydroxyl value 96 - 108 81-96 65 - 80 Saponification value 40-50 45-55 45-55 Peroxide value <10.0 <10.0 <10.0 HLB 16.7 14.9 15.0 CMC 0.0499 0.0167 0.015 Table 3: Typical chemical properties of Kolliphor PS grades The HLB value of non-ionic emulsifiers is very much temperature dependent. Meaning the HLB decreases with elevated temperatures. This leads to a change in the behavior of the emulsifier, wich is then no longer hydrophilic but lipophilic This is a result of the temperature sensitivity of the hydrogen bonds of the molecule. The polarity of the molecule can change strongly, as with the elevated temperature the lipophilic interactions are in favor and this can lead to a phase inversion of an emulsion. Furthermore, Kolliphor PS 20, 60 and 80 meet the requirements of the above- mentioned monographs. The chemical characterization shown in Table 3 above is only for information purposes and should be interpreted as typical properties of Kolliphor PS 20, 60 and 80. See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Specifications
Additional chemical characterization Differential scanning calorimetry (DSC) Figure 1: DSC of Kolliphor PS 20 Kolliphor PS 60 Figure 2: DSC of Kolliphor PS 60
Kolliphor PS 80 Figure 3: DSC of Kolliphor PS 80 Typical physical properties Solubility in water Kolliphor PS 20 Kolliphor PS 60 Kolliphor PS 80 Miscible in all parts Up to 5 % Miscible in all parts Application Polysorbates are mainly used as solubilizers, emulsifiers or suspension stabilizers for pharmaceutical applications. Depending on the HLB value and the miscibility in water of the product, they either act more as a solubilizer or emulsifier. Products like Kolliphor PS 20 and Kolliphor PS 80 are more suitable for use as a solubilizer of poorly water soluble drug substances in either liquid or solid oral dosage forms. Kolliphor PS 60 is more likely to be used as an emulsifier in topical applications like cream and lotions. a6es yd peag suo} eBesop pinbq Jequeyus uole.}9UEd US Bulsseooid plop SUUO} aBeSOp PI OS-!LUES SULUO} eBesop pljos je1O Jezijiqeys uolsuedsng ABZI[IQN OS JOYISINW MWVO JOYISINW O/M Ph. Eur. Product Kolliphor PS 20 Polysorbate 20 Kolliphor PS 60 Polysorbate 60 Kolliphor PS 80 Polysorbate 80 Overview of applications of Kolliphor PS grades
Application as solubilizer for liquid or solid oral dosage forms Pharmaceutical scientists increasingly face the challenge of formulating poorly water soluble active pharmaceutical ingredients (API). This trend is likely to increase, as new APIs in pharmaceutical research become more and more lipophilic and complex molecules. A high-throughput screening robot was established at BASF SE to reduce development time and formalize early solubilizer screening activities. The aim of this study is to screen the solubilizing performance of three Polysorbate grades based on model APIs with different physico-chemical profiles. The solubilizer concentration with max. 20% exceeds the typical usage levels in standard pharma- ceutical liquid or solid formulations in order to assess a potential saturation effect. Performance of different Polysorbate grades based on model APIs The selected model APIs differ in molecular weight, estimated logP values, estimated water solubility and melting point. Table 4 shows an overview of these attributes for all selected model compounds. Molecular Weight logP Water solubility Tm g/mol mg/mL 5 Carbamazepin 236.27 2A 1.52 x 107 201 - 206 Cinnarizin 368.514 5.19 1.72 x 10 117-120 Danazol 337.455 3,62 7.07 x 10% 224 227 Fenofibrate 360.831 4.86 1.76 x 10? 80.5 Ketoconazol 531.431 4.3 9.31 x 10 146 Piroxicam 331.346 2.2 1.43 x 107 198 - 200 Table 4: Overview of physico-chemical properties of the selected model APIs Figure 4 shows the enhancement of the saturation solubility of Kolliphor PS 60 by using only 1 and 5% of the solubilizer stock solution. Figure 4: Solubility enhancement of model APIs by using Kolliphor PS 60 (Polysorbate 60)
Both Kolliphor PS 20 and PS 80 form clear solutions in water at concentration levels ranging from 1 20%. Therefore, these substances are adequate for the evaluation of a potential saturation effect by solubilizer concentration. The results of figure 4 and 5 support this and show, that the solubility enhancement of all substances increase with solubilizer concentration. Figure 6: Solubility enhancement of model APIs by using Kolliphor PS 80 (Polysorbate 80) Conclusion: Conclusion: Overall, Kolliphor PS 80 shows the best improvement in the saturation solubility of all three excipients regardless of the physico-chemical attributes of the model API. For most of the APIs, the solubility enhancement is linear to the usage con- centration of the solubilizer and dependent on the alkyl chain. This is the case even at high concentrations of about 20%. Kolliphor PS 60 shows a limitation with regards to its ability to form clear solutions at higher concentrations. This may explain the preference of Kolliphor PS 60 to be used in emulsion type systems.
Kolliphor PS 20 and Kolliphor PS 80 for Hot melt extrusion (HME): Formulation Ritonavir Kollidon VA 64 Kolliphor PS 20/Kolliphor PS 80/ Kolliphor RH 40 API: Polymer: Solubilizer: API Polymer Solubilizer 30.0% 70.0% = 30.0% 67.5% 2.5% 30.0% 65.0% 5.0% 30.0% 62.5% 7.5% Process Kolliphor PS 20 is the best solubilizer in study. All Kolliphor PS grades are easy tc handle in HME applications. No significant difference can be observed in handling compared to other semi-solid solubilizer such as Kolliphor RH 40. Enhancement of concentration of solubilizer shows no influence on drug dissolution.
Semi-solid/Topical Application A topical formulation is a complex mixture of ingredients with varying functionality. The majority of such products are stabilized emulsions of an emollient in water. The formulation needs to deliver both water-soluble actives and oil-soluble ingredients to the stratum corneum and preferentially control the penetration of these substances to the epidermis and dermis. The formulation typically needs a shelf life of more than 24 months. The physical stability of the system is maintained primarily by the viscosity-building effect of the emulsifiers and consistency factors. Finally, the formulation also needs to be aesthetically and acceptable in order to meet patient demands. The choice of emulsifiers for specific applications depends on the desired properties of the formulation (e.g. stability, viscosity, skin feel and API), or on the desired processing technology (e.g. PIT, Hot or cold processing). Formulation procedure: Besides the well-known emulsifying process with two hot phases there is also the possibility to formulate an emulsion at room temperature. The processing of O/W emulsions at room temperature has several significant benefits. For example, it is no longer necessary to heat the water and oil phase to 70 80 C. This saves considerable amounts of energy and reduces the production time as the cooling step is eliminated. Another very important advantage is that heat-sensitive APIs can be added to the emulsions at any point. Kolliphor PS 60 is very suitable for this kind of application.
Semi-solid Formulation examples (Hot-hot processing) Semi-solid Formulation examples (Hot-hot processing) Phase Ingredients Chemical name Mia) A Kollicream OD Octyldodecanol ZO 20 52051920) 0 0 0 0 Kollisolv MCT 70 Triglycerides Medium- 0 0 0 0 20 20 20 20 chain Kolliwax CA Cetyl Alcohol 3 0 0 0 3 0 0 0 Kolliwax S Stearic Acid 0 3 0 0 0 3 0 0 Kolliwax SA Stearyl Alcohol 0 0 3 0 0 0 3 0 Kolliwax MA Myristyl Alcohol 0 0 0 3 0 0 0 3 Kolliwax GMS II Glyceryl Monostearate 1.25 1.25 1.25 1.25 2.08 2.08 2.08 2.08 40-55 (typ Il) Kolliphor PS 60 Polysorbate 60 Sif) OOO 200 3510 E292 e202 1929202. 92: B Deionized Water 69.8 69.8 69.8 69.8 69.8 69.8 69.8 69.8 Carbopol ETD 2020 Polymer Acrylates/C,,, 4, Alkyl 0.2 0.2 02 0.2 02 02 0.2 0.2 Acrylate Crosspolymer Cc Triethanolamine 1 1 1 1 1 1 1 1 D Germaben 1 1 1 1 1 1 1 1 HLB can be lowered by mixing with Kolliwax GMS II to achieve stable and aesthetically acceptable cream or lotion emulsions with Kollicream IPM. Phase Ingredients Chemical name Wt% A Kollicream IPM lsopropylmyristate 20 20 Kolliwax GMS II Glyceryl Monostearate 40-55 (typ Il) AS 1.45 Kolliphor PS 60 Polysorbate 60 3.55 0 Kolliphor PS 80 Polysorbate 80 0 3.55 B Deionized Water 72.8 72.8 Carbopol ETD 2020 Polymer Acrylates/C,,, ., Alkyl Acrylate Crosspolymer 0.2 0.2 Cc Triethanolamine 1 1 D Germaben II Propylene Glycol (and) Diazolidiny! Urea (and) 1 1 Methylparaben (and) Propylparaben Kollicream 3C has demonstrated excellent mildness in clinical studies. Kolliphor PS 60 or PS 80 can be used to make very stable, aesthetically acceptable, emulsion creams with Kollicream 3C. Phase Ingredients Chemical name Wt% A Kollicream 3C Cocoyl Caprylocaprate 20 20 Kolliwax GMS II Glyceryl Monostearate 40-55 (typ Il) 25 25 Kolliphor PS 60 Polysorbate 60 2.5 0 Kolliphor PS 80 Polysorbate 80 0 2.5 B Deionized Water 72.8 72.8 Carbopol ETD 2020 Polymer Acrylates/C,,, ., Alkyl Acrylate Crosspolymer 0.2 0.2 Cc Triethanolamine 1 1 D Germaben II Propylene Glycol (and) Diazolidiny! Urea (and) 1 1 Methylparaben (and) Propylparaben The following processing steps apply in all of the above formulations: 1. Phase A was weighed in a clean beaker and heated until the waxes melted. 2. In another beaker, water was heated to 80 C and sprinkled with carbopol while stirring. 3. Phase A was added into phase B with stirring and then neutralized with TEA. 4. The mixture was homogenized for about 2 minutes. 5. Mixture was allowed to cool under mild shear. Germaben ] (Phase D) was added durina coolir _ Mixture was allowed to cool under mild shear. Germaben II (Phase D) was added during cooling mixing step
http:/Awww.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm IIG listing All Kolliphor PS types have a good skin tolerance. Skin Tolerance Raw material origin All Kolliphor PS grades are based on vegetable and synthetic raw materials. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreemer In originally sealed containers all Kolliphor PS types can be stored for at least 18 months. It is important that they are protected from moisture and stored at less than 30 C. Stability and storage Handling and Disposal Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.


Table of Contents Introduction 6 Ibuprofen 8 Chemical information . wl Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality .. 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Chemical information 20 Product information 20 Chemical and physical properties 21 Particle characterization 21 Regulatory status 21 Specification 21 Medical indication 22 Ibuprofen Sodium Dihydrate 24 Chemical information 24 Product information 24 Storage 25 Regulatory status 25 Specification 25 Medical indication 26 Table of Contents Introduction Ibuprofen 8 Chemical information 8 Chemical and physical properties 9 Particle characterization 10 Ibuprofen DC 85 W 12 General information on processing of Ibuprofen 14 ZoomLab Your Virtual Formulation Assistant 15 Example formulations 16 Handling & Safety 18 Product specification 18 Regulatory & Quality 18 Publications 18 PRD and article numbers 18 MyProductWorld & RegXcellence 19 Racemic Ibuprofen Lysinate (RIBL) 20 Ibuprofen Racemic Ibuprofen Lysinate (RIBL) Ibuprofen Sodium Dihydrate Ibuprofen Sodium Dihydrate


Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, antipyretic and anti-inflammatory actions, it is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever. Due to its analgesic, antipyretic and anti-inflammatory actions, it is used The common active ingredient dosage in tablets is 200, 400, 600 and 800 mg. The OTC dosage forms are mainly the 200 and 400 mg forms (except for the United States and some other countries, where the 200 mg form is the only OTC form). Other common dosage forms are capsules, syrups, suspensions, suppositories, and topical dosage forms like creams and gels. Pharmacokinetics Orally administered ibuprofen is absorbed rapidly in the Gl tract.? After a single oral dose on an empty stomach, peak plasma levels are reached within 45 to 90 minutes and the apparent plasma volume of distribution is reported to be between 0.1 to 0.2 I/kg.-> Ibuprofen has an extensive protein binding capacity (+98%) and is excreted via the kidneys. The biological half-life is between 2 and 4 hours.? After 24 h, 100% of the active substance is excreted in the urine.
Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as histamine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C. bata Te Ta Tort) U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Gillespie, W. R. et al., Relative Bioavailability of Commercially Available Ibuprofen Oral Dosage Forms in Humans, Journal of Pharmaceutical Sciences, 71:1034-1038, 1982. Verbeeck, R. K., Pathophysiologic Factors Affecting the Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs, Journal of Rheumatology, 15:44-57, 1988. Jamali, F. and D. R. Brocks, Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers, Clinical Pharmacokinetics, 19:197-217, 1990. Vowles, D. T. and B. Marchant, Protein Binding of Ibuprofen and Its Relationship to Drug Interactions, British Journal of Clinical Practice, 1:13-19, 1980. Whitlam, J. B. and K. F. Brown, Ultrafiltration in Serum Protein Binding Determinations, Journal of Pharmaceutical Science: Tio Teel atc oa Rudy, A. C. et al., Stereoselective Metabolism of Ibuprofen in Humans: Administration of R-, S- and Racemic Ibuprofen, Journal of Pharmacology and Experimental Therapeutics, 259:1133-1139, 1991. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(6): 986-1000, 2011.
Ibuprofen (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid Chemical name (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid 15687-27-1 239-784-6 C,,H,,0. 13) 182 206.28 g/mol CAS number EINECS number Molecular formula Molecular weight 3ASF offers 4 grades based on different particle size distributions (see particle charac- erization). Furthermore, a direct compressible grade is offered: Ibuprofen DC 85 W, the somposition of which can be found in chemical and physical properties section below. Product grades (+)-2-[4-(2-methylpropyl)phenyl]propanoic acid; (+)-Benzeneacetic acid, alpha-methyl- 4-(2-methylpropy)); (+)-p-lsobutylhydratropic acid; (+)-2-p-lsobutylphenylpropionic acid Ibuprofen meets the current Ph. Eur., USP, JP and IP monographs. DMFs and CEP are available upon request. Regulatory status Ibuprofen is the racemate of (+)-lbuprofen and (-)-lbuprofen (optical rotation = 0). According to the literature the pharmacologically active form is (+)-lbuprofen. Approximately 30 to 70% of the (-)-lbuprofen is converted to the active form (+)-lbuprofen in the body. This process proceeds solely from the (-)- form to the (+)- form.
Chemical and physical properties Ibuprofen grades 25, 38, 50, 70 Crystalline powder Solubility in phosphate buffer pH 7.2 (37 C) Partition coefficient n-octanol/water The chemical parameters of all pure ibuprofen powder grades are identical. The only difference is the particle size distribution (see particle characteristics).
Particle characterization Ibuprofen 25 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 25 is between 20 um and 33 pm. Ibuprofen 50 Particle Size Distribution Bulk density Tapped density An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 50 is between 45 um and 60 pm. Approximately 0.34 g/ml. Approximately 0.60 g/ml.
Ibuprofen 38 Particle Size Distribution An example of the particle size distribution, as determined by lase diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 38 is between 33 um and 45 pm. ibuprofen 70 Particle Size Distribution Bulk density Approximately 0.38 g/ml. Tapped density Approximately 0.68 g/ml. An example of the particle size distribution, as determined by laser diffraction using a dry powder morphology, is given in the diagram above. The median particle size for Ibuprofen 70 is between 60 pm and 85 pm.
Ibuprofen DC 85 W The ibuprofen used to manufacture Ibuprofen DC 85 W meets the current Ph. Eur., USP, JP and IP monographs. A Technical Package and a US-DMF are available upon request. Granules, free flowing, homogeneous material Appearance SEM photograph
Recommendation for direct compression Today the manufacturing of ibuprofen tablets is often done by direct compression. Using this method, the expensive and time-consuming wet granulation method can be avoided. But in general, ibuprofen has the disadvantage of sticking on the tablet tools so that the process must be interrupted often. Therefore, direct compression formulations with a high content of ibuprofen per tablet are often avoided. Mostly tablets with an ibuprofen content of maximum 60% are compressed. BASF offers a formulated ibuprofen product ideal for direct compression: Ibuprofen DC 85 W. The direct compression (DC) grade ensures that tablet sticking is minimized and allows for excellent tablet engraving. Furthermore, Ibuprofen DC 85 W has a lower angle of repose compared to standard grades, resulting in improved flowability.
General information on processing of Ibuprofen Ibuprofen is used mainly in three (3) different dosage forms: Ibuprofen 50, Ibuprofen 70, Ibuprofen DC 85 W (for direct compression) Recommended grade(s) High concentrations of magnesium stearate as a lubricant are not recommended. For direct compression, the ready-to-use Ibuprofen DC 85 W reduces sticking. For a film coating, Kollicoat IR has a reduced viscosity in aqueous solutions compared to HPMC suspensions, which leads to higher solids content and a faster coating process. Formulation guidance Creams & Gels Recommended grade(s) Recommended grade(s) To stabilize against sedimen- tation, fine particles should be used. The pH of the sus- pension should be in the acid range so that ibuprofen is undissolved, which will reduce bitter taste if any. lbuprofen is dissolved in the ipophilic phase of creams, thus there is no impact of particle size. Propylene glycol or low molecular weight polyethylene glycols are recommended as the oily component. Formulation guidance Formulation guidance
-oomLab - Your Virtual Formulation Assistant Access example formulations and build your own ZoomLab Formulation Wizard identifies suitable excipients and calculates potential formulations depending on the selected dosage form, defined target profile, and properties of the active ingredient. Example formulations include creams, tablets, and more! - Evaluate bioequivalence of your final formulation A WHO biowaiver monograph is available for ibuprofen. The ZoomLab dissolution module can be used to calculate difference and similarity factors (f1, f2) required for showing bioequivalence. ZoomLab provides values for parameters relating to particle size, powder density, flowability, and tabletability. The parameters are scaled from 0 to 10, a risk analysis is run, and an interpretation of results/formulation advice is provided.
Example formulations Production of granules for 200, 400, 600 and 800 mg forms The following ingredients are placed in a high shear mixer and granulated with water: Ibuprofen 50 60.1% w/w Amount of water: approximately 0.2 kg water per 1 kg __ ibuprofen. Wet sieving (4 mm) and drying in a fluid bed Lactose 18% w/w granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following Corn starch 9% w/w additives to form granules suitable for tableting. Kollicoat IR 3.6% w/w Extra granular material Avicel PH 102 3.6% w/w AcDiSol 4.8% w/w Magnesium stearate 0.6% w/w Aerosil 200 0.3% w/w Coating formulations for Ibuprofen tablets oes Fraction with reference to the Fraction with reference Composition atomised suspension [%] to the dry film [%] Polymer Kollicoat IR 16.0 64 Pigments Talc 6.0 24 Sicovit Red 30 3.0 12 Total 25 100 Amount of water: approximately 0.2 kg water per 1 kg ibuprofen. Wet sieving (4 mm) and drying in a fluid bed granulator at 60 C (inlet air) for approximately 30 minutes and sieved dry (1 mm). The batch is mixed with the following additives to form granules suitable for tableting. Corn starch Kollicoat IR Extra granular material Magnesium stearate Coating formulations for Ibuprofen tablets
Handling & Safety Product specification The current version of the product specification is avail- able on RegXcellence or from your local BASF sales representative. Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on MyProduct- World or from your local BASF sales representative. Publications Regulatory & Quality Publications including scientific posters are available on: Please refer to the individual document quality & regu- latory product information (QRPI) which is available on RegXcellence and from your local sales representative The QRPI covers all relevant information including retest dates and storage conditions.
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Racemic Ibuprofen Lysinate (RIBL Racemic Ibuprofen Lysinate (RIBL Chemical information Chemical information Ibuprofen Lysinate (+) (+)- (+ (+ -2-[4-(2-methylpropyl)phenyl]propanoic acid lysinate -Benzeneacetic acid, alpha-methyl-4-(2-methylpropyl) lysinate -p-lsobutylhydratropic acid lysinate -2-p-lsobutylphenylpropionic acid lysinate Empirical formula Molecular weight
Chemical and physical properties White to almost white, very fine crystalline powder witt a high volume. In the literature the solubility of Ibuprofen (acid) in distilled water is reported to be less than 0.1%. The solubility of Ibuprofen Lysinate is 1:5, or about 17%. Particle characterization An example particle size distribution is shown below. The median particle size for RIBL is approximately 10 pm Regulatory status No monographs exist. E-DMF is available upon request.
The term RIBL is the acronym for Racemic Ibuprofen Lysinate. Racemic signifies that the ibuprofen drug substance and the lysine anion are both racemic compounds. RIBL differs from the common ibuprofen acid, gen- erally referred to as ibuprofen, in that it is more rapidly absorbed from the intestinal tract and reaches peak plasma levels and t,,., more quickly. After absorption, RIBL is available in the form of pure ibuprofen acid and is therefore to be handled like ibuprofen. Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, anti- pyretic and anti-inflammatory effects, ibuprofen is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, headache, and fever.? For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. For RIBL the usual dosage ranges are tablets containing 340 mg and 680 mg. RIBL has not yet been approved in the USA. Pharmacokinetics RIBL is readily and quickly absorbed from the gastrointestinal tract.!? The peak plasma level of the free acid is reached within 30 to 60 min (with the free acid ibuprofen, t,,,, was measured between 60 and 120 minutes, depending on the dosage form).: After absorption, there is no difference between RIBL and the free acid.
From a pharmacological point of view, there is no difference between RIBL and the free ibuprofen acid because it is the free acid and not the RIBL salt that is the active form. The mode of action of ibuprofen, while not completely understood, is believed to involve reversible inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have among other properties a powerful effect on the smooth muscles. In case of inflammatory stimuli or blood flow disorders, PGs are synthesized in increased amounts, making the tissues sensitive to the action of other agents such as histamine and kinins. As a result, symptoms like pain and inflammation occur. The in- cidence of fever is raised by the influence of the PGs on the heat regulation center in the hypothalamus. There they scale up the normal set point of 37 C. bats CUe Ta Tort) 1 Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration of Ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990. Hermann, T. W. et al., Bioavailability of Racemic Ibuprofen and its Lysinate from Suppositories in Rabbits, Journal of Pharmaceutical Sciences, 82(11):1102-1111, 1993. U.S. Food & Drug Administration Ibuprofen Drug Facts Label Revised 6 April 2016. Neupert, W. et al., Effects of lbuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vascular Biology, 31(5): 986-1000, 2011. Davies, N. M., Clinical Pharmacokinetics of Ibuprofen, Clinical Pharmacokinetics, 34:101-154, 1998. Martin, W. et al., Pharmacokinetics and Absolute Bioavailability of Ibuprofen After Oral Administration o ibuprofen Lysine in Man, Biopharmaceutics & Drug Disposition, 11(3): 265-278, 1990.
Ibuprofen Sodium Dihydrate Chemical information Ibuprofen Sodium Dihydrate 2-(4-isobutylphenyl)-propionate sodium dihydrate Chemical name Se IS ee ee ee a en re ae ee ee 31121-93-4 C,,H,,0,Na x 2 H,O 228.26 + 36.03 g/mol Empirical formula Molecular weight
Storage Ibuprofen Sodium Dihydrate should be stored in the original, tightly sealed container. It should be placed ina well-ventilated room at ambient temperature and protected from light. The retest period of Ibuprofen Sodium Dihydrate is 60 months for material stored in the original, unopened containe! and according to our recommendations. Regulatory status Currently there are no monographs describing Ibuprofen Sodium Dihydrate in the major Pharmacopoeias (USP, Ph. Eur.. and JP).
According to the literature, ibuprofen sodium dihydrate dissolves more quickly in vitro and is absorbed into blood plasma more quickly than con- ventional ibuprofen, whereas tolerability and safety profiles of the two APIs are comparable.? In an investigation of the dissolution, plasma pharmacokinetics, and safety of ibuprofen sodium dihydrate versus conventional ibuprofen, the following results were reported:? @ buprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 compared to conventional ibuprofen. @ lbuprofen sodium dihydrate reached the t,,,, significantly earlier than conventional ibuprofen. @ lbuprofen sodium dihydrate showed significantly higher c_, compared to conventional ibuprofen. @ buprofen sodium dihydrate was characterized by significantly higher mean plasma concentration (10 min post-dose) compared to conventional ibuprofen. tax iS the necessary time until the maximum plasma concentration of a drug is reached; this is relevant for the drug onset. Generally, reaching the t_ early is of great advantage for analgesic treatment. According to the literature, the first signs of pain relief occurred significantly earlier in ibuprofen sodium dihydrate treated patients, and pain intensity was reduced to half after 30 min for ibuprofen sodium dihydrate compared to 57 min for conventional ibuprofen. In summary, ibuprofen sodium dihydrate causes faster and more efficient pain relief during the first hour after oral intake compared to conventional ibuprofen.
The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (CO)) which is responsible for the biosynthesis of prostaglandin (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues and have, among other properties, a powerful effect on the smooth muscles. In case of an inflamma- tory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitize the tissues to the action of other agents such as hista- mine and kinins. As a result, symptoms such as pain and inflammation appear. Fever occurs by the influence of the PGs on the heat regulation center in the hypothalamus. There they raise the normal body temperature of 37 C.? c Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandii Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997. Ricciotti, E. and G. A. FitzGerald, Prostaglandins and Inflammation, Arteriosclerosis Thrombosis, and Vas FeYToltote CHI (2) Rc) =\ coal O00 Soergel, F. et al. Pharmacokinetics of Ibuprofen Sodium Dihydrate and Gastrointestinal Tolerability of Short-Term Treatment with a Novel, Rapidly Absorbed Formulation, International Journal of Clinical Pharmacology and Therapeutics. 43(8):140-149, 2005. Schleier, P. et al., Ibuprofen Sodium Dihydrate, an Ibuprofen Formulation with Improved Absorption Characteristics, Provides Faster and Greater Pain Relief than Ibuprofen Acid, International Journal of Clinical Pharmacoloay and Therapeutics. 45(2):89-97. 2007. Neupert, W. et al., Effects of Ibuprofen Enantiomers and Its Coenzyme a Thioester on Human Prostaglandir Endoperoxide Synthases, British Journal of Pharmacology, 122:487-92, 1997.
www.pharma.basf.com For sample requests contact us ai pharma-solutions@basf.com Meet your Virtual Pharma Assistants! ZoomLab, RegXcellence, and MyProductWorld, your interactive guides for optimizing drug formulations, navigating quality and regulatory compliance, and browsing ingredients. Learn more and sign up at https://info-mypharma.basf.com/ Inspiring Medicines for Better Lives This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been preparec in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury to the extent caused by BASFs sole negligence, (ii) BASFs willful misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertake your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) The user is responsible for confirming that the user has retrieved the most current version of this document from BASF as appropriate RegXcellence is a registered trademark of BASF. 2021 BASF Corporation. All Rights Reserved.
Technical Information Kollidon VA 64 and Kollidon VA 64 Fine are vinylpyrrolidone-vinyl acetate copolymers. They are used in the pharmaceutical industry as dry binder in tablets, as matrix formers for amorphous solic dispersions, as retarding and as film-forming agents. July 2022 Supersedes issue dated March 2019 Last change WF-No. DAWF-2022-0821 = Registered trademark of BASF in many countries.
1. Introduction Kollidon VA 64 and Kollidon VA 64 Fine are vinylpyrrolidone-vinyl acetate copoly- mers which are soluble both in water and in alcohols. They are well-known by thei monographic name Copovidone or Copolyvidone. In the pharmaceutical industry they are widely used as dry and wet binder in tablets, as film forming agent or ir retard formulations. A major application of Kollidon VA 64 is as matrix in amorphous solid dispersions. For further details that are beyond the scope of this leaflet, please consult the book, Kollidon Polyvinylpyrrolidone excipients for the Pharmaceutical Industry (03_030748e). 2. Technical properties Description Kollidon VA 64 and Kollidon VA 64 Fine are spray dried polymer powders of a co- polymer derived from the monomers N-vinylpyrrolidone (NVP) and vinyl acetate (VAc) with a weight ratio of approx. 6:4. The powders are white or slightly yellowish, have a faint characteristic odor and practically no taste. CAS-number 25086-89-9 Structural formula Infrared spectrum The infrared spectrum shown in Fig. 1 was obtained with a tablet of Kollidon VA 64 in potassium bromide. Arrows indicate where the spectrum differs from that of povidone.
Molecular weight The average molecular weight is usually expressed as a K value. The exact weight- average molecular weight, Mw of the product is best determined by measuring the light scatter of a solution. Values in the range of 45,000 - 70,000 have been determined for Kollidon VA 64 and Kollidon VA 64 Fine. Solubility Kollidon VA 64 and Kollidon VA 64 Fine readily dissolve in all hydrophilic solvents. Solutions of more than 10% concentration can be prepared in: water, ethanol, isopropanol, methylene chloride, glycerol and propylene c Viscosity The values shown in Fig. 2 were determined at 25 C in a capillary viscometer. They represent typical values. Fig. 2: Viscosity of Kollidon VA 64 in water and isopropanol. Bulk density The bulk density of Kollidon VA 64 Fine usually lies in the range of 0.08 0.15 g/ml. The bulk density of Kollidon VA 64 is above that one of Kollidon VA 64 Fine and is in the range of about 0.2 0.4 g/ml. Particle size distribution Typical values for the particle size of Kollidon VA 64 and Kollidon VA 64 Fine are as follows: Kollidon VA 64 Kollidon VA 64 Fine >250 um [%] max. 7% max. 2% <50 um [%] max. 35% min. 35%
Hygroscopicity Kollidon VA 64 and Kollidon VA 64 Fine absorb only about one third of the quantity of water absorbed by povidone, e.g. Kollidon 30 (Fig. 3). Fig. 3: Hygroscopicity of Kollidon VA 64 and Kollidon 30. 3. Example application General Copovidone has been used for decades in the pharmaceutical industry. Up to about 1975 it was marketed under the name of Luviskol VA 64, which today is used only for the technical/cosmetic grade of this copolymer. This is why older publications often refer to the use of Luviskol VA 64 in pharmaceuticals. Binder for tablets and granules Kollidon VA 64 and Kollidon VA 64 Fine are excellent binders for tablets and granules. Between 2% and 8%, as a proportion of the final weight of the preparation, is usually used. An important property of Kollidon VA 64 and Kollidon VA 64 Fine in this application is the plasticity, which distinguishes the products from povidone (e.g. Kollidon 30). This property often gives granules and mixtures that are less susceptible to capping during tabletting, and tablets that are less brittle. Dry Binder for direct compression Kollidon VA 64 and Kollidon VA 64 Fine have been found to be excellent dry binders for direct compression. Especially the Kollidon VA 64 Fine gives much better results than any of the Povidone grades or other dry-binders of the group of cellulose derivatives. The hardness, friability, porosity and disintegration time of lactose and starch placebo tablets produced with Kollidon VA 64 are directly related to the compression force used (see Table 1).
Table 1: Tablet properties related to the compression force Compression Hardness Friability Porosity Disintegration force time [kp] IN] [%] [%] [s] 500 23.5 3.07 13.03 17 1000 55.8 0.98 6.87 58 1500 61.7 0.59 6.41 77 2000 65.7 0.49 5.33 90 2500 67.6 0.35 5.07 102 Kollidon VA 64 and Kollidon VA 64 Fine can be added to materials such as sorbitol, mannitol, starch, or direct compression aids, e.g. micro crystalline cellulose, whose own binding strength is inadequate, to give tablets with very good properties. Table 2, for example, is suitable for direct compression. The literature contains a large number of vitamin formulations with Kollidon VA 64 (see Generic Drug Formulations latest edition). Table 2: Ascorbic acid chewable tablets 100 mg Ascorbic acid powder 42.4% Sucrose ground 13.0% Sucrose crystalline 8.0% Microcrystalline cellulose 28.3% Kollidon VA 64 2.4% Polyethylene glycol 6000 powder 2.0% Orange aroma + strawberry aroma (2 + 1) 1.2% Cyclamate sodium 2.4% Saccharin sodium 01% Aerosil 200 0.2% Equipment Rotary press: Korsch PH 100/6 Punch diameter: 8 mm, biplanar Speed: 30 rpm Tablet Properties: Weight 250 mg Hardness 157N Friability <0.1% The following examples show the properties of Kollidon VA 64 Fine in formuations for direct compression.
Table 3: Acetyl salycilic acid tablets 500 mg formulated with Kollidon VA 64 Fine Acetylsalicylic acid 500.0 mg Avicel PH 102 200.0 mg Kollidon VA 64 Fine 60.0 mg Kollidon CL 25.0 mg Magnesium stearate 3.0 mg Total 788.0 mg TNUMIGUOTT VEN OS TIS MYM TYE Kollidon CL 25.0 mg Magnesium stearate 3.0 mg 788.0 mg Total The individual components were sieved through a 0.8 mm sieve. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN respectively. Equipment Rotary press: Korsch PH 100/6 Punch diameter: 12 mm beveled edge Speed: 30 rpm Tablet properties Compression _ Tablet weight Hardness Disintegration _ Friability Force [kN] [mg] [IN] [min:sec] [%] 6.8 772.3 81 04:13 0.4 10.7 777.5 140 08:25 0.2 16.5 768.0 187 15:03 <0.1 788.0 mg The individual components were sieved through a 0.8 mm sieve. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN respectively. Tablet properties Compression _ Tablet weight Hardness Disintegration Friability Feu [mg] [IN] [min:sec] [%] 6.8 772.3 81 04:13 0.4 10.7 777.5 140 08:25 0.2 16.5 768.0 187 15:03 <0.1 Table 4: Indomethacin Tablets 50 mg formulated with Kollidon VA 64 Fine Indomethacin Kollidon VA 64 Fine 20.0 mg Di-tab 212.0 mg Kollidon CL 15.0 mg Magnesium stearate 3.0 mg 300.0 mg Total The individual components were sieved through 0.8 mm. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN, respectively. Equipment Rotary press: Punch diameter: Speed: Equipment Rotary press: Punch diameter: Speed: Korsch PH 100/6 8 mm, beveled edge 30 rpm
Tablet properties Compression Tablet weight Hardness _ Disintegration Friability Force [kN] [mg] [IN] [min:sec] [%] 5.6 301.9 62 00:22 0.16 9.7 304.5 101 00:36 <0.1 15.9 304.0 158 01:12 <0.1 Table 5: Atenolol Tablets 50 mg formulated with Kollidon VA 64 Fine Atenolol 50.0 mg Ludipress 135.7 mg Kollidon VA 64 Fine 15.0 mg Kollidon CL 25.0 mg Aerosil 200 1.3mg Magnesium stearate 3.0 mg Total 230.0 mg Total The individual components were sieved through 0.8 mm. After a blending time of 10 minutes in a Turbula Blender the powder blend is compressed with compression forces of 6, 10, and 18 kN, respectively. Korsch PH 100/6 8 mm, beveled ed: 30 rom Tablet properties Compression _ Tablet weight Hardness Disintegration Friability Force [kN] [mg] [IN] [min:sec] [%] 5.8 230.8 94 03:54 <0 9.6 221.4 132 04:14 <0.1 15.8 218.6 147 05:08 <01
Wet granulation Kollidon VA 64 and Kollidon VA 64 Fine can also be used as a binder in wet granulation for the production of tablets and granules, since it is readily soluble in all the usual solvents. It can then be added either as a solution during granulation, or dry to the other ingredients, in which case the solvent is added alone during granulation. Trials so far conducted with both methods, using equal quantities of liquid, produced tablets of much the same hardness. A combination of the two methods, i.e. mixing some of the Kollidon VA 64 with the active ingredient, and dissolving the rest in the solvent, sometimes gives the best results. This is particularly recommended if the active ingredient does not readily absorb the solvent. Since it is less hygroscopic than povidone (e.g. Kollidon 25 or 30), Kollidon VA 64 gives granules that have less tendency to stick to the punches of the tabletting machine, when operating under humid conditions. The binding power of Kollidon VA 64 is comparable to that of Kollidon 25 and Kollidon 30. The formulations in Table 3 are typical of those used for producing tablets by wet granulation (see Generic Drug Formulations, latest edition). Table 6: 500 mg ampicillin tablets and 400 mg cimetidine tablets formulatec with Kollidon VA 64 Ampicillin trinydrate 500 g i Cimetidine = 400 g Corn starch 242 g 170g Il Kollidon VA 64 25g 20g lsopropanol or water q.s. qs. Ill Kollidon CL 15g - Magnesium stearate 10g 3g Aerosil 200 89g = Mixture is granulated with solution Il, dried and sieved. The granules are then mixed with Ill and pressed into tablets at low to medium pressure. Tablets obtained in the laboratory had the following properties: Weight 798 mg 601 mg Diameter 16mm 12mm Hardness 170 N 91N Disintegration in gastric juice 5 min 91 min Friability 0.35% 0.5% Dissolution (USP) 10 min: 62% 20 min: not 91% 30 min: tested 100% Apart from its use in tablets, Kollidon VA 64 can also be used to produce very stable granules, e.g. for instant multivitamin drinks.
Roller compaction Kollidon VA 64 Fine was specifically suitable for the application in roller-compaction and is the material of choice in terms of particle size distribution and particle shape for this application. Due to the particle size it is able to cover a bit surface area and to form numerous bridges in the tablet structure that lead to hard tablets with a reduced friability. The formulations in tables 4 and 5 are typical examples for Kollidon VA 64 Formulation using this technique. Table 7: Allopurinol Tablets 300 mg formulated with Kollidon VA 64 Fine 1. Allopurinol 100.0 mg 2. Ludipress 50.0 mg 3. Kollidon VA 64 Fine 10.0 mg 4. Kollidon CL 6.0 mg 5. Magnesium stearate 1.0 mg 2. Ludipress 50. 3. Kollidon VA 64 Fine 10. 4. Kollidon CL 6. 5. Magnesium stearate 1. The compounds were compacted using a Gerteis compactor under the follc conditions Roller compactor: Gerteis Type Mini-Pactor M1114 Roll width: 25mm Compression force: 2 kN/cm Gap width: 3mm Tamping/feeding ratio: 120% Roll speed: 2 rpm Mesh sizes 1.25 mm Aftar camnartinn the matorial wae hlanded far 10 mini tac in a Thirhiila hlander wy 1e compounds were compacted using a Gerteis compactor ur ditions ler compactor: oll width: ompression force: ap width: imping/feeding ratio: Il speed: esh sizes Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm The compounds were compacted using a Gerteis compactor under the following conditions After compaction the material was blended for 10 minutes in a Turbula blender with the remaining Ludipress and the magnesium stearate and tableted as follows. Allopurinol compacted formulation 167.0 mg Ludipress 133.0 mg Magnesium stearate 1.0 mg Total weight 301.0 mg Equipment Tablet press: Korsch PH 100/6 Compression force: 18kKN Punch diameter: 8 mm, beveled edge Compression speed: 30 rpm Tablet properties: Compression _ Tablet weight Hardness Disintegration _ Friability force time [kN] [mg] [IN] [min:sec] [%] 16.4 280.8 246 09:29 <0 Allopurinol compacted formulation Tablet properties: Compression _ Tablet weight Hardness Disintegration Friability force time [kN] [mg] [IN] [min:sec] [%] 16.4 280.8 246 09:29 < 0.1
Table 8: Paracetamol Tablets 300 mg formulated with Kollidon VA 64 Fine Paracetamol Powder 500.0 mg 2. Avicel PH 102 131.0 mg 3. Kollidon VA 64 Fine 45.0 mg 4. Kollidon CL 21.0 mg 5. Aerosil 200 5.0 mg 6. Magnesium stearate 3.0 mg Se See Se eee The compounds 1 to 6 were compacted using a Gerteis compactor und following conditions. Roller compactor: Roll width: Compression force: Gap width: Tamping/feeding ratio: Roll speed: Mesh size: Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm The compounds 1 to 6 were compacted using a Gerteis comp following conditions. Roller compactor: Roll width: Compression force: Gap width: Tamping/feeding ratio: Roll speed: Mesh size: Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm me COMpounas to 6 Were COMpacted USING a GEItelSs COMPpactor following conditions. Roller compactor: Roll width: Compression force: Gap width: Tamping/feeding ratio: Roll speed: Mesh size: Gerteis Type Mini-Pactor M1114 25mm 2 kN/cm 3mm 120% 2 rpm 1.25 mm After compaction the material was blended for 10 minutes in a Turbula blender with the remaining Kollidon CL and the magnesium stearate and tableted as follows. Paracetamol compacted formulation 695.0 mg Kollidon CL 7.0 mg Magnesium stearate 3.0 mg Total weight 705.0 mg Equipment Tablet press: Korsch PH 100/6 Compression force: 18 kN Punch diameter: 12 mm, beveled edge Compression speed: 30 rpm Tablet properties: Compression _ Tablet weight Hardness Disintegration _ Friability force [kN] [mg] [N] [min:sec] [%] eR AN:42 I7F7R RQ2Q Tablet properties: Compression _ Tablet weight Hardness Disintegration _ Friability force [kN] [mg] [N] [min:sec] [%] 17.6 683.8 66 00:18
Film-coating Kollidon VA 64 forms films that are soluble at all pH values. They are less hygroscopic and more elastic than those formed by povidone (e.g. Kollidon 30). Nevertheless, Kollidon VA 64 usually still absorbs too much water, so that it can seldom be used as the sole film-forming agent in a formulation. It is therefore recommended to combine it with less hygroscopic substances such as cellulose derivatives, shellac or poly- ethylene glycol. Plasticizers are normally not required. The formulations in Tables 4 and 5 are typical formulations for tablet coatings. They were tested on 9 mm diameter, 3.4 mm thick, 200 mg placebo tablet cores in the laboratory. Kollidon VA 64 significantly improves their brittleness and solubility when it is combined with cellulose derivatives. When it is used in film coatings based on shellac, the properties of the film are more consistent. Table 9: Sugar film coating (Accela Cota 24) Suspension: Sucrose 200 g Kollidon VA 64 50g Macrogol 4000 40g Sicovit color lake 15g Sicovit titanium dioxide 30g Talc 50g Water ad 1,200 g Sontinuously spray 1,200 g of this suspension onto 5 kg of tablet cores. The spray conditions are as follows: Continuously spray 1,200 g of this suspension onto 5 kg of tablet cores. The spray conditions are as follows: BAR SAGEM SE NANA TAN RNR ER, Set sae eta: NAL NE Nea Inlet air temperature 45C Outlet air temperature 36 C Nozzle diameter 0.8 mm Spraying pressure 2.0 bar Coating pan speed 15 rpm Spraying time 50 min Quantity of film former applied 4 mg/cm?
Table 10: Film coating with Hypromellose (Accela Cota 24) Kollidon VA 64 53 g PEG 6000 12 g HPMC 6 mPa:s 79 g Water 732 g Il Sicovit Titanium Dioxide 36 g Sicovit Iron Oxide Red 30 18 g Talc 54 9 Water 216 g Total 1200 g Mix Solution with Suspension II, pass through a disc mill. The spray dispersion is calculated to be suitable for 5 kg of cores. The quantity of film former applied is about 3 mg/cm?. The cores size was 9 mm, biconvex. The coating process is performed using the following conditions: Pan speed 12 rpm Spraying rate [1 nozzle] 50 g/min Spraying time 34 min Quantity of applied film former 3.1. mg/cm? 5 min Final drying at 60 C Subcoating If it is intended to coat tablet cores with aqueous solutions or suspensions, it is recommended to provide them with a barrier if they contain a watersensitive active ingredient or a highly effective disintegrant (e.g. Kollidon CL) that is activated by water. This also applies if the cores are too soft or if their adhesive properties are inadequate for aqueous coatings. The cores are warmed to about 35 C and sprayed with a 10% solution of Kollidon VA 64 dissolved in an organic solvent, e.g. isopropanol, ethanol, ethyl acetate or acetone. As soon as a barrier film of adequate thickness has been built up, the aqueous coating can be applied. It has been found that 0.4 mg Kollidon VA 64/cm? is adequate. Sugar-coating Kollidon VA 64 is used in sugar-coating to improve the adhesion of the coating to the surface of the tablet core and to increase the capacity of the coating solution for pigments and improve their dispersibility. However, Kollidon VA 64 helps not only in the application of sugar coatings but also in the automation of the sugar-coating process.
Sprays Because of its good film-forming properties, Kollidon VA 64 can also be used in topical sprays. The formulation in Table 6 provides a typical example of a spray bandage. Table 11: Polidocanol wound spray SERA Gira SNE Mee ee Polidocanol 5g Lutrol E 400 20g Kollidon VA 64 50g Ethocel 20 (Dow) 50g Ethyl acetate 675 g lsopropanol 200 g Fill this solution into spray cans together with the necessary quantity of propellant. Amorphous Solid Dispersions Poorly water-soluble drugs are a constant and growing challenge within the pharmaceutical industry. One proven and viable technology to overcome this challenge is the production of amorphous solid dispersions or ASDs. ASDs are prepared by dissolving the poorly soluble drug within a polymeric matrix, which then releases the drug upon contact with aqueous media, and results in an overall increase of drug solubility and dissolution rate. ASDs may be prepared using well proven methods such as hot melt extrusion, or for temperature sensitive drugs, spray drying. For both technologies, Kollidon VA 64 has proven its suitability to generate thermodynamically and kinetically stable forms of solid API dispersions in a polymer matrix. Amorphous Solid Dispersions by melt extrusion The formulation of stable amorphous solid dispersion by melt extrusion based on Kollidon VA 64 has been established for more than two decades. This polymer has proved its suitability for this application because of its low glass transition temperature (101 C), high temperature resistance (up to 220 C) and optimum thermorheological properties. A number of product parameters have been optimized to minimize degradation of the API during melt extrusion and to ease powder handling. First, the LOD/water content of Kollidon VA 64 was adjusted to a level below the compendial upper limit to reduce the concentration of AP! degradation products during processing. Secondly, the particle size and morphology were optimized to reduce dust formation during powder dispensing, mixing operations and extruder feeding. The resulting intermediate extrusion products can be processed downstream by either filling them directly into hard gelatin capsules or by subsequently milling the extrudates and processing tablet cores or coated tablets.
Amorphous Solid Dispersions by spray drying For the manufacturing of solid dispersions using spray drying, it is essential that both API and matrix polymer are soluble in a suitable volatile organic solvent. Kollidon VA 64 is soluble in a number of organic solvents (see section 2.5) at levels greatly exceeding 10 % [w/w] while simultaneously retaining a low viscosity, which is crucial for successful spray drying. An example of spray dried Kollidon VA 64 from methanol as a model solvent is shown in Figure 4. Figure 4: Spray dried Kollidon VA 64 from methanol from a 10% solution. The high solubility, when combined with the low viscosity of the achieved polymer/ API-solutions, as well as the strong thermodynamic and kinetic interactions with poorly soluble drugs, make this polymer an outstanding matrix polymer for this application. Inhibition of the crystallization of APIs in liquid soft gel formulations Another aspect to the challenge of poorly water-soluble drugs is the ability to retain them in solution once dissolved, thereby maximizing absorption during the transit time of the gastrointestinal tract. Compounds that expand this absorption window are often called crystallization inhibitors as they retain drugs in a supersaturated state for a prolonged time through what is known as the parachute effect. This is in contrast with the spring effect, where drugs immediately recrystallize once in contact with gastrointestinal media. Kollidon VA 64 exhibits these effects when utilized with poorly water-soluble compounds. In this case, the oral dose primarily includes a hard or softgel capsule where Kollidon VA 64 is dissolved in hydrophilic fill formulations such as low molecular weight polyethylene glycols (PEGs), such as Kollisolv PEG 400. With Kollidon VA 64, it is possible to prevent recrystallisation and to achieve a Parachute Effect in both low pH stomach conditions and high pH intestinal conditions. Under stomach conditions, this is shown in Figure 5 for the model poorly soluble drug Danazol with Kollidon VA 64 used at 5% w/w in a PEG 400 liquid fill. The effect is compared with known crystallization inhibitor Kollidon 12 PF and solubilizer Kolliphor RH 40, which exhibits a spring effect. Drug dissolution was determined using a Pion Inform system with 50 ml buffer system of pH 2.0 and pH 6,8, respectively, and 0.5 ml of liquid formulation representing the filling volume of a soft gel capsule.
Figure 5: Parachute effect of Kollidon VA 64 under stomach conditions (pH = 2). Under gastric, acidic conditions, the effect is self-evident, showing Kollidon VA 64 with a significantly improved absorption window. Under intestinal conditions, the same effect is achieved, as shown in Figure 6. Figure 6: Parachute effect at pH 6.8 under intestinal conditions. Under intestinal conditions, a classic spring model for Kolliphor RH 40 is observed, while very little effect of Kollidon 12 PF is noted. However, Kollidon VA 64 shows a significantly improved absorption window.
4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on BASF RegXcellence or from your local BASF sales representative. 5. Product specification The current version of the product specification is available on BASF RegXcellence or from your local BASF sales representative. 5. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI) which is available on BASF WorldAccount, RegXcellence , and from your local sales representative The QRPI covers all relevant information including retest dates, and storage conditions. 7. Toxicology The safety of the polymer in Kollidon grades as pharmaceutical excipient in film coating of solid oral dosage forms is supported by a comprehensive non-clinical study. A summary of the study is available on BASF WorldAccount, RegXcellence or from your local sales representative. A detailed report can be shared as part of a non-disclosure agreement. https://worldaccount.basf.com, RegXxcellence (https://mypharma.basf.com/) 8. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30499395 Kollidon VA 64 60131775 35 kg PE drum with PE liner 30499398 Kollidon VA 64 50131776 35 kg PE drum with PE liner 30239644 Kollidon VA 64 Fine 57071976 15 kg Cardboard box with PE liner aluminium laminated BASFs commercial product number. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Glycerol Monostearate Functional excipient for semi-solid formulations and solid oral dosage forms. April 2019 Supersedes issue dated February 2016 WF-No. 137110 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes a total of ten products, most of them being predo- minantly used as consistency factors in topical applications. While the fatty acid and alcohol based products are summarized in the general Technical Information sheet on the Kolliwax grades, two products (namely Kolliwax HCO and Kolliwax GMS ! are provided with their own, dedicated technical information sheet due to the broac application areas: this document focuses on Kolliwax GMS II, our pharmaceutical grade glycerol monostearate, which covers a broad range of pharmaceutical applications ranging from a consistency factor and (co-)emulsifier in topical applications (i.e. lotions and creams), to solid oral dosage forms, where it can be used e.g. as a lubricant ir the tableting process, and/or as an anti-tacking agent for coatings. Kolliwax GMS II complies with the following compendial monographs: Ph.Eur.: Glycerol monostearate 40-55 (type II) USP/NF: Mono- and Diglycerides For further details please refer to the product specification sheet, as well < quality and regulatory product information (QRPI). Kolliwax GMS II complies with the following compendial monographs: Ph.Eur.: Glycerol monostearate 40-55 (type II) USP/NF: Mono- and Diglycerides For further details please refer to the product specification sheet, as well as the quality and regulatory product information (QRPI). yure 1: Chemical Structures of the major components that make up for Kolliwax GMS II. Lead components are the two monoglyceride compounds 1-glycerol monostearate (1), and 2-glycerol monostearate (2); according to the Ph.Eur. monography, these must make up for 40 - 55% of the mixture (hence the name). The product also contains the 1,3 and 1,2 diglycerides (3 and 4, respectively), as well as the triglyceride (5). Please refer to the products specification sheet for details on the distribution of the compounds, as well as possible ratios of C,,/C,, fatty acids. For simplicity reasons, only stearic acid (C,,) is shown in this scheme as the hydro- phobic moiety. 2. Technical properties Description Kolliwax GMS II is an off-white to slightly yellowish, waxy substance derived from natural resources such as coconut- and palm kernel oil. It contains mostly mono- and diesters of mainly stearic (C,,), but also palmitic (C,,) acid with glycerol (Fig. 1). Kolliwax GMS II is practically insoluble in water, but soluble in hot ethanol (> 50% at 60 C). Owing to free hydroxyl groups on the glycerol end of the molecule, the product exhibits an amphiphilic character that is reflected in the HLB value of approx. 3.8, and a melting point of 54 64 C, which is significantly higher than that of the respective triglycerides (please refer to the documents on our Novata Grades for further information). Kolliwax GMS II is an off-white to slightly yellowish, waxy substance derived fro! natural resources such as coconut- and palm kernel oil. It contains mostly mono and diesters of mainly stearic (C,,), but also palmitic (C,,) acid with glycerol (Fig. 1) Kolliwax GMS II is practically insoluble in water, but soluble in hot ethanol (> 505 at 60 C). Owing to free hydroxy! groups on the glycerol end of the molecule, the product exhibits an amphiphilic character that is reflected in the HLB value of approx. 3.8, and a melting point of 54 64 C, which is significantly higher than that of the respective triglycerides (please refer to the documents on our Novata Grades for further information).
Figure 2: Kolliwax GMS Il is provided as a free-flowing powder (left), consisting of spherical particles that are formed during the spray crystallization process. These structures can be seen in the scanning electron microscope image (right). Powder Characteristics The following values are typical for a representative sample of Kolliwax GMS II. However, as they are not part of the product specification, the values are for gui- dance only: Particle size distribution Figure 3: Typical particle size distribution of a Kolliwax GMS II sample. dig 198 um dso 383 ym oo 676 um Bulk density 0.52 g/cms Tapped density 0.61 g/cms Hausner factor 1.17 Angle of response 30.1 BET surface 1.0 m2/g
Differential Scanning Calorimetry Differential Scanning Calorimetry (DSC) was performed using 6.5 mg of sample material. At a rate of 10 C/min, the sample was heated to 120 C, cooled to 20 C, and reheated to 120 C. The DSC plot reveals that the melting point measured at the second melting incident has shifted to smaller temperatures compared to the initial value. This effect, commonly referred to as post-hardening, is known from other gly- cerides and can be explained by polymorphism: while the product predominantly crystallizes in its alpha form, ageing leads to a partial transformation into its beta form that has a slightly higher melting point. Figure 4: DSC plot of Kolliwax GMS II. The sample was heated (orange), subsequently cooled (gray), and reheated (black). 3. Application Overview Kolliwax GMS II is a versatile pharmaceutical formulation aid, featuring a broad range of applications, some of which are listed in the following table. Solid oral dosage forms Alternative for inorganic materials (e. g. Talc): e Lubricant in the (direct compression) tableting process Anti-tacking agent for coatings Skin delivery Consistency factor/(co-)emulsifier for topical formulations (creams and gels) Suppositories Matrix former/melting point correction factor LBDDS Lipophilic surfactant in lipid based drug delivery systems
Lubricant in the Tableting Process In the tableting process for solid oral dosage forms, lubricants are generally addec to the solid formulation to prevent ingredients from clumping to undesired aggregate: and from sticking to the tablet punches or capsule filling machine. Lubricants such as Kolliwax GMS II can reduce friction during tabletting, and also reduce the ejection force. In the example shown below, tablets were made from Ludipress, our lactose-basec direct compression excipient. Mixing was performed in a tubular blender at 5 min blending time, 10 mm flat tablets with 300 mg mass were then prepared with a Korsch XL 100 rotary press. When tableting is performed without any lubricant, the formulation tends to stick onto the punch faces, whereby the compression force is limited to approx. 5 KN. This, in return, results in tablets of very low hardness (merely 18 N, values are not shown in fig. 5). Kolliwax GMS II acts as an efficient lubricant at concentrations as low as 1.5 %, and has no measurable influence on hardness and disintegration time of the tablets (fig. 5). Figure 5: Top: Kolliwax GMS II reduces the ejection force (left), while raising the compression force of the lower punch (right). Bottom: The addition of Kolliwax GMS II to the formulation has no measurable influence on tablet strength (left), as well as dissolution time (right).
Anti-Tacking Agent for Coatings Kolliwax GMS II can be used as anti-tacking agent in the spray-coating process of tablets, pellets, and crystals. It will eliminate the need for talc, which is generally subject to sedimentation, which in return can lead to separation in the tubing system, clogging of the spraying nozzles, and inhomogeneous films. The following formulation example shows the use of Kolliwax GMS II in an enteric coating formulation based on Kollicoat MAE 30 DP. The core specimens, round- shaped tablets with 9.0 mm diameter, were comprised of: Name Chemistry Role Conc. [wt.-%] Ludipress LCE Lactose-based direct Filler 74.0 compression excipient Caffeine (gran. 0.2 - 0.5) API 15.5 Kollidon CL-F Crospovidone Disintegrant 5.0 Kollidon VA 64 VP / VA Copolymer Dry binder 5.0 Mg-Stearate Lubricant 0.5 Coating of the 9.0 mm round-shaped tablets was performed in a batch size of 4.0 kg using a vented pan coater (Manesty XL Lab 01) equipped with a middle-sized drum (480 mm) running at drum speed of 12 rpm. The inlet air quantity was set to 450 ms/t at a temperature of 55 C. A spray rate of 13 g/min was achieved by employing an OptiCoat spray gun with a bore diameter of 0.8 mm, with atomizing- and pattern air pressures set to 1.8 bar. Exemplary enteric coating formulation (1 kg) using Kolliwax GMS II as anti-tackin agent (see Fig. 6 for preparation procedure): Step Name Function Amount [9] 1 Water (first 50 %) Solvent 200 Kolliphor PS 80 Polysorbate Emulsifier 3.0 2 Kolliwax GMS II Anti-Tacking Agent 8.0 Triethyl Citrate Plasticizer 25.0 3 Water (remaining amount) Solvent 208 4 Kollicoat MAE 30 DP Enteric Coating Dispersion 556 (30 % solid content) Triethyl Citrate Water GMS Emulsion Kolliphor PS 80 EX peo) > i Kolliwax GMS II <30C . . bs <= <== ) ) Step1 Step 2 Step 3 Step 4 Surfactant Solution Emulsification GMS Emulsion Spray Suspension Dissolve Kolliphor PS 80 in approx. half of the total water amount, heat the solution to a temperature of 70-80 C. Add Kolliwax GMS Il and triethyl citrate while homogenizing with a high-shear mixer. Keep homogenizing the mixture for 10 min. Let the mixture cool under stirring while slowly adding the remaining half of the water amount. Slowly add the cold GMS Emulsion to the coating suspension, continue stirring to obtain a homo- geneous mixture. igure 6: Procedure for the preparation of a coating suspension containing Kolliwax GMS II as anti-tacking agent. Pigments can be dispersed into the remaining water amount and added accordingly in step 3. Before spraying, the suspension should be passea through a 0.5 mm sieve.
As the dissolution curves show (Fig. 7), Kolliwax GMS II has no measurable influence on dissolution. However, its anti-tacking effectiveness at concentrations as low as 4% (relative with respect to the dry matter of polymer) in combination with the stability of the suspension towards sedimentation make it a powerful additive in this application field. igure 7: Dissolution profiles of cores coated with different Kollicoat MAE 30 DP formulations with Kolliwax GMS II as insoluble component. Dissolution tests were performed at a padale speed of 50 rpm, at (37 + 0.5) C; O- 2 h 880 mL (0.08 mol/L HCI, pH = 1.1) 2-4h 900 mL (phosphate buffer, pH = 6.8). Given value: mean (n = 3) + std. dev. Consistency Factor/(Co-)Emulsifier in Topical Formulations A topical (semi solid) formulation is a complex mixture of ingredients with varying functionalities. The majority of these formulations are based on o/w or w/o emulsions where several different emulsifiers are typically required to achieve proper stabilization of the two-phase system. Depending on the nature of the API, the formulation needs to be adapted to deliver APIs that are either soluble in water, or in oil. The main function of Kolliwax GMS II in topical formulations is a (co-)emulsifier or consis- tency factor, which enhances the viscosity of the formulation. It is typically added in concentrations ranging from 0.1 to 15%. Glycerol monostearate is compatible with most vegetable and animal waxes and can therefore be used in combination with fatty alcohols and other consistency factors. Its relatively high melting point can aid increasing the high-temperature storage stability of an emulsion. Procedure for the preparation of example formulations: Figure 8: Scheme for the preparation of a topical formulation via the hot-hot process.
The following formulation can be prepared by the procedure outlined above. The emulsifier system comprised of Kolliphor PS 80 and Kolliwax GMS II with our versatile Emollient Kollicream 3 C yields a cream of medium viscosity (14 Pa-s @ 1s) with a smooth feel. Phase Ingredients Chemical name Role Mass [wt%] A Kollicream 3C = Cocoyl Caprylocaprate Emollient 20.00 Kolliphor PS 80 Polysorbate 80 Solubilizer, emulsifier 3.00 Kollwax GMS Il Glycerol Monostearate Consistency factor, 3.00 40-55 (Type II) co-emulsifier Kolliwax CSA 70 Cetostearyl Alcohol Viscogen, 5.00 consistency factor B Deionized Water Solvent 68.00 Euxyl PE 9010 Phenoxyethanol Preservative 1.00 Especially when used at high concentrations, Kolliwax GMS II may tend to crystallize, resulting in the formulations to weep or bleed (a phenomenon called syresis), and take on a dull appearance as well as a grainy texture. This effect can be prevented by adding stearic acid (Kolliwax S, or Kolliwax S Fine) to the formulation, or by in- creasing its content. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets (MSDS) are available on BASF WorldAccount, or from your local BASF sales representative. 5. Product specification The current version of the product specification is available on BASF WorldAccount or from your local BASF sales representative. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI) which i is available on BASF WorldAccount and from your local sales representative. he QRPI covers all relevant information: including. retest dates, and storage onditions. https://worldaccount.basf.com
7. PRD and Article numbers 7. PRD and Article numbers PRD-No. 30554444 Product name Kolliwax GMS II Article numbers Packaging 50263842 0.5 kg Plastic bottle 50264282 25 kg Plastic film bags BASFs commercial product number. Eree non-GMP samples (0.5 ka) for testing purposes are available on request. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
PronovaPure 500:200 TC Chemical names of active ingredient Description ee eo PronovaPure 500:200 TG is a pale yellow fish oil concentrate. PronovaPure 500:200 TG is a pale yellow fish oi concentrate. The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Scombridae and Carangidae). The product is a triglyceride (TG), rich in omega-3 fatty acids. The content of EPA (Eicosapentaenoic acid expressed as TG) and DHA (Docosahexaencic acid expressed as TG) is min. 700 mg/g. Articles Country of origin
Composition Stability, Storage and Handling Ingredients in descending order of weight: Fish oil concentrate, tocopherol-rich extract (E 30 Stored in its unopened original packaging at ambient conditions (0 25 C), the product is stable for at least 36 months. mainly derived from soybean (from identity preserved, not genetically modified origin) Solubility Practically insoluble in water, very soluble in acetone and heptane, slightly soluble in anhydrous ethanol. Applications Specification Specification  PronovaPure 500:200 TG is intended for use in dietary supplements such as in soft gel capsules. as triglycerides Ph. Eur. 1352/2.4.29 EPA (Eicosapentaenoic acid) 500 560 mg/c DHA (Docosahexaenoic acid) 200-250 mg/c EPA & DHA (Eicosapentaenoic 700-780 mg/c & Docosahexaenoic acid) Note PronovaPure 500:200 TG must be handled in accordance with the Material Safety Data Sheet. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of th For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access) Standards AL MIN fee eee ee eae ne eae Sek Meee NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. Produced under cGMP and HACCP principles. Monographs and Regulations PronovaPure ) TG meets the requirements for an omega-3 fatty acid source in most countries. The product complies with the Ph. Eur. monograph on Omega-3-acid triglycerides (1352). Further, the product conforms to the voluntary GOED mono- graph in the current version. Fish oil concentrates are accepted for use in dietary supplements in most countries. However, specific regulations on the product and its ingredients in the respective countries and for its intended use have to be observed.
Technical Information February 2019 Supersedes issue dated June 2011 Last change WF-No. DAWF-2019-0217 = Registered trademark of BASF in many countries.
1. Introduction Kollicoat Smartseal 30 D is a low viscous aqueous dispersion of a film forming polyme for taste masking and moisture barrier applications. It provides effective protection from unpleasant taste and humidity while ensuring quick release of active ingredients in the stomach. Kollicoat Smartseal 30 D can be employed in aqueous film coating processes. A spray dried powder grade of the same polymer is available as Kollicoat Smartseal 100 P. Kollicoat Smartseal 100 P has a separate Technical Information Sheet which can be found on BASF WorldAccount. 2. Technical properties Description Kollicoat Smartseal 30 D is an aqueous dispersion of a methyl methacrylate (MMA) and diethylaminoethy! methacrylate (DEAEMA) copolymer. The molar ratio of the monomers MMA and DEAEMA in the copolymer is 7:3. The dispersion is stabilized with approx. 0.6% macrogol cetostearyl ether and 0.8% sodium lauryl sulfate and has a solid content of approx. 30%. The polymer dispersion is a milky white to yellowish liquid with a pleasant characteristic odor. Trivial names Methyl methacrylate and diethylaminoethyl methacrylate copolymer 7:3 dispersion. CAS number 27027-16-3 Molecular weight The weight average molecular weight (Mw) of the polymer is approx. 200 000 Dalton (method: size exclusion chromatography (SEC) coupled with light scattering). Glas Transition Temperature (T,) SAR ee, SEN (method: differential scanning calorimetry (DSC)) The polymer of Kollicoat Smartseal 30 D is brittle. Therefore, a plasticizer is needed. Minimum film forming temperature (MFFT) oe (method: heating block system) The polymer of Kollicoat Smartseal 30 D is very lipophilic. This means that water cannot act as a plasticizer during film coating and a plasticizer is needed for lowering the MFFT.
Particle size The mean particle size of the polymer droplets in the dispersion is approx. 150 nm (method: light scattering). Solubility The Kollicoat Smartseal 30 D polymer is insoluble in water at neutral and basic pt values. Below pH < 5.5 it becomes water soluble. The Kollicoat Smartseal 30 D dispersion is miscible with water while retaining its milky white appearance and low viscosity. When water-miscible organic solvents are added, the polymer precipitates first, but re-dissolves after continuous stirring. 3. Functionality Taste Masking The premise for an effective protection from unpleasant taste is the insolubility of the film coating polymer in the saliva (pH 6.8 7.2). Polymer films obtained with Kollicoat Smartseal 30 D can be formulated in a way that they are insoluble in neutral or basic media for more than 2 hours. In acidic media with pH < 5.5 the polymer dissolves due to protonation of the amino functional groups. This pH-dependent solubility ensures an effective protection in saliva and a quick release of active ingredients in the stomach. A coating level of 2-6 mg/cm? is recommended for taste masking applications on tablets. Figure 1: Dissolving time of 100 tm isolated Kollicoat Smartseal films at different pH values.
Moisture Protection Film coatings with low water vapor permeability can delay the moisture uptake of sensitive dosage forms. As the copolymer of Kollicoat Smartseal 30 D is very lipophilic water vapor permeation is low and polymer films provide an effective moisture barrier functionality. A coating level of 5 - 20 mg/cm? is recommended for moisture barrier applications on tablets. Figure 2: Sorption isotherm of 100 um isolated polymer films obtained from Kollicoat Smartseal 30 D. The moisture barrier properties of isolated films obtained from Kollicoat Smartseal 30 D can be optimized by employing lipophilic plasticizers (such as acetyl tributyl citrate) or by the addition of talcum. Figure 3 shows the water vapor permeability of isolated polymer films that contain different amounts of talcum (w/w based on the polymer). Figure 3: Impact of talcum on the water vapor permeability of 100 tm isolated polymer films obtained from Kollicoat Smartseal 30 D.
4. Application and Processing General handling recommendations Kollicoat Smartseal 30 D is a polymer/ latex dispersion. Polymer dispersions give irreversible coagulation when exposed to harsh conditions. Therefore, freezing (temperatures < 5 C) and ultraturrax treatment need to be prevented. Moreover, ingredients like plasticizers or pigments shall be added to dispersions carefully or ir a diluted manner. Kollicoat Smartseal 30 D contains a basic copolymer. Therefore, acidic ingredients need to be added with care as they may impact the functionality of the polymer. Selection of a plasticizer Kollicoat Smartseal 30 D needs a plasticizer for two reasons: EL EEO ee RR EUR see aN eA eee e The dried polymer is brittle. Dried polymer films need a plasticizer for preventing crackings and for retaining film functionality. The minimum film forming temperature MFFT is very high (~ 57 C). Therefore, a plasticizer is needed to reduce the MFFT to temperature regions where film coating experiments are typically carried out. This is necessary as the polymer is very lipophilic and dispersion water has no plasticizing effect. Recommended plasticizer concentration (w/w based on the polymer): 13-15% The following plasticizers are suitable for Kollicoat Smartseal 30 D: The following plasticizers are suitable tor Kollicoat smartseal 30 D: Acetyltributyl citrate (ATBC) Triethyl citrate (TEC) Dibutyl sebacate (DBS) Suitable but without history of use in human oral dosage forms: tributyl citrate (TBC) and acetyltriethy! citrate (ATEC) When using TEC or ATEC it is important that film coating dispersions are freshly prepared prior t use. Reason is that both plasticizers have shown to hydrolyse into acids and thus impact functionalit when dispersions are stored overnight. When using ATBC or DBS the use of 2% docusate sodium is recommended to facilitate plasticiz incorporation. The addition of plasticizers leads to a strong decline of the minimum film forming temperature. Figure 4: Impact of plasticizers on the MFFT.
Plasticizers have an impact on the mechanical properties of the films. Figure 5 shows that the recommended plasticizer concentration of 13 15% (w/w based on the polymer) increases the elongation at break to approximately 100%. Figure 5: Impact of plasticizers on the mechanical properties of isolated polymer films o1 Kollicoat Smartseal Addition of an antioxidant Kollicoat Smartseal 30 D based films always require an antioxidant to stabilize the aminoester moiety of the polymer. Without plasticizer, yellowing and a delayed dissolution may occur. The recommendation is to use 1.0 2.5% of the lipophilic antioxidant butylated hydroxytoluene (BHT) based on polymer weight. Alternatively, hydrophilic antioxidants like sodium carbonate can be used. Curing Coatings obtained from Kollicoat Smartseal 30 D always need curing. This is necessary for assuring proper film formation and stable dissolution profiles that do not change over time. Recommended conditions: 2 hours at 60 C. Curing for longer time allows to reduce temperatures. Anti-tacking agents An anti-tacking agent is recommended to prevent sticking. It is recommended to add talcum as anti-tacking agent to the coating suspension in amounts between 4 and 8% relative to the polymer. Alternatively, coated dosage forms can be blended directly after the coating process by addition of micro talcum.
Preparation of the coating suspension Figure 6: Preparation of the coating suspension Cleaning recommendations As the polymer is readily soluble below pH 5.5, weak acids are suitable for cleaning off residues of Kollicoat Smartseal 30 D based formulations from coating equipment. Recommended are e.g. aqueous solutions of acetic acid, formic acid or citric acid, or commercially available cleaning agents. 5. Example application Caffeine tablets Cores round, convex @ 9 mm, 350 mg, composition: caffeine 15.5%, Ludipress LCE 74.0%, Kollidon VA 64 fine 5.0%, Kollidon CL-F 5.0%, magnesium stearate 0.5%. Composition of spray suspension Ingredients Content [%] Kollicoat Smartseal 30 D 34.6 Acetyltributyl citrate (ATBO) 1.4 (13% rel. to polymer) Butylated hydroxytoluene (BHT) 0.3 (2.5% rel. to polymer) Talcum 8.0 (40.0% rel. to polymer) Water 55.8 Total 100 Solid content in the spray suspension 20 Polymer content in the dried film 52.0
Process parameters Parameter Value Machine Manesty Accela Cota XL Lab01 Batch size 5 kg Inlet air temperature 55C Product temperature 37-39 C Nozzle diameter 1.2mm Spraying rate 20 23 g/min Spray pressure 1 bar Atomized air 1.2 bar Inlet air 350 I/s Drum speed 10 Upm Final drying ~ 45 C product temperature Curing 2h@60C Coating level 3 mg/cm? Theophylline granules Substrate Theophylline granules 0.2 - 0.7 mm. Composition of spray suspension Ee ee Re ee ee ee ee Ingredients Content [%] Kollicoat Smartseal 30 D 33.33 Tributyl citrate (TBC) 1.5 (15% rel to polymer) Butylated hydroxytoluene (BHT) 0.1 (1% rel. to polymer) Talc 8.00 Colorant 0.40 Water 56.67 Total 100 Solids content in the spray suspension 20.00 Polymer content in the dried film 50.00 Ingredients Content [/] Kollicoat Smartseal 30 D 33.33 Tributyl citrate (TBC) 1.5 (15% rel to polymer) Butylated hydroxytoluene (BHT) 0.1 (1% rel. to polymer) Talc 8.00 Colorant 0.40 Water 56.67 Total 100 Solids content in the spray suspension 20.00 Polymer content in the dried film 50.00 Process parameters Machine Ventilus 1 with IPC1 (Innojet) Inlet air temperature 55 65 C Inlet air volume 45 m%/h Batch size 0.25 kg Outlet air temperature 30 - 34 C Spraying rate 5-10 g/min Nozzle diameter IRN2-V 1.0 mm Spray pressure 0.8 bar Blending 0.2% colloidal silica for 10 min in a Turbula blender Process parameters Ventilus 1 with IPC1 (Innojet) Machine Ventilus 1 with IPC1 (Innojet) Inlet air temperature 55 65 C Inlet air volume 45 m%/h Batch size 0.25 kg Outlet air temperature 30 - 34 C Spraying rate 5-10 g/min Nozzle diameter IRN2-V 1.0 mm Spray pressure 0.8 bar Blending 0.2% colloidal silica for 10 min in a Turbula blender Coating level (taste masking) 8 28% weight gain Taste masking can be achieved with 18% weight gain.
Example granules: Theophylline (0.2 - 0.7mm) Figure 7: Microscopic pictures of coated and uncoated theophylline granules. Figure 8 a: Theophylline granules: Dissolution at pH 6.8. Figure 8 b: Theophylline granules: Dissolution at pH 1.2.
Moisture protection (Sorbitol tablets) Sorbitol tablets are highly hygroscopic and were therefore chosen as model to evaluate moisture barrier functionality of the coating. Composition of tablets Cores: Sorbitol (Neosorb P 60 W): 49.75%, Ludipress 49.75%, Magnesium stearate: 0.5%, round, convex , @ 9 mm; Hardness: 110 N Composition of spray suspension Ingredients Content [%] Kollicoat Smartseal 30 D 34.66 Tributyl citrate (TBC) 1.35 (13% rel to polymer) Butylated hydroxytoluene (BHT) 0.26 (2.5% rel. to polymer) Talc 8.00 Water 56.67 Total 100 Solids content in the spray suspension 20.0 Polymer content in the dried film 52.0 Process parameters Machine Perforated pan coater aA Va Water 56.67 Total 100 Solids content in the spray suspension 20.0 Polymer content in the dried film 52.0 Process parameters Machine Perforated pan coater Glatt GC 300 Inlet air temperature 70 C Batch size 1.5 kg Product temperature 40C Spraying rate 11g/min Nozzle diameter 1.2mm Spray pressure 2.0 bar Final drying 40 C, 15 min (product temperature) Coating level up to 20 mg/cm? sme Omg/com2 m+ 9 mg/cm? -@- 3mg/cm? = @~- 12 mg/cm? 25 soe 4.5 mg/cm? s+ 20 mg/cm? Moisture uptake [%] 6 mg/cm? Time [d] ae ee ak a a a a i a cam aa Figure 9: Moisture uptake of sorbitol tablets during storage at 30 C and 70% relative humidity. Kollicoat Smartseal 30 D based formulations can significantly reduce moisture uptake during storage. The barrier effect increases with higher coating levels.
Caffeine granules Substrate / caffeine granules 0.2/0.5 ym Composition of spray suspension Ingredients Content [%] Kollicoat Smartseal 30 D 40.6 Acetyltriethy citrate (ATEC) 1.5 (12.5% rel. to polymer) Butylated hydroxytoluene (BHT) 0.3 (2.5% rel. to polymer) Talc 6.0 Water 51.6 Total 100 Solid content in the spray suspension 20 Polymer content in the dried film 52.0 Old COMLENt IY Wie Spray SUSPENSiO! Polymer content in the dried film 52.0 Process parameters Parameter Value Machine Glatt GPCG 3.1 Spray set-up Bottom spray, 25 cm Wurster 7 column Batch size 1.3kg Inlet air temperature 55 C Product temperature 31-34 C Nozzle diameter 1.0mm Spray rate 15-18 g/min Spray pressure 1.5 bar Inlet air 88 - 100 m/h Final drying ~ 45 C product temperature Curing 2h@60C Weight gain 15, 20, 25% Process parameters
Figure 10: Dissolution of caffeine granules with different weight gains with and without curing. Figure 11: Dissolution of caffeine granules with 25% weight gain at different pH values
6. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment. In addition they are available on BASF WorldAccount or from your local BASF sales representative. 7. Product Specification The current version of the product specification is available on BASF WorldAccount or from your local BASF sales representative. Please refer to the individual document quality & regulatory product information (QRPI) which is available on BASF WorldAccount and from your local sales representative. The QRPI covers all relevant information: including. retest dates, and storage conditions. The safety of the polymer in Kollicoat Smartseal 30 D as pharmaceutical excipient in film coating of solid oral dosage forms is supported by a comprehensive non-clinical study. A summary of the study is available on BASF WorldAccount or from your local sales representative. A detailed report can be shared as part of a non-disclosure agreement. https://worldaccount.basf.com 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30492630 Kollicoat Smartseal 30 D 50138477 25 kg PE jerrican BASFs commercial product number. 11. Publications Publications including scientific posters are available on http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Fatty acids and alcohols: Consistency factors for topical formulations, and excipients for solid oral dosage forms. Oktober 2021 WF-No. 137189 = Registered trademark of BASF in many countries.
1. Introduction Our Kolliwax portfolio includes fatty acids and alcohols that can be used as (co-) emulsifiers and consistency factors in topical pharmaceutical applications, but may also function as excipients in solid oral dosage forms, e.g., as matrix formers and lubricants. This document focuses on fatty acids and alcohols of the Kolliwax family. Please refer to the individual technical information sheet for specific information on our two glyceride based grades Kolliwax GMS II and Kolliwax HCO (Glycerol Monostearate, and Hydrogenated Castor Oil, respectively). Trade name Compendial Name Kolliwax CA Ph.Eur.: Cetyl Alcohol USP/NF: Cetyl Alcohol Kolliwax CSA 50 Ph.Eur.: Cetostearyl Alcohol USP/NF: Cetostearyl Alcohol JP: Cetostearyl Alcohol Kolliwax CSA 70 Ph.Eur.: Cetostearyl Alcohol Kolliwax MA USP/NF: Myristyl Alcohol Kolliwax SA Ph.Eur.: Stearyl Alcohol Kolliwax SA Fine USP/NF: Stearyl Alcohol JP: Stearyl Alcohol Kolliwax S Ph.Eur.: Stearic Acid 50 Kolliwax S Fine USP/NF: Stearic Acid 50 llPe Stearic Acid 50 Table 1: Compendial names for fatty alcohols and acids of the Kolliwax family. Description 2. Technical properties Kolliwax grades are white to slightly yellowish, waxy substances derived from natural ressources, namely coconut oil, palm kernel oil, and/or palm stearine. With melting points above room temperature, these products are either supplied as powder, pearls, or pelletts (see table1 and table 2 for details). The numeric part of the name of the two grades of Kolliwax CSA represents the approximate weight percentage of stearyl alcohol. es ene Trade name Chemical nature CAS-No. Melting ranges [cy Kolliwax CA Cetyl Alcohol (C,,) 36653-82-4 46-52 Koliwax CSA S0_ Cety/Stearyl Alcohol 7769 97.9 1666 Kolliwax CSA70_ (Cie/Cra) Kolliwax MA Myristyl Alcohol (C,,) 112-72-1 36-42 Kolliwax SA Stearyl Alcohol (C,,) 112-92-5 57-60 Kolliwax SA Fine Koliwax?S Stearic/Palmitio Acid g 7754 93.05 308 Kolliwax S Fine (Cil/Cy6) Values given for guidance only, see specification sheets for detailed information on melting and/or freezing temperatures. Table 2: Properties of fatty alcohols and acids of the Kolliwax family.
Figure 1: Typical appearance of the Kolliwax grades. The scale in the back is metric, with 1 mm per mark. For detailed information on particle size distributions, please refer to the individual product specification sheets. Scanning electron mircroscopy (SEM) igure 2: SEM images of Kolliwax S, and Kolliwax S Fine. Please refer to the individu: specification sheets for detailed information on particle size distributions.
3. Application Overview The following table 3 gives an overview on the most important applications and functions of the Kolliwax fatty alcohols and acids: while fatty acids and alcohols are generally used as consistency factors, our fine grades of stearic acid and stearyl alcoho (Kolliwax S Fine and Kolliwax SA Fine, respectively) allow to use these substances in the preparation of solid dosage forms, where they can aid as lubricants or matrix formers. Table 3: Application of the Kolliwax grades. Emulsions Exhibiting excellent skin tolerance, the Kolliwax grades can be used for all kinds of topical pharmaceutical applications, such as creams, gels, lotions, and ointments. The typical usage concentration in emulsions is about 1- 5%. All Kolliwax grades will act as consistency factors and co-emulsifiers at the same time. With their amphiphilic structure, they will stabilize the interface between oil and water and will help to enhance the viscosity by building up a liquid crystalline network (lamellar sheet structure). Stabilizing w/o and 0/w emulsions, they also aid in bringing a unique softness and creaminess to the targeted formulation. Lubricants In tableting processes for solid oral dosage forms, lubricants are used to prevent ingredients from clumping to undesired aggregates and from sticking to the tablet punches or capsule filling machine. In addition, lubricants hamper the friction that would hinder tablet formation and ejection. Among inorganic materials (e.g. talc or silica), fat based substances like vegetable stearin, magnesium stearate or stearic acid are commonly used as lubricants in tablets or hard gelatin capsules. Lubricants are added in small quantities to tablet and capsule formulations to improve certain processing characteristics. Formulation examples Guideline for the preparation of the model formulations: MaYIGenne 1Or UWle PrepalrauviOrl OF WIE MIOQE! fOMTIUlAvOrls. 1. Heat components of phase A to 80 - 85 C and stir until transformed into a homo- geneous melt. 2. Heat components of phase B to 80 85 C. Under constant stirring, slowly add phase A to phase B, homogenize for 5 min at 5000 rpm. Let cream cool to 35 C while mixing at 200 rpm, and add preservative.
Model formulation Rich Cream: This formulation utilizes Kolliwax CSA 70 and Kolliphor PS 60 as emulsifiers to create avery stiff cream that offers a slow spread and a cushioned feeling when rubbing into the skin. Its high immediate smoothness results from the utilization of Kollicream IPM, a fast spreading oil with broad penetration enhancement properties that can aid as a solubilizer for lipophilic drugs. Ingredient Phase Ph. Eur. name Role Amount [wt.-%] A __ Kolliwax CSA 70 Cetostearyl Alcohol Consistency Factor, 7.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 25 40-55 (Type Il) Co-Emulsifier Kolliphor PS 60 Polysorbate 60 Emulsifier 4.2 Kollisolv@ MCT 70 Medium Chain Emollient 11.5 Triglycerides Kollicream IPM Isopropyl Myristate Emollient 1.3 B Deionized Water 69.2 Solvent _____. Glycerol 3.3 C_ Euxyl PE 9010 Preservative 1.0 Table 4: Model formulation for a rich Cream. Model formulation Light Cream: This formulation is a smooth cream with easy distribution, medium viscosity, and a glossy finish. Due to the difference in HLB values, the blending ratio of Kolliphor CS 12 and Kolliphor CS 20 can be used as a factor to maximize emulsion stability. Phase Ingredient Ph. Eur. name Role Amount [wt.-%] A_ Kolliwax CSA 50 Cetostearyl Alcohol Consistency Factor, 4.0 Co-Emulsifier Kolliwax GMS II Glycerol Monostearate Consistency Factor, 5.0 40-55 (Type Il) Co-Emulsifier Kolliphor CS 20 Macrogol Cetosteary! Emulsifier 2.0 Ether 20 Kolliphor CS 12 Macrogol Cetostearyl Emollient 0.8 Ether 12 Kollicream CP 15 Cetyl Palmitate 15 Emollient 0.8 Kollicream IPM Isopropyl Myristate Emollient TA B__ Deionized Water 74.0 Solvent Glyerol 5.0) C_ Euxyl PE 9010 Preservative 1.0 in Si Pe Table 5: Model formulation for a light cream. 4. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are available on request and are sent with every consignment.
5. Product specification The current version of the product specification is available on BASF WorldAccount, or from your local BASF sales representatives. 6. Regulatory & Quality Please refer to the individual document quality & regulatory product information (QRPI), available on BASF WorldAccount and from your local sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. 7. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554718 olliwax CA 50253459 25 kg Plastic film bag 50259499 0.5 kg Plastic bottle 30554719 olliwax CSA 50. 50253501 25 kg Plastic film bag 50259500 0.5 kg Plastic bottle 30554721 olliwax CSA 70 50253504 25 kg Plastic film bag 50259502 0.5 kg Plastic bottle 30554492 olliwax MA 50375472 20 kg Corrugated fiberboard box with PE liner 50259498 0.5 kg Plastic bottle 30554720 olliwax SA 50253503 25 kg Plastic film bag 50259501 0.5 kg Plastic bottle 30563963 olliwax SA Fine 50284249 25 kg Plastic film bag 50372378 0.5 kg Plastic bottle 30554752 olliwax S 50253532 25 kg Plastic film bag 50259521 0.5 kg Plastic bottle 30554750 olliwax S Fine 50253810 25 kg Plastic film bag 50259508 0.5 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples (0.5 kg) for testing purposes are available on request. http://pharmaceutical.basf.com/en.html This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
November 2012 Hard Fat for suppository masses
PRD-No., Article-No. and CAS.-No. PRD-No. Article-No. CAS.-No. Novata B PH 30531224 50209107 67701-26-2 Novata BC PH 30531225 50209108 67701-26-2 Novata BCF PH 30531226 50209109 67701-26-2 Novata BD PH 30531227 50209110 67701-26-2 See separate documents: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). All Novata PH Grades are complying to the Monograph Hard fat Ph. Eur. Regulatory Status Product characteristics All Novata PH grades are white to slightly yellowish, brittle pellets which are used for the production of suppositories. On account of its mean hydroxyl value range and the melting point, the product can be used as universal suppository mass, alsc in the chemists shop. Typical Properties Novata B PH BC PH BCF PH BD PH Acid value <0.5 <0.5 <0.5 <0.5 lodine value <3.0 $3.0 <3.0 <3.0 Peroxide value <3.0 <3.0 <3.0 <3.0 Alcaline impurities (mL) <0.15 <0.15 <0.15 <0.15 Total ash (%) <0.05 <0.05 <0.05 <0.05 Unsaponifialble (%) <0.6 <0.6 <0.6 <0.6 Hydroxyl value 20-30 30 - 40 20-30 5-15 Saponification value 225 240 225-240 225-240 230-245 Melting point (C) 33.5-35.5 33.0-34.5 35-37 33.5-35.5 Heavy metals as sum <10.0 <10.0 <10.0 <10.0 Pb (ppm)
Application The main application of the Novata PH Grades are suppositories. Suppository is a drug delivery system that is inserted into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository), where it dissolves or melts. Suppositories may be used for patients (e.g. children) in case it may be easier tc administer than tablets or syrups. Suppositories may also be used when a patient has a vomiting tendency, as oral medication can be vomited out. Another benefit of suppositories is, that drugs which often cause stomach upset during oral intake, for example diclofenac sodium are better tolerated in suppository form. Suppositories are made from a greasy or waxy base, containing different Novata PH grades in which the active ingredient and the other excipients are dissolved. The main important point in formulating a suppository, is adjust the melting temperature of the complete formulation to the body temperature. Apart from suppository manufacturing, solid triglycerides (hard fats) are used as carriers in capsule fillings, inlets, ointments and creams and in dental products. In topical formulation they can act as a sensory enhancer, because of their low melting point. All Novata grades are based on vegetable origin. The raw material origin is coconut or palm kernel oil. Raw material origin The toxicological abstracts are available on request. Individual reports can be shared under secrecy agreement Toxicology In the original sealed containers all Novata grades can be stored for at least 18 month, protected from moisture at below 30 C. Stability and storage Please refer to the individual Material Safety Data Sheet (MSDS) for instructions c safe and proper handling and disposal. Handling and Disposal Formulations 1. Pain Relief Suppository with Novata B PH Ingredient Tuts Amount (g) Kollisolv MCT 70 Medium Chain Triglycerides 0.200 Phenacetin 0.300 Codeinphosphate 0.010 Acetyl Salicylic Acid 0.500 Soya Lecithin 0.010 Il Novalgin 0.200 Ill Novata B PH Hard Fat ad. 2.000 Remark Tube rise melting point: 34.5 C. Preparation Phase is suspended and triturated with Phase II. Phase Ill is melted on a water bath at 50 C after cooling to 38 C is mixed to a pasty consistency with the additive trithiratinn Ciihean ant ta avan dictrihi tian of all additivee the cammn ind 2 EE EE Phase is suspended and triturated with Phase II. Phase Ill is melted on a water bath at 50 C after cooling to 38 C is mixed to a pasty consistency with the additive trituration. Subsequent to even distribution of all additives, the compound is cast into moulds at 33 C.
2. Suppository with Novata BC PH against Hemorrhoids Ingredient Name Amount (g) Zink Oxide 0.100 Perugen 0.040 Novata BC PH Hard fat ad. 2.000 Witch hazel extract, dest. 0.200 Bismuth Gallate, basic 0.100 Remark Tube rise melting point: 34 C. Preparation Phase is melted 45 C, it is suspended with Phase Il at 45 C. Phase Ill is triturated, added at 40 C to the melt and cast into moulds at 38 C. ai Et RARER ES Phase is melted 45 C, it is suspended with Phase Il at 45 C. Phase Ill is triturated, added at 40 C to the melt and cast into moulds at 38 C. 3. Pain relief suppository 6 ES EEE SAR eee: Ingredient Name Amount (g) Isopropyl Phenazone 0.300 Novata BD PH Hard Fat ad. 2.000 Coffein 0.050 Remark 34.4C Tube rise melting point: an ee er Melt Phase at 50 C on a water bath. At a temperature of 38 C cast the compounc into slightly cooled moulds. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Maxomega EPA 96 EE Maxomega EPA 97 EE =thyl Ilcosapentate (JP) June 2021 DAWF-2021-0805 = Registered trademark of BASF in many countries.
1. Introduction Maxomega EPA 96 EE and Maxomega EPA 97 EE are oils containing a minimum of 96% of the primary omega-3 acid eicosapentaenoic acid (EPA) in ethy! ester (EE) form. Omega-3 fatty acids, in general, are naturally occurring nutrients that are of high importance for human health. They cannot be synthesized by the human body but are vital for normal metabolism. Omega-3 fatty acids are poly unsaturated fatty acids with a double bound from the 3rd carbon atom from the end (omega). The most abundant omega-3 fatty acids are EPA, docosahexaenoic acid (DHA) and alfa-linoleic acid (ALA). EPA and DHA are long-chain fatty acids found in algal oil and fish. EPA and DHA have been widely studied for medical and nutritional applications. Maxomega EPA 96 EE and Maxomega EPA 97 EE are equivalent products, but with slightly different specifications as they are intended for different markets with different requirements. They are produced the same way from crude fish oil by a transesterification step from a triglyceride to an ethyl ester compound and several concentration and purification steps including liquid chromatography and silica refining. The fish oil is sourced from body oil of wild fatty fish. The only additional ingredient to EPA EE is the antioxidant alfa tocopherol, which is added in a concentration of approximately 0,2%. The minor part (3-4%) that are not EPA EE consists of other naturally occurring fatty acids, including other omega-3 fatty acids. Due to the high amount of unsaturated fatty acids, the product will easily oxidize in contact with air, and needs to be protected from contact with oxygen. The container is therefore flushed with nitrogen prior to, during and after filling. Maxomega EPA 96 EE and Maxomega EPA 97 EE are used as active ingredients in pharmaceutical preparations for oral application after approval by the concerned medicinal authority for a defined indication.
2. Description Name Maxomega EPA 96 EE and Maxomega EPA 97 EE United States Adopted Names (USAN) Icosapent ethyl International nonproprietary name (INN) Icosapent ethyl Pharmacopeia name Chemical names 5Z,8Z,11Z, 14Z, 17Z)-Eicosa-5,8,11,14,17-Pentaenoic Acid Ethyl Ester, Eicosapentaenoic acid etyl ester, Timnodonic acid ethyl ester, Ethyl-EPA Molecular formula Relative Molecular mass Structural formula
3. Physical and chemical properties Appearance Maxomega EPA 96 EE and Maxomega EPA 97 EE are clear, colourless to pale yellow liquid oils. Solubility Maxomega EPA 96 EE and Maxomega EPA 97 EE are practically insoluble in water, very soluble in organic solvents such as hexane, acetone, ethanol, and methanol. Boiling point 417.0 + 34.0 C at 760 Torr Flash point 103.1 + 24.0 C Vapour pressure 3.65E-7 Torr at 25 C Enthalpy of Vaporization 67.04 + 3.0 kJ/mol at 760 Torr
4. Medical information Applications Maxomega EPA 96 EE and Maxomega EPA 97 EE are active pharmaceutical ingredient oils. For application, they are typically filled into soft gelatin capsules as the sole fill ingredient. This dosage form is suitable for EPA EE because it protects the API from oxygen and masks taste and odour. As a consequence, EPA EE is not suitable for liquid multidose formulations as it will readily oxidize in contact with atmospheric oxygen, and also has an unpleasant taste and odour. Therapeutic indication Maxomega EPA 96 EE and Maxomega EPA 97 EE are used as active ingredients for the documented indication in pharmaceutical drug products after approval by the competent authority. The approved indications may be different in different countries. Please refer to the approved indications for finished products containing Ethy! Icosapentate/ Icosapent ethyl in the concerned market. Clinical Pharmacology Mechanism of Action The mechanisms of action for EPA are likely multi-factorial. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Ilcosapentate/ Icosapent ethyl. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Ilcosapentate/ Icosapent ethyl. Pharmacokinetics Absorption: After oral administration, EPA EE is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Icosapentate/ Icosapent ethyl. Please refer to the approved Summary of Product Characteristics (SmPC) /Full Prescribing Information for finished products containing Ethyl Icosapentate/ Icosapent ethyl.
5. Handling & Safety Please refer to the individual material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. Material safety data sheets are sent with every consignment or can be requested from your BASF sales representative Re-test period & Storage Conditions Please refer to the document Quality & Regulatory Product Information which is available in RegXcellence (RegXcellence (basf.com)). Packaging The commercial product is filled in epoxy phenolic lined mild steel drum. The liner contains iron oxide and titan dioxide pigments and have a golden brown colour. The closure is made of the same material. The product is stored under nitrogen atmosphere to prevent oxidation. The external surface is blue. 6. Product specifications The current version of the product specifications are available at RegXellence (RegXcellence (basf.com)) or from your BASF sales representative. 7. Regulatory & Quality 7. Regulatory & Quality Please refer to the document Quality & Regulatory Product Information which is available in RegXcellence (RegXcellence (basf.com)). PRD and Article numbers PRD-No. Product name Article numbers Packaging 30572258 Maxomega EPA 96 EE 50306243 (sample) 50356278 0,1 kg aluminum bottle 190kg steel drum 30572259 Maxomega EPA 97 EE For the Japanese market only 50306248 (sample) 0,1 kg aluminum bottle 50305109 190kg steel drum BASFs commercial product number. This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE.
Technical Information Propylene Glycol USP, Ph. Eur., JP, FCC December 2022 Supersedes issue dated October 2018 Last change WF-No. 136681 = Registered trademark of BASF in many countries.
1. Technical properties Chemical nature 1,2 Propandiol, (RS)-propane-1,2 diol Structural formula Empirical formula CAS-number Properties Kollisolv PG is a clear, colorless viscous liquid of low volatility with a boiling range of 184 189 C. It is odorless, neutral and hygroscopic. It is miscible in all proportions with water, lower alcohols, esters and ketones. Kollisolv PG is a germicide of approximately equal strength to ethanol. In solutions it suppresses the growth of microorganisms. The concentration required depending on the species, though generally 15 30% Kollisolv PG in the solution achieves the desired effect. 2. Handling Refer to the material safety data sheet (MSDS) for instructions on safe and proper handling and disposal. MSDS are available on request and are sent with every consignment. 3. Example applications Applications Kollisolv PG is manufactured in line with the current Good Manufacturing Practices (Joint IPEC-PQG GMP Guide for Pharmaceutical Excipients) as a high purity grade Kollisolv PG is used in a variety of pharmaceutical formulations: KOHISOIV FG IS USed IN a variety Of pharmaceutical formulations: As apreservative As acarrier and humectant for emulsifiers and as a vehicle for flavours As an extractant for active principles from natural products As a plasticizer in aqueous film-coating formulations - As a solvent or cosolvent for a wide variety of active ingredients e Asa solvent and stabilizer in vitamin formulations 4. Safety data sheet Safety data sheets are available on request and are sent with every consignment. >. Retest date and storage conditions Refer to the individual document quality and regulatory product information (QRPI), available on RegXcellence and from your local BASF sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. Kollisolv PG is stable over the retest period in the original sealed containers. It is information (QRPI), available on RegXcellence and from your local BASF sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. Kollisolv PG is stable over the retest period in the original sealed containers. It is important to prevent contact with air, e.g. by storing under a blanket of dry nitrogen. This precaution prevents any significant deterioration, even on prolonged storage. If atmospheric oxygen is not excluded, peroxides may be formed, which, in turn, may
decompose into aldehydes and acids, spoiling the product. Smaller containers should be kept tightly closed and stored in a well-ventilate The current version of the product specification is available on RegXcellence and MyProductWorld or from your local BASF sales representative. Refer to the individual document quality and regulatory product information (QRPI), available on RegXcellence and from your local BASF sales representative. The QRPI document covers all relevant information including retest periods and storage conditions. Kollisolv PG nas been toxicologically assessed. On the basis of information at our disposal and provided that the recommended concentrations and fields of applications are adhered to, there is no evidence of any toxicological risks associated with its use. We will gladly supply details of the investigations on request. 9. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554051 Kollisolv PG 50259795 0.5kg Aluminum bottle (non-GMP sample) 50253486 220 kg Plastic drums 50260032 1000 kg Composite IBC BASFs commercial product number.
10. ZoomLab, RegXcellence & MyProductWorld ZoomLab Your virtual formulation assistant ee eee eee ea Eliminate trial and error by instantly optimizing and predicting your next starting formulation - Explore a robust knowledge base of active ingredients, excipients, and Formulations Create personalized development projects while maintaining drug chemistry confidentiality Predict your next drugs starting formulation instantly RegXcellence Your virtual quality & regulatory assistant TOUP VITtUal QUALITY & FEQGUIALOry assistallit Instantly download standard quality and regulatory documents Find comprehensive compliance information and request customizec documentation Stay in compliance with automated change notifications Make quality and regulatory compliance a breeze MyProductWorld Your virtual product assistant we ee Find your favorite excipient and active ingredients, browse comprehensive product information, request 3rd party audit reports, and more Request and track samples, order products, and more via your personalized ricer nrofile Find pharma grade excipients and API solutions faster. Register for free at info-mypharma.basf.com and meet your 24/7 Virtual Pharma Assistants today!
Disclaimer This document and any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF: (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, WRITTEN OR ORAL, BY FACT OR LAW, INCLUDING ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A_ PARTICULAR PURPOSE, SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISING FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE AND BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILITY RESULTING FROM OR IN CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, without limitation, any liability for any direct, consequential, special, or punitive damages relating to or arising therefrom, except in cases of (i) death or personal injury, (ii) BASFs or its agents and assistants willful misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful for BASF to exclude or restrict liability under the applicable laws; inet: at einai ome (b) Any information provided herein can be changed at BASFs sole discretion anytime and neither this document nor the information provided herein may be relied upon to satisfy any obligations you may have to undertake your own inspections and evaluation; (c) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable law; and (d) You are responsible for confirming that you have retrieved the most current version of this document from BASF BASF Nutrition & Health www.pharma-ingredients.basf.com
Supersedes issue dated September 2008 Excipient based on lactose monohydrate for direct tabletting.
Ludipress combines the three functionalities of a filler, binder and disintegrant ir a ready-to-use excipient for tabletting using the direct compression technology. Ludipress is composed of Lactose monohydrate, Povidone K30 (Kollidon 30) and Crospovidone (Kollidon CL). It is a white, free-flowing granulated powder that is odorless and tasteless. See separate document: Standard Specification (not for regulatory purposes available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Lactose monohydrate is determined using a polarimetric assay. For Kollidon CL a gravimetric method is in place. Kollidon 30 is determined photometricly. Analytical methods Analytical methods are available on request. Fig. 1 shows the sorption isotherm for Ludipress, expressed in terms of the dry weight. The initial value corresponds practically to the hydrate water of the lactose. Fig. 1 shows the sorption isotherm for Ludipress, expressed in terms of the dry weight. The initial value corresponds practically to the hydrate water of the lactose. Owing to the ability of the Kollidon CL disintegrant to swell, irregular surfaces may be formed when tablets prepared with Ludipress are exposed for long periods to high humidities. Fig. 1: Sorption isotherm of Ludipress at 30 C
Grain size distribution The following typical values are based on measurements using a screen tower: Fig. 2 shows an example of a particle size distribution as determined by laser diffraction techniques and dry sample preparation. Fig. 2: Ludipress particle size distribution as measured by laser diffraction techniques Tabletting properties Fig. 3 shows the behaviour of Ludipress in the press in comparison to a physical mixture of the same composition. Fig. 3: Ludipress Compression behavior in comparison to a physical mixture
Regulatory status No monographs exist. The components Lactosemonohydrate and Povidon K30 (Kollidon 30) are specified according to the current versions of Ph. Eur., USP and JP. ING THT AV ls GAOL. The components Lactosemonohydrate and Povidon K30 (Kollidon 30) are specified according to the current versions of Ph. Eur., USP and JP. Microbiological status The microbiological status is determined according to Ph. Eur. 2.6.12: less than 1,000 viable aerobic counts/g less than 100 yeasts and fungi/g Absence of pathogenic nuclei E. coli/g Salmonella/10 g Pseudomonas aeruginosa/g Staphylococcus aureus/g less than 100 other entero bacteria/g Application Ludipress has been specially developed for direct tabletting, but is also very suitable as a filler for hard gelatine capsules. The addition of a disintegrant may be indicated when there is a high amount of active matter in the formulation. Also an addition of a dry binder like Kollidon VA 64 Fine may improve tablet hardness in this case. The following examples of formulations may serve as a guideline. A rotary tabletting press was used at the compaction force indicated in each formulation. Acetylsalicylic Acid Tablets (400 mg) Formulation 1 Se OE ere rE ae Acetylsalicylic acid, crystalline 400 g Ludipress 99g Stearic acid 1g Kollidon CL 159 Mix all components, pass through a 0.8 mm sieve and press with low compression force. Tablet properties Tablet properties Weight 516 mg Diameter 12mm Form biplanar Hardness 90N Disintegration <1 min Friability 0.4% Dissolution, 10 min 84% 30 min 97% Chemical stability Storage time RT 40 C O months 100.0% 100.0% 16 months 100.0% 100.0% 12 months 98.4% 99.1% Tha rantant af fraooa calinvlic anid ramaingadn ahaave hala, 0 90, Weight Diameter Form Hardness Disintegration Friability Dissolution, 10 QD) Chemical stability The content of free salicylic acid remained always below 0.2%.
Vitamin E Chewable Tablets (100 mg) Formulation 2 nin E acetate SD 50 200 g oress 493 g sil 200 7g Mix all components, pass through a 0.8 mm screen and press with high compression force. Properties Weight Diameter Form Hardness Disintegration Friability 727 mg 12mm biplanar 102 N 15 min 0% Ibuprofen Tablets (400 mg) Formulation 3 . Ibuprofen Aerosil 200 . Ludipress Kollidon CL Magnesium stearate . Ibuprofen Aerosil 200 Il. Ludipress Kollidon CL Magnesium stear Mix I, add the components of II, and press with low compression force. Properties Weight Diameter Form Hardness Disintegration Friability Dissolution, 10 min 15 min 727 mg 16mm biplanar 112N 2-3 min 0.4% 82% 91% Physical stability (20 - 25 C) 6 Months 8 Months 12 Months Hardness - 121N 120 N Disintegration = 2-3 min - Friability 0.4% 0.4% 0.2% Dissolution, 10 min 85% = 89% 20 min 87% 91% 88%
Formulation 4 Famotidine Tablets (40 mg) Famotidine Ludipress Magnesium stearate Stearic acid Aerosil 200 No. 1 40g 105g 3g 4g No. 40. 104. Famotidine Ludipress Magnesium stear Stearic acid Aerosil 200 Stearic acid - 2g Aerosil 200 49 4g Mix all components, pass through a 0.8 mm sieve and press with low compression force. Properties No. 1 No. 2 Weight 149 mg 148 mg Diameter 8mm 8mm Form biplanar biplanar Hardness 74N 49N Disintegration (gastric juice) 3 min 1 min Friability < 0.1% 0.3% Dissolution, 10 min 63% not tested 30 min 95% not tested Glibenclamide Tablets (5 mg) No. 1 No. 2 Glibenclamide, micronized 5.0g - Glibenclamide = 5.0g Ludipress 120.0 g 194.09 Magnesium stearate 0.59 1.09 Mix all components, pass through a 0.8 mm sieve and press with low compression force (about 10 kN). Mix all components, pass through a 0.8 mm sieve and press with low compression force. Properties Weight Diameter Form Hardness Disintegration (gastric juice) Friability Dissolution, 10 min 30 min No. 1 149 mg 8mm biplanar 74N 3 min < 0.1% 63% 95% No. 2 148 mg 8mm biplanar 49N 1 min 0.3% not tested not tested Glibenclamide Tablets (5 mc Formulation 5 Glibenclamide, micronized Glibenclamide Ludipress Magnesium stearate No. 1 5.0g 120.0 g 0.59 No. 2 5.0g 194.0g 10g Mix all components, pass through a 0.8 mm sieve and press with low compression force (about 10 kN). Properties Weight Diameter Form Hardness Disintegration Friability Dissolution, 10 min 30 min 60 min No. 1 125 mg 7mm biplanar 80 N 2-3 min < 0.2% 50% 69% 75% No. 2 201 mg 8mm biplanar 107N 3-4 min <0.1% Influence of the compression force on the physical tablet properties (No. 2) 5 kN Hardness 47N Disintegration 2-3min Friability < 0.1% Compression force 10 kN 107N 3-4 min < 0.1% 20 kN 158 N 3-4 min < 0.1% 25 kN 191N 5 min <0.1%
Formulation 6 Propranolol Hydrochloride Tablets (10 mg, 50 mg and 100 mg) Propranolol hydrochloride Ludipress Magnesium stearate No. 1 10g 490 g 2.59 No. 2 50g 450 g 2.59 No. 3 100 g 400 g 2.59 Mix all components, pass through a 0.8 mm sieve and press with low compression force. Properties Sst NeeWeen pee seo sn Cte Nea Weight Diameter Form Hardness Disintegration Friability No. 1 514 mg 12mm biplanar 112N 2 min 0.1% No. 2 496 mg 12mm biplanar 86N 2 min 0.2% No. 3 505 mg 12mm biplanar 101N 3 min 0.1% Remarks In the case of formulation No. 1 or No. 2 the amount of Ludipress and the tablet weight may be reduced. These formulations may be also used for tablet cores. Vitamin C Tablets (200 mg), Addition of Dry Binder Kollidon VA 64 Formulation 7 scorbic acid, powder udipress ollidon VA 64 Nagnesium stearate No. 1 200.0 g 256 g 2.5.9 No. 2 200.0 g 256.0 g 25.0g 2.59 Mix all components, pass through a 0.8 mm screen and press with medium compression force (18 KN). Properties rroperties Weight Diameter Form Hardness Friability Dissolution, 30 min No. 1 475 mg 12mm biplanar 56N 3.2% > 90% No. 2 499 mg 12mm biplanar 73N 0.4% > 90% Weight Diameter Form Hardness Friability Dissolution, 30 min
Multivitamin Tablets Formulation 8 Vitamin A Acetate Dry Powder 500.00 I. U./g Thiaminmononitrate Riboflavin Nicotinamide Calcium D-pantothenate Pyridoxinhydrochloride Cyanocobalamine 0.1% SD Ascorbic Acid, Powder Vitamin E Acetate Dry Powder SD 50 Ludipress Magnesium stearate Saccharin-Sodium Orange Flavor 10.0g 2.2g 2.2g 16.59 11.0g 2.2g 6.0g 85.0 g 31.0g 321.0g 3.0g 2.59 7.29 Vitamin A Acetate Dry Powder 500.00 I. U./g Thiaminmononitrate Riboflavin Nicotinamide Calcium D-pantothenate Pyridoxinhydrochloride Cyanocobalamine 0.1% SD Ascorbic Acid, Powder Vitamin E Acetate Dry Powder SD 50 Ludipress Magnesium stearate Saccharin-Sodium Orange Flavor Mix all components, pass through a 0.8 mm sieve and press with a medium compression force. Properties PERE MD ASAE Es, et onan te Weight Diameter Form Hardness Disintegration Friability 500 mg 12mm biplanar 68 N 5 min 0.2% 20 kg cardboard boxes with PE inner liners Packaging Keep containers tightly closed at <25 C. Storage Retest period of the product in original unopened containers is at least 24 months if they are properly stored. Storage stability This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. Disclaimer