product name is ludipress®. ludipress® – a granulate that means quicker, easier, and more cost-effective tableting. description of the ludipress® polymer is supplied as white, free-flowing granules that are tasteless. it is a mixture of lactose monohydrate (93%), kollidon® 30 (3.5%) and kollidon® cl (3.5%).. the product is manufactured in germany. packet sizes are 1kg plastic bottle 20kg fiberboard boxes. the benefits of the product are a three-in-one system comprising filler, binder and disintegrant with very low hygroscopicity and excellent flowability us fda approved and iid-listed (inactive ingredient database)  accelerated product development and process validation  with ludipress®, you save precious time on developing, analyzing and blending. you simply add your active ingredient, a lubricant, and compress your tablets - it is that easy  reduced costs – for storage, production and analysis  quick and easy tablet compression resulting in outstanding tablets with rapid disintegration in spite of ideal hardness, low friability and fast active ingredient release.
product name is ludipress® lce. a ready-to-use lactose-based direct compression excipient. description of the ludipress® lce polymer is supplied as white, free-flowing granules for direct compression. it is a mixture of lactose monohydrate (96.5%), kollidon® 30 (3.5%).it has a neutral taste.. the product is manufactured in germany. packet sizes are 20kg fiberboard boxes 1kg plastic bottle. the benefits of the product are streamlines the production process, reducing complexity and effort like no other direct-tableting excipient  completely water-soluble  outstanding binding power  excellent flowability and ideal particle size distribution  produces tablets of exceptional hardness  accelerates product development.
product name is maxomega dha 95 ee as. docosahexaenoic acid ethyl ester as an active pharmaceutical ingredient (api). description of the docosahexaenoic acid ethyl ester (dha 95 ee as) is a clear, colorless-to-faint-yellow liquid containing a minimum of 94 % (w/w) dha ee. tocopherol is added as an antioxidant.. the product is manufactured in uk. the compendial name of the product is deoconexent ethyl. packet sizes are 0,1kg aluminium drums 190kg steel drums. the benefits of the product are an ip-protected technology allowing for the environmentally friendly production of maxomega dha 95 ee as at exceptional purity levelswe have 20 years of production and research experience in omega-3-based pharmaceuticals.
product name is maxomega epa 96 ee. icosapent ethyl as active pharmaceutical ingredient (api). description of the maxomega epa 96 ee is a clear, colorless-to-faint-yellow liquid containing a minimum of 96.0 % (w/w) icosapent ethyl / eicosapentaenoic acid ethyl ester (epa ee). tocopherol is added as an antioxidant. maxomega epa 96 ee is a highly concentrated omega-3 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 uk. packet sizes are 0,1kg aluminium drums 190kg steel drums. the benefits of the product are an ip-protected technology allowing for the environmentally friendly production of maxomega epa 96 ee at exceptional purity levels. we have 20 years of production and research experience in omega-3-based pharmaceuticals.maxomega epa 96 ee is used as active ingredient in pharmaceutical drug products for the documented indication after approval by the competent authority. the approved indications may be different in different countries..
product name is maxomega epa 97 ee - japanese market. icosapent ethyl as active pharmaceutical ingredient (api), specified for the japanese market. description of the maxomega epa 97 ee is a clear, colorless-to-faint-yellow liquid containing a minimum of 96.5 % (w/w) icosapent ethyl / eicosapentaenoic acid ethyl ester (epa ee). tocopherol is added as an antioxidant. maxomega epa 97 ee is a highly concentrated omega-3 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 uk. the compendial name of the product is ethyl icosapentate (jp). packet sizes are 0,1kg aluminium drums190kg steel drums. the benefits of the product are an ip-protected technology allowing for the environmentally friendly production of maxomega epa 97 ee at exceptional purity levels.we have 20 years of production and research experience in omega-3-based pharmaceuticals.maxomega epa 97 ee issued as active ingredients in pharmaceutical drug products for the documented indication after approval by the competent authority. the approved indications may be different in different countries..
product name is novata® b ph. the best option for suppository masses or solid compositions. the benefits of the product are hard fat offering a sharp melting point for suppository applications  can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions  best option for suppository masses or solid compositions.
product name is novata® b ph. the best option for suppository masses or solid compositions. description of the white or almost white, waxy, brittle pellets. the product is manufactured in germany. the compendial name of the product is hard fat (ph.eur.). packet sizes are 0,5kg plastic bottle 20kg fiberboard boxes. the benefits of the product are hard fat offering a sharp melting point for suppository applications  can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions  best option for suppository masses or solid compositions.
product name is novata® bc ph. the best option for suppository masses or solid compositions. the benefits of the product are hard fat offering a sharp melting point for suppository applications  can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions  best option for suppository masses or solid compositions.
product name is novata® bc ph. the best option for suppository masses or solid compositions. description of the white or almost white, waxy, brittle pellets. the product is manufactured in germany. the compendial name of the product is hard fat (ph.eur.). packet sizes are 0,5kg plastic bottle 20kg fiberboard boxes. the benefits of the product are hard fat offering a sharp melting point for suppository applications  can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions  best option for suppository masses or solid compositions.
product name is novata® bcf ph. the best option for suppository masses or solid compositions. the benefits of the product are hard fat offering a sharp meltin gpoint for suppository applications  can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions  best option for suppository masses or solid compositions.
product name is novata® bcf ph. the best option for suppository masses or solid compositions. description of the white or almost white, waxy, brittle pellets. the product is manufactured in germany. the compendial name of the product is hard fat (ph.eur.). packet sizes are 0,5kg plastic bottle 20kg fiberboard boxes. the benefits of the product are hard fat offering a sharp melting point for suppository applications  can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions  best option for suppository masses or solid compositions.
product name is pronovapure® 150:500 ee. fish oil ethyl ester concentrate, min. 150 mg/g epa and 500 mg/g dha. description of the pronovapure® 150:500 ee is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 150:500 ee is a light yellow fish oil ethyl ester concentrate. 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. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 60. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 150:500 tg. fish oil concentrate, min. 150 mg/g epa and 500 mg/g dha. description of the pronovapure® 150:500 tg is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 150:500 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 (docosahexaenoic acid expressed as tg) is min. 650 mg/g. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid triglycerides. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 360:240 ee. fish oil ethyl ester concentrate, min. 360 mg/g epa and 240 mg/g dha. description of the pronovapure® 360:240 ee is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 360:240 ee is a light yellow fish oil ethyl ester concentrate. 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. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 60. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 360:240 tg. fish oil concentrate, min. 360 mg/g epa and 240 mg/g dha. description of the pronovapure® 360:240 tg is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 360:240 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 (docosahexaenoic acid expressed as tg) is min. 600 mg/g. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid triglycerides. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chainmember of goed (global organization for epa and dha.
product name is pronovapure® 400:200 ee. fish oil ethyl ester concentrate, min. 400 mg/g epa and 200 mg/g dha. description of the pronovapure® 400:200 ee is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 400:200 ee is a light yellow fish oil ethyl ester concentrate. 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. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 60. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 400:200 tg. fish oil concentrate, min. 400 mg/g epa and 200 mg/g dha. description of the pronovapure® 400:200 tg is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. 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 (docosahexaenoic acid expressed as tg) is min. 600 mg/g. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid triglycerides. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 460:180 ee. fish oil ethyl ester concentrate, min. 460 mg/g epa and 180 mg/g dha. description of the pronovapure® 460:180 ee is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 460:180 ee is a light yellow fish oil ethyl ester concentrate. 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. 640 mg/g. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 60. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 46:38 ee. fish oil ethyl ester concentrate, min. 430 mg/g epa and 347 mg/g dha. description of the pronovapure® 46:38 ee is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 46:38 ee is a light yellow fish oil ethyl ester concentrate. 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. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 90. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 500:200 ee. fish oil ethyl ester concentrate, min. 500 mg/g epa and 200 mg/g dha. description of the pronovapure® 500:200 ee is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 500:200 ee is a light yellow fish oil ethyl ester concentrate. 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. 700 mg/g. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid ethyl esters 60. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pronovapure® 500:200 tg. fish oil concentrate, min. 500 mg/g epa and 200 mg/g dha. description of the pronovapure® 500:200 tg is an omega-3 concentrate intended for use in dietary supplements such as in soft gel capsules. pronovapure® 500:200 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 (docosahexaenoic acid expressed as tg) is min. 700 mg/g. 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). the product is manufactured in norway. the compendial name of the product is omega-3-acid triglycerides. packet sizes are 0,11kg aluminium bottle190kg steel drums. the benefits of the product are produced in our gmp and fssc 22000 certified production site in sandefjord, norway  global presence secures an end-to-end supply  sustainable sourcing of raw material  we are managing our omega-3 production towards a zero-waste value-chain  member of goed (global organization for epa and dha).
product name is pvp iodine 30/06. free-flowing powder. description of the pvp-iodine 30/60 is a brown, free-flowing powder. it is soluble in water, ethanol, propanol and insoluble in acetone, chloroform, methylene chloride, heptane and hexane.. the product is manufactured in usa. the compendial name of the product is povidone iodine; pvp-iodine; 2-pyrrolidinone, 1-ethenyl-, homopolymer, compd. with iodine. packet sizes are 0,5kg plastic bottle 70kg plastic drums 500kg ibc flexible 70kg pe-drum, removable head not specified 1kg plastic bottle. the benefits of the product are prophylaxis of skin and mucous membrane antisepsis and surgical and hygienic hand disinfection  treatment of burns, decubitus, varicose ulcers, dermatomycosis, pyoderma, acne and vaginitis.
product name is racemic ibuprofen lysinate. salt form of ibuprofen. description of the racemic ibuprofen lysinate is supplied as very fine crystalline powder with a high volume.. the product is manufactured in germany. the compendial name of the product is (±)-2-p-isobutylphenyl propionic acid lysinate. packet sizes are 0,1kg plastic bottle 25kg fiber drums. the benefits of the product are very high water solubility than ibuprofen acid  it dissolves more quickly in vitro and is absorbed more rapid (shorter tmax and faster onset of action) than conventional ibuprofen.
product name is soluplus®. the first polymeric solubilizer and matrix forming polymer.. description of the white to yellowish granules.. the product is manufactured in germany. packet sizes are 0,5kg plastic bottle 12,5kg plastic drums 25kg fiberboard boxes 2,5kg plastic jerrycans. the benefits of the product are outstanding solubilization properties, especially for poorly soluble apis  solubility effects due to ph shifts can be avoided  enables bioavailability enhancement  soluplus® with its glass transition temperature of around 70°c is a well extrudable polymer and shows no chemical degradation even after extrusion at 220°c.  ideal for hot melt extrusion.
Technical Information Direct compression excipient for fast-disintegrating solid oral dosage forms. February 2019 Supersedes issue dated January 2016 Last change WF-No. 137243 = Registered trademark of BASF in many countries.
1. Introduction Ludiflash is a formulation for fast disintegrating solid oral dosage forms. The formulation of co-processed ingredients consists of three compendial ingredients: A sugar alcohol, crospovidone and a polymer dispersion based on polyvinyl acetate. It is tailored to disintegrate readily on the tongue with a pleasant creamy mouth-feel without a chalky or sandy sensation. Ludiflash is suitable for direct compression manufacturing by simply blending the excipient with the active and a lubricant, and is thus applicable for a very cost efficient production pathway. 2. Technical properties Composition Ludiflash consists of D-mannitol, crospovidone, polyvinyl acetate and small amounts of povidone. Polyvinyl acetate is incorporated into the system as Kollicoat SR 30 D, a polyvinyl acetate dispersion stabilized with povidone. The used D-mannitol fully complies to the monographs of the European Pharma- copeia, USP/NF and Japanese Pharmacopeia. CAS numbers D-Mannitol 69-65-8 Crospovidone (Kollidon CL-SF) 9003-39-8 Polyvinyl acetate (Kollicoat SR 30 D) 9003-20-7 Povidone (Kollidon 30) 9003-39-8 Description Ludiflash is a white to off-white powder with good flowability. The angle of repose was determined to be ~38 . Sorption isotherm The product has a very low hygroscopicity, driven by the specific character of D-mannitol. Figure 1: Sorption isotherm at 23 C
Solubility Due to the content of crospovidone and polyvinyl acetate, the product does not dissolve completely in water, nor is it entirely soluble in organic solvents. Properties The properties described in the following paragraph are considered to be typical values. Particle size distribution > 0.400 mm max. 20% (determined) < 0.200 mm max. 90%, min. 45% < 0.063 mm max. 45%, min. 15% Bulk density 0.42 - 0.58 g/ml (DIN ISO 697, Apparatus from Coesfeld, no specification parameter) Typically batches show a 0.53 - 0.58 g/ml bulk density between PH value .5-6.5 (5% in water, partially dissolved) Notice: As the product contains D-mannitol it can have a mild laxative effect. 3. Application General remarks To achieve fast disintegrating solid oral dosage forms, it is important to have tablets with high porosity which allows water to penetrate very fast. The careful control of the compression force is thus very important. 50 MPa to 90 MPa tabletting pressure, which corresponds to 3-6 kN compression force for a 10 mm tablet are most suitable. Furthermore the control of humidity throughout tablet manufacturing and the use of vapor resistant packaging materials for the finished tablets should be considered. The storage temperature for Ludiflash and formulations with Ludiflash should not exceed 25 C, to avoid an undesired increase of disintegration times. Recommendations for Lubricants Detailed tests revealed magnesium stearate and sodium stearyl fumarate to be appropriate lubricants for fast disintegrating formulations based on Ludiflash. Recommendations for Taste Optimization Tablets with optimum properties can be achieved when the following excipients are applied in the ranges given: 1. Sweeteners like aspartame in concentrations ranging from 0.3 to 0.7% or saccharine sodium in a concentration ranging from 0.05% to 0.1% were tested in various formulations and can be recommended. 2. To achieve an effervescent effect the combination of citric acid with sodium hydrogen carbonate can be formulated. Both compounds are applied in quantities of 0.5%. 3. To control the acidity of a tablet ascorbic acid or combinations of ascorbic acid and sodium ascorbate in concentrations, as well as citric acid can be used. 4. Vanilla flavor in a concentration of around 0.5% or L-Menthol in the range of 0.1% to 0.8% can be used with good tabletting results for aroma purposes. Recommended API Loading Possible drug loads depend very strongly on the properties of the API. Most APIs can easily be formulated in concentrations of up to 20%. Several APIs, like for example Acetaminophen, can be formulated at even higher concentrations of up to 60% and still disintegrate and dissolve very quickly.
Formulation 1 To demonstrate the basic properties of the excipient Ludiflash, placebo tablets were manufactured and checked for their properties. Ludiflash placebo formulation BRUGINaoll VIdGCeNY IOPuUlatigor Ludiflash (BASF) 98% Sodium stearyl fumarate (JRS Pharma) 2% Manufacturing All components were blended in a Turbula blender for 10 minutes, passed through a sieve with a mesh size of 0.8 mm and compressed into tablets. abletting equipment Korsch XL 100 rota ablet size/shape 101 otal tablet weight Even at very low compression forces (figure 2) in the range of 5 KN to 10 kN, which still allow very porous tablets, it is possible to achieve tablets sufficiently stable and showing a low friability. The disintegration time is in the range of less than 30 seconds when determined in a disintegration tester (figure 3). Figure 2: Hardness and friability as function of compression force Figure 3: Disintegrations time as function of compression force
In long time production runs the influence of tabletting speed on the uniformity of mass hardness and friability was checked. For the tests rotation speeds of 20 rom, 40 rom and 60 rpm were used. The uniformity of mass (tested on 20 tablets) is well within the compendial ranges (figure 4). Figure 4: Uniformity of the tablet mass as function of rotation speed Formulation 2 Loperamide fast disintegrating tablet: 2 mg Loperamide HCl (Select Chemie) 2.0 mg Ludiflash (BASF) 94.5 mg Kollidon CL-SF (BASF) 1.0 mg Chocolate aroma (Symrise) 1.5 mg Sodium stearyl fumarate (JRS Pharma) 1.0 mg Total tablet weight 100.0 ma Total tablet weight Manufacturing All components were blended in a Turbula free fall blender for 10 minutes, passed through a sieve with a mesh size of 0.8 mm and compressed into tablets at 3.8 kN. Tablet properties Tablet weight 100.0 mg Form 7 mm concave Hardness 32N Friability 0.09% Disintegration time tis (phosphate buffer pH 7.2) Dissolution 94.7% (0.01 N HCI/100 rpm) (380 min) Taste quickly disintegrating in the oral cavity, slightly bitter, chocolate taste, very smooth mouth- feeling
The content uniformity (figure 5) and the dissolution profile (figure 6) of the Loperamid tablets are shown in the following figures: Figure 6: Dissolution profile of Loperamide tablets (2 mg) Formulation 3 Loratadine fast disintegrating tablet: 10 mg Sea he bet a aa eae eee laa Loratadine (Select Chemie) 10.00 mg Ludiflash (BASF) 39.70 mg Saccharin-Sodium (Merck) 0.26 mg Il Kollidon 25 (BASF) 1.02 mg Ill Ludiflash (BASF) 142.02 mg Peppermint-aroma (Bell Flavours & Fragrances) 3.00 mg Magnesium stearate (Baerlocher) 4.00 mg Total tablet weight 200.00 mg Manufacturing Se ea a The components of were granulated with a 6.5% aqueous solution of Il in a Glatt GPC G8 fluid bed granulator (atomizing pressure 0.5 bar, inlet air temperature 45 50 C outlet air temperature 30 C). The resulting granules were blended with Ill in a Turbule blender for 10 min, passed through a 0.8 mm sieve and compressed into tablets ai 2.8 KN.
Tablet properties Tablet weight 200.0 mg Tablet form 8mm, flat Hardness 37.0N Friability 0.25% Disintegration time 38s (phosphate buffer pH 7.2) Dissolution 98.8% (0.1 N HCI/SO rpm) (10 min) The content uniformity and the dissolution profile of the Loratadine tablets are showr in the following figures: Figure 7: Content uniformity of Loratadine tablets (10 mg) Figure 8: Dissolution profile of Loratadine tablets (10 mg)
Formulation 4 Famotidine fast disintegration tablet: 20 mg Famotidine (Various sources) 20.0 mg Ludiflash (BASF) 267.1 mg Aerosil 200 (Degussa) 3.0 mg L-Menthol (Symrise) 0.9 mg Aspartame (Ajinomoto) 4.5 mg Sodium stearyl fumarate (JRS Pharma) 4.5 mg Tatal tahlet waiqht QNN 0 ma Total tablet weight Manufacturing All components were blended in a Turbula free fall blender for 10 minutes, passed through a sieve with a mesh size of 0.8 mm and compressed into tablets at 0.8 ton/cm?, corresponding to ~10 kN for a 10 mm tablet. Tablet properties fabiet properties Tablet weight 300 mg Tablet form 10mm, 10R Rotation speed 40 rpm Hardness 51N Friability <0.2% Disintegration time 278 (phosphate buffer pH 7.2) Dissolution (n=10); 0.05 mol/l 98.8% acetic acid/Na-acetate buffer (10 min) pH 4.0, 50 rom 120 100 = = 80 3 S 60 2 = 40 a 20 0 i T T 0 5 10 15 20 Time [min] Figure 9 Dissoli tion of Famotidine Figure 9: Dissolution of Famotidine Content uniformity (n=10) Ave.= 100.5% Max= 101.5% Min= 97.4% SD= 1.2%
Formulation 5 Cetirizine fast disintegration tablet: 5 mg WENA IAOE MICOS YE GLIUEL LEE hs ww PEED Cetirizine Ludiflash Aerosil 200 Avicel PH 101 Grapefruit powder L-Menthol Aspartame Sodium stearyl fumarate (Daito) (BASF) (Degussa) (FMC) (Symrise) (Takasago International) (Ajinomoto) (JRS Pharma) 5.0 mg 163.4 mg 2.0 mg 20.0 mg 2.0 mg 0.6 mg 4.0 mg 3.0 mg Total tablet weight 200.0 ma Total tablet weight Manufacturing All components were blended in a Turbula free fall blender for 10 minutes, passed through a sieve with a mesh size of 0.8 mm and compressed into tablets at 0.8 ton/cm?, corresponding to ~14 KN for a 8.5 mm tablet. Tablet properties Tablet properties Tablet weight 200 mg Tablet form 8.5mm, 12R Rotation speed 40 rom Hardness 51N Friability <0.2% Disintegration time 32s (phosphate buffer pH 7.2) Dissolution (n=10); 98.8% water, 50 rpm (10 min) 120 100 oo = 80 4 60 2 2 40 a 20 0 1 1 1 1 0 5 10 15 20 Time [min] Figure 10: Dissolution of Cetirizine Figure 10: Dissolution of Cetirizine Content uniformity (n=10) Ave. = 101.4% Max = 102.7% Min= 98.6% SD = 1.6% Content uniformity (n=10) Ave. = 101.4% Max = 102.7% Min= 98.6% SD= 1.6%
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 30280988 _Ludiflash 56513304 20 kg Corrugated fiberboard box with PE liner 53269227 1 kg Plastic bottle BASFs commercial product number. BASFs commercial product number. Free non-GMP samples for testing purposes are available on request. http://pharmaceutical.basf.com/en.htm 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 Kollisolv PYR 2-Pyrrolidone <MarComm-2022-00316> Page 1 of 4
Chemical information Chemical name 2- Pyrrolidone Chemical formula C4H7NO Molecular weight 85.1 g/mol CAS number 616-45-5 Structural formula Typical physical parameters Kollisolv PYR is a colorless or slightly yellow liquid which solidifies at room temperature and has a characteristic odor. Darkening of the color of the product occurs over time, especially when stored at temperatures higher than 25 C. Kollisolv PYR is soluble in water and a number of organic solvents, e.g. ethanol, isopropyl alcohol and aromatic hydrocarbons. Properties Handling recommendation Kollisolv PYR needs to be homogenized prior use. Therefore, the product needs to be melted down by careful heating followed by gentle mixing. Appropriate tests showed after seven days at 50 C no change in the analytical properties of the product. Storage recommendation Refer to the individual document quality and regulatory product information (QRPI), available on RegXcellence and 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. Refer to the individual document quality and regulatory product information (QRPI), available on RegXcellence and from your local BASF sales representative.
Product Details: PRD number 30555079 Packaging and article 200 kg composite packaging, number (ART 50254756) Sample and article number _0.5 kg glass bottle (ART 50259812) Retest period 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. 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.
Disclaimer 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 gl (a) To the fullest extent not prohibited by the applicable laws, BASF EXPRESSLY DISCLAIMS ALL OTHEF REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES OF ANY KIND, WHETHEF 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 II CONNECTION WITH THIS DOCUMENT OR ANY INFORMATION PROVIDED HEREIN, including, withou 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 willft misconduct, fraud or fraudulent misrepresentation or (iii) any matter in respect of which it would be unlawful fo 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 documen nor the information provided herein may be relied upon to satisfy from any and all obligations you may have to undertak your own inspections and evaluations; (c) BASF rejects any obligation to, and will not, automatically update this document and any information providec herein, unless required by applicable law; and BASF Nutrition & Health www.pharma.basf.com/
PronovaPure 500:200 EI Chemical names of active ingredient CAS-No. 86227-47-6 EPA ethyl ester 81926-94-5 DHA ethyl ester Description PronovaPure 500:200 EE is a light yellow fish oil ethyl ester concentrate. Articles 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. 700 mg/g. Country of origin
Composition Stability, Storage and Handling ee ae er Ingredients in descending order of weight: Fish oil ethyl ester concentrate, tocopherol-rict 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). mainhs darivod fram aenvhaan (fram idantity 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, in ethanol (96 per cent), in heptane and in methanol. Applications  Se PronovaPure 500:200 EE is intended for use in dietary supplements such as in soft gel capsules. Specification Note as ethyl ester Ph. Eur. 2063/2.4.29 EPA (Eicosapentaenoic acid) 500 560 mg/ DHA (Docosahexaenoic acid) 200 250 mg/ EPA & DHA (Eicosapentaenoic 700-780 mg/ & Docosahexaenoic acid) PronovaPure 500:200 EE 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 ot 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, 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 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 the products upon delivery or any other obligation For further information see separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Ne Ree One SRS ae AN Se Se Se ee re 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 00:200 leets 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. June 2017
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 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.
Supersedes issue dated June 2008 Lactose-based direct compression excipient.
Ludipress LCE is a granulated excipient consisting of Lactose monohydrate and Povidone K30 (Kollidon 30). The product consists of white to slightly yellowish, free-flowing powder for direct compression. It is odorless and has a neutral taste. Description Ludipress LCE was developed as an extension of the BASF range of direct compression excipients for use in chewable tablets and lozenges, for effervescent tablets and as bulking agent in hard gelatin capsules. Applications However, in combination with Kollidon CL-F or Kollidon CL as tablet disintegrant, all other types of formulation are possible. Moreover high-dose forms can be produced using Kollidon VA 64 Fine. See separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: httos://worldaccount.basf.com (registered access). No monographs exist. The components Lactose monohydrate and Povidone K30 (Kollidon 30) are specified according to the current versions of Ph.Eur., USP and JP. The Hausner ratio of the tapped density and bulk density is typically 1.20 + 0.10. The bulk density is typically 0.56 + 0.06 g/cm. Guideline values The particle size distribution for Ludipress LCE shows the following typical values. The measurements were carried out in a sieve shaker. im max. 20% im 40 to 65% im max. 20% Figure 1 shows an example of the particle size distribution measured by laser diffraction. Figure 1: Particle size distribution of Ludipress LCE (laser diffraction; dry measurement)
Figure 2 shows the sorption isotherm for Ludipress LCE at 20 C. Ludipress LCE adsorbs only very small amounts of water even at high humidities. The initial level of aorund 5 % represents the water in lactose monohydrate. Hygroscopicity
Tabletting characteristics The behaviour of Ludipress LCE on compression is shown in Figure 3, compared with a physical mixture consisting of Ludipress LCE and Kollidon CL and with lactose and the corresponding mixture with Kollidon 30 and Kollidon CL. The tablet hardnesses which can be achieved with Ludipress LCE are distinctly higher. The following examples may serve as guidelines for formulations. The tablets were produced in a rotary press using the compression conditions and punches stated in each case. Typical formulations Further formulations using BASF excipients for the pharmaceutical industry can be found in the compendium Generic Drug Formulations. It is available on request as a loose-leaf file, or on diskette or CD-ROM. 14 1.4.4 1.1.2 Cetylpyridinium lozenge [2.5 mg] Formulation Cetylpyridinium chloride 2.5 Ludipress LCE 370.0 Menthol, crystalline 6.0. Aspartame 4:5 Polyethylene glycol 6000, powder 20.0. Production (direct compression) The components are mixed, passed through a sieve with 0.8 mm mesh size and compressed using low compression force. 1.1.3 Tablet properties 24 2.1.4 2.1.3 Tablet weight 402m Diameter 10 mr Form biplane Hardness 80! Disintegration time > 10 mi Friability < 0.19 Chewable tablets Vitamin E chewable tablet [100 mg] Formulation Vitamin E acetate dry powder 50% DC 200.0. Ludipress LCE 258.0. Polyethylene glycol 6000, powder 35.0 Aerosil 200 7.0. Production (direct compression) The components are mixed, passed through a sieve with 0.8 mm mesh size and compressed using low compression force. Tablet properties Tablet weight 500 m Diameter 10 mr Form biplane Hardness 871 Friability < 0.19 1.1.1 Formulation Tablet weight Diameter Form Hardness Disintegration time Friability SS ee Ge Re ESCM eT ee ere ea ee The components are mixed, passed through a sieve with 0.8 mm mesh size and compressed using low compression force. P.O TaANICL PIVUPCILICS Tablet weight 500 mg Diameter 10mm Form biplanar Hardness 87 N < 0.1% Friability Tablet weigh Diameter Form Hardness Friability
2.2.2 2.2.3 3.1.1 Lalclum Citrate OU. Ludipress LCE 297.5 Citric acid, anhydrous 100.0 Polyethylene glycol 6000, powder 80.0 Orange flavour 30.0 Aerosil 200 17.0 Aspartame 5.0 Production (direct compression) The components are mixed, passed through a sieve with 0.8 mm mes size and compressed using low compression force. Tablet properties Tablet weight 2417 n Diameter 20m Form biplan Hardness 201 Friability 0.2 Effervescent tablets Beta-carotene + vitamin C + vitamin E effervescent tablet [12 mg + 150 mg + 25 mg] Formulation Lucarotin dry powder 10% CWD G/Y 120 Ascorbic acid, crystalline 150 Vitamin E acetate dry powder 50% DC 50 Ludipress LCE 705 Kollidon VA 64 50 Citric acid, anhydrous 450 Sodium bicarbonate 320 Polyethylene glycol 6000, powder 75 Aspartame 30 Orange flavour 50 Production (direct compression) The components are mixed, passed through a sieve with 0.8 mm mes size and compressed using high compression force at a maximum relativ humidity of 30%. Tablet properties Tablet weight 2045 n Diameter 20m Form biplan Hardness 95 Disintegration time (water) 3 Friability 0.9
V.cel 3.2.2 3.2.3 3.4 3.4.1. 3.4.2 3.4.3 POrmihiulatiorr Cimetidine 406 Ludipress LCE 686 Sodium bicarbonate 606 Tartaric acid 45 Aspartame 3 Polyethylene glycol 6000, powder a Orange flavour q. Production (direct compression) The components are mixed, passed through a sieve with 0.8 mm mes size and compressed using high compression force at a maximum relati\ humidity of 30%. Tablet properties Tablet weight 2250 1 Diameter 20n Form biplar Hardness 107 Disintegration time (water) 4n Friability 1.( Multivitamin effervescent tablet with beta-carotene Formulation Lucarotin dry powder 10% CWD G/Y 23.( Vitamin E acetate dry powder 50% DC 40. Thiamine mononitrate 2.( Riboflavin 2.( Nicotinamide 22.( Calcium D-pantothenate 11. Pyridoxine hydrochloride 2.( Cyanocobalamin 0.1% SD 6. Ascorbic acid, powder 85.( Ludipress LCE 477.( Sodium bicarbonate 600.( Tartaric acid 400.( Polyethylene glycol 6000, powder 90. Orange flavour 60.( Aspartame 30.( Production (direct compression) The components are mixed, passed through a sieve with 0.8 mm mes size and compressed using high compression force at a maximum relati\ humidity of 30%. Tablet properties Tablet weight 1850 1 Diameter 20n Form biplar Hardness 91 Disintegration time (water) tn Friability 0.
4.1.1 FR a ee ee ee ee Formulation Propranolol HCI Methocel K 15 M Ludipress LCE Aerosil 200 Magnesium stearate 160.0 g 80.0 g 100.0 g 3.4g 1.69 4.1.1 Formulation 4.1.1 Formulation Geled 4.1.2 4.1.3 4.2 4.2.1 4.2.2 Formulation Propranolol HCI Methocel K 15 M Ludipress LCE Aerosil 200 Magnesium stearate 160.0 80.0 100.0 3.4 1.6 Production (direct compression) The components are mixed, passed through a sieve with 0.8 mm mesh size and compressed using low compression force. Tablet properties Tablet weight 345.0 m Uniformity of mass (s rel.) 1.75% Diameter 10.0 mrr Form biplana Hardness 145 N Friability 0% Release (paddle, 50 rpm, 2 h gastric fluid pH 1.2 then 2 h: 30% intestinal fluid pH 6.8) 4h: 44% 8h: 64% 12 h: 81% 20 h: 97% Verapamil sustained release tablet Formulation Verapamil HC! 240.0 Ludipress LCE 230.0 Methocel K 15 M 75.0 Talc 75.0 Aerosil 200 2.5 Magnesium stearate 5.0 Production (direct compression) Thea cromnonente are mived nacced throiiqh 9 cieve with 0 28 mm mech Propranolol HCI Methocel K 15 M Ludipress LCE Aerosil 200 Magnesium stearat 4.2 Verapamil sustained release tablet 4.2.1 Formulation 2.1 Formulation Verapamil HCl Ludipress LCE Methocel K 15 M Talc Aerosil 200 Magnesium stearate 240.0 g 230.0 g 75.09 75.0 g 2.59 5.0g ~ The components are mixed, , passed through a sieve with 0.8 mm mesh size and compressed using low compression force. 2.3 Tablet properties Tablet weight Uniformity of mass (s rel.) Diameter Form Hardness Friability Release (paddle, 50 rpm, 2 h gastric fluid pH 1.2 then intestinal fluid PH 6.8) 627.5 mg 0.6% 12 mm biplanar 100 N 01% 4h: 35% 8h: 51% 12 h: 62% 16 h: 73% 20 h: 81% 24 h: 90%
PRD-No. Packaging Store at room temperature in tightly closed containers. Ludipress LCE can be stored for 24 months under these conditions. Storage/Shelf life 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. Disclaimer June 2017
PronovaPure 360:240 EI Valid for batches produced from January 2014 Chemical names of active ingredient CAS-No. Description PronovaPure 360:240 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
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) PronovaPure 360:240 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 vol- untary 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. 2063/2.4.29 EPA (Eicosapentaenocic acid) min. 360 mg/g DHA (Docosahexaenoic acid) min. 240 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. 360 mg/c DHA (Docosahexaenoic acid) min. 240 mg/c EPA & DHA (Eicosapentaenoic 600-700 mg/c & Docosahexaenoic acid) Total Omega-3 content min. 650 mg/c Applications Qe ee: Dietary supplement: oT eee PronovaPure 360:240 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 360:240 EE 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 the products upon delivery or any other obligation AS MPATASAKITIE. GE ARRZ, (RGA, TITCIEEY ELORESO. AB GIBCIER Standards Produced under cGMP and HACCP principles. OE RON Pen eee ele ME EDL et ne Se Rte 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 All-in-one direct compression excipient for solid oral dosage forms Figure 1. Kollitab DC 87 L SEM image (left). Kollitab DC 87 L flowing through a funnel (right).
1. Introduction Direct compression (DC) formulations typically require multiple excipients to obtair good material flow and compressibility, fast disintegration and efficient lubrication. However, it is often both time-consuming and expensive to determine the proper excipient combinations and concentrations. Even after optimizing the mixture of excipients, the formulation requires several processing steps in order to create the final blend. Formulations based on coprocessed excipients are a solution to these challenges. Coprocessed excipients combine multiple excipients into a single material to offer an all-in-one functionality. Their use reduces the number of excipients required to achieve excellent processability and performance; consequently, they reduce drug product development time, manufacturing complexity, and may significantly expedite time-to-market. Kollitab DC 87 L is an all-in-one lactose-based coprocessed excipient designed for direct compression of solid oral dosage forms. As an all-in-one excipient, it contains all the functionalities required for formulating an immediate release tablet: filler, disintegrant, binder and lubricant. Each ingredient in its composition was expertly selected with the end-use in mind. Furthermore, the manufacturing process was designed specifically to reduce chemical and physical instabilities. The composition can be found below in Table 1. Kollitab DC 87 Lis composed of four ingredients which are assayed; the results which are listed in the certificate of analysis add up to 100 %. Kollitab DC 87 L is manufactured via aqueous spray drying. A chemical reaction among the ingredients was reduced under the mild processing conditions, and potential incompatibilities were taken into account. Table 1: Composition of Kollitab DC 87 L. Name Function Composition Lactose Filler ~87 % a-Lactose monohydrate!) Ph.Eur., USP-NF, JP?! Kollidon CL-F Disintegrant ~9 % Crospovidone Ph.Eur., USP-NF, JP Kollicoat IR Binder ~3 % Polyethylene glycol-polyvinyl alcohol graft polymer Ph.Eur., USP-NF, JPE Sodium Stearyl Fumarate Lubricant ~1% Sodium steary! fumarate Ph.Eur, USP-NF JPE [1] The process is optimized to prevent the formation of amorphous lactose, which is undesired due to its instability. [2] Lactose hydrate A summary of Kollitab DC 87 L components can be found below: e Lactose monohydrate is a water-soluble filler. Lactose in general has good compactability, narrow particle size distribution, and provides good blending properties. Kollicoat IR is a highly soluble, peroxide-free binder. It is commonly used as film-former, but it also performs extremely well in wet granulation, having similar or even better binding properties than PVP K30. Kollidon CL-F is the fine grade of the disintegrant crospovidone. Fine crospo: vidone particles provide not only fast disintegration, but also excellent compres: ibility due to their high surface area.
e Sodium stearyl fumarate is utilized as a more hydrophilic tablet lubricant than magnesium stearate. It has a high degree of API compatibility and robustness to over-lubrication, lessening the impact on drug dissolution and tablet processability when blended for long periods of time. Furthermore, it is suited for high-speed, direct compression of tablets. Kollitab DC 87 L was designed to achieve excellent blend, tableting, and flow properties for manufacturing robust and rapidly disintegrating tablets with high content uniformity. 2. Technical Properties Kollitab DC 87 Lis a free-flowing powder comprised of spherical particles produced during the spray-drying process. The median particle size of ~160 um (Table 2 and Figure 2) and overall morphology is shown in Figure 1. Table 2: Properties of Kollitab DC 87 L (n = 5 batches). igure 2: Averaged Particle Size Distribution (PSD) curves of five batches, measured with a Malvern Mastersizer 2000 (Dispersant: 0.5 bar air) in conjunction with a Scirocco 2000 powder feeder (setpoint: 50 %). The solid red line shows the volume fraction values, while the cumulative distribution values are given by the grey dotted line.
Flowability According to the specifications for the Hausner Ratio and Angle of Repose, Kollitab DC 87 L has good and excellent flowing properties, respectively. This ensures high process robustness during blending and compression, and low tablet weight variability. Table 3: Value range for powder characteristics derived from the characterization of five batches of Kollitab DC 87 L. Parameter Unit of Measure Typical Values Bulk Density g/mL 0.53 to 0.54 Tapped Density g/mL 0.60 to 0.61 Hausner Ratio NA 1.11 to 1.15 Angle of Repose () 26.5 to 27.5 Figure 3: Kollitab DC 87 L flowing through a funnel. Water Sorption Kollitab DC 87 Ls manufacturing process was optimized to minimize the formation of hygroscopic amorphous lactose. When opened and exposed to typical 40 50 % relative humidity, Kollitab DC 87 L has a moisture absorption of less than 3 %, as shown in Figure 4; this is due to the crospovidone. During transport and use, the material is protected from moisture by a thick, double-layer liner. Figure 4: Sorption curve of Kollitab DC 87 L measured at 25 C, determined with approx. 600 mg of sample material.
Compressibility Kollitab DC 87 L can produce high-strength tablets across a broad range of compression forces (low and high), reducing both stress and punch damage from the machine resulting in the reduction of tablet defects. Composition Tableting fapleting Technology Compaction Simulator Type STYLOne EVO Punch 10.0 mm Shape Round; flat face Comp. Forces [kN] 6, 9, 14, 18, 23 Figure 5: Tablets of pure Kollitab DC 87 L. As a general rule of thumb, the desired tablet strength (in N) is typically a value that is approximately ten times that of the tablet diameter (in mm) or a tensile strength of 1.7 2.0 MPa. This value is considered ideal to obtain strong tablets, thus allowing for subsequent processing such as packaging or coating. As shown in Figure 6, strong Kollitab DC 87 L tablets can be achieved at low (~9 kN) and high compression forces. Figure 6: Manufacturability Profile (above) and Tabletability Profile (below) of Kollitab DC 87 L tablets.
In accordance with USP chapter <1062>, Kollitab DC 87 L tablets show high compressibility and compactability and low ejection force. These are possible due to the binding properties from Kollicoat IR and Kollidon CL-F which provide high compactability and compressibility. The complementary lubrication effect from sodium steary! fumarate reduces ejection force. Figure 7: Processability charts of Kollitab DC 87 L tablets.
Kollitab DC 87 L ensures low tablet weight variability and high tableting performance. As observed in Figure 8, it provides low mass variation in a broad range of com- pression pressure. Figure 8: Mass variation (%) of 10 Kollitab DC 87 L tablets compressed in a broad range of compression pressure. Disintegration Time Kollitab DC 87 L achieves fast tablet disintegration for quick and reliable delivery of the intended benefits of the API. This is especially valuable for high-strength tablets that tend to take longer to disintegrate (Figure 9). Figure 9: Disintegration time of Kollitab DC 87 L tablets in water at 37 C. 3. Application Formulation 1: Aspirin or acetylsalicylic acid (ASA) is a medication used to treat pain, fever, and infla- mmation and reduces the risk of major adverse cardiovascular events (drugbank.com). When developing an ASA direct compression formulation, high flowability and com- pressibility are required to prevent process issues. High strength tablets are required to avoid problems during the coating process, as well as a fast disintegration time to minimize impact on the drug release.
Formulation: Acetylsalicylic acid 81 mg tablet Figure 10: Acetylsalicylic acid crystals (left), and acetylsalicylic acid 81 mg tablets (right). Tableting Blend Tableting bit Technology Type Punch Shape Comp. Forces [kN] Compaction Simulator STYLOne EVO 9.0 mm round and convex 7.5, 9.3, 11.1, 14.7, 19.1 KN Acetylsalicylic acid (ASA) 24.5 % Figure 11: Particle size distribution (laser diffraction) of crystal and milled acetylsalicylic acic (ASA) and pure Kollitab DC 87 L. When adding acetylsalicylic acid to Kollitab DC 87 L, an excellent tabletability can be maintained (Figure 12). At a low compression pressure of less than 180 MPa, tablets with a tensile strength of about 2.0 MPa are achieved. There is merely a minor difference between the two ASA grades; tablets of non-milled crystals show slightly lower tensile strength at higher compaction pressures. Independent of tablet strength, tablets with no friability (~O.0 %) were obtained.
Figure 12. Processability of ASA 81 mg tablets (uncoated). Adding unlubricated ASA to Kollitab DC 87 L leads to an increase of ejection stress, but at an acceptable level that does not impact processability. During drug development, it is important to evaluate the amount of unlubricated surface area that is brought into the formulation, which is dependent on the APIs particle size and drug load. Coarse material results in low ejection stress. For high drug load and/or micronized APIs, extra lubricant may be required in the formulation (evaluate case by case). As shown in Figure 13, ASA tablets had a fast disintegration time of less than 300 seconds regardless of tablet strength or API particle size. Figure 13. Disintegration time of ASA 81 mg tablets (uncoated) in water at 37 C.
Formulation 2 Formulation: Vardenafil tablets Vardenafil HCl is a phosphodiesterase-5 inhibitor indicated to treat erectile dysfunction (drugbank.com). It is a fine powder that impacts drug flowability and processability, making it a challenging drug for direct compression. Figure 14: Vardenafil HCI powder (left), vardenafil HC] SEM (center) and Kollitab DC 87 L blended with vardenafil HCI (right). Tableting Blend Tableting Ce Technology Equipment Punch Mass Direct compression KORSCH XL 100 9.0 mm 250 mg Vardenafil HCI 2 and 8 % Kollitab DC 87L 98 and 92% Figure 15: Manufacturability profile of vardenafil HC! tablets (2 and 8 % drug load) and pure Kollitab DC 87 L.
Figure 16: Disintegration time of vardenafil HCI tablets (2 and 8 % drug load) and pure Kollitab DC 87 L. To overcome direct compression challenges presented by cohesive APIs such as vardenafil HCI, Kollitab DC 87 L is the ideal solution as it can provide high process consistency. The excellent compressibility of pure Kollitab DC 87 L tablets and Kollitab DC 87 L + vardenafil tablets at 2 and 8 % drug load can be observed in the manufacturability profile (Figure 15). In addition, Kollitab DC 87 L and vardenafil can also produce quickly disintegrating tablets at all compression forces as observed in Figure 16. Formulation 3: To better compare the functionality of coprocessed excipients, Kollitalb DC 87 L and a similar blend of excipients were mixed with 2 % of vardenafil HC] and compressed into tablets. Formulation: Lactose blend vs. Kollitab DC 87 L blend Tableting Blend a se Vardenafil HCI 2% Kollitab DC 87L 98 % Lactose blend 98 % Technology Equipment Punch Mass Direct compression KORSCH XL 100 9.0 mm 250 mg V blender for 15 min at 17 rom API Particle Size Vardenafil HCI d10: 7 um d50: 28 um d90: 112 um Sieving (Tableting Blend)
Table 4: FT4 powder rheology of Kollitab DC 87 L and lactose blend. Material Compressibility % Flow Function Cohesion kPa @ 15.0 kPa Kollitab DC 87L 5.9 37 0.17 Lactose Blend 9.45 4 2.00 The lactose blend consisted of the following ingredients: 87 % lactose monohydrate, 9 % crospovidone (Kollidon CL-F), 3 % copovidone (Kollidon VA 64) and 1 % sodium stearyl fumarate. For a DC process, Kollidon VA 64 is recommended as a dry binder. Kollicoat IR is used as a binder in wet granulation only. As shown in Table 4, Kollitab DC 87 L demonstrated lower compressibility (%), which meant a lower percentage of change in volume as a function of applied force, lower cohesion, and a much higher flow function than the lactose blend. Based on these results, Kollitab DC 87 L was shown not to have a tendency towards agglomeration; instead, this coprocessed excipient remained free-flowing regardless of the handling conditions (storage, filling/dispensing). In contrast, the lactose blend had a lower flow function, higher compressibility, and cohesion, typical of materials that agglomerate and flow poorly. These results demonstrate the superior functionality and processability of Kollitab DC 87 L when compared to a blend composed of similar, individual excipients intended to be used in a DC process. Figure 17: Manufacturability profile of pure Kollitab DC 87 L, tablets of vardenafil HC: 2 % drug load with Kollitab DC 87 L, and tablets with the lactose blend. Kollitab DC 87 L with 2 % vardenafil produced strong tablets at all compression forces with no ejection problems. On the other hand, the lactose blend and 2 % vardenafil led to delamination and punch sticking, not even achieving the required hardness of 90 N (ten times that of the punch size) as shown in Figure 17. When both materials were blended at 2 % drug load, the addition of Kollitab DC 87 L improved vardenafil compressibility and processability via direct compression. In contrast, the individual lactose blend did not offer the same performance, resulting in tablets defects and poor tabletability.
Formulation 4 Formulation: Valsartan 40 mg Valsartan is an angiotensin II receptor blocker used to treat high blood pressure (drugs.com). Valsartan fine particles can be challenging to process via direct compression. For this reason, manipulating valsartan can require additional manufacturing considerations to ensure suitable flowability and compressibility. This study tested valsartan with Kollitab DC 87 L in a direct compression process Tableting Blend Tableting Tableting Figure 18: Manufacturability profile of valsartan 40 mg tablets. Figure 19: Disintegration time and friability of valsartan 40 mg tablets.
Kollitab DC 87 L enabled a successful direct compression formulation with valsartan 40 mg at 20 % drug load. Good compressibility was observed throughout the process, achieving ideal tablet hardness at low compression force (Figure 18). In addition, even for high tensile strength tablets, disintegration time remained under 2 minutes and friability was close to 0.1 % at all tablet strengths (Figure 19). 4. ZoomLab Figure 20: ZoomLab spider diagram summarizing Kollitab DC 87 Ls excellent tableting properties. ZoomLab is the BASFs Virtual Formulation Assistant. It aims to predict formula: tions and expedite drug development. Start with an active ingredient, define your target profile, and input your preferences. Include Kollitab DC 87 L among the most relevant excipients. Then let the advanced algorithm optimize the formulation. The parameters evaluated and presented on the ZoomLab spider diagram fot Kollitab DC 87 L (Figure 20) are: e d10 Value (D10), d50 Value (D50), d90 Value (D90), Distribution span (DSP): refer to particle size distribution Kollitab DC 87 L has a narrow particle size distribution with low fines for better uniformity and reduced process variability. Fine powders are often characterized by insufficient flowability, increased wall adhesion, and dust formation. Very coarse powders can lead to poor content uniformity, slow dissolution profiles, or reduced mechanical strength of tablets. Bulk density (DBU), Tapped density (DTA), Carr index (CAR), Hausner ratio (HAI Angle of repose (AOR): refer to flowability Kollitab DC 87 L has excellent flowability due to its spherical shape, reducing tablet weight variability. The bul density determines the amount of powder that can fit into a blender, hopper, o die of a tablet press. Large differences between bulk and tapped density are associated with strong interparticulate interactions and poor powder flow. Compaction pressure at 0.85 solid fraction (CPR), Tensile strength at 0.85 soli fraction (CMP), Tensile strength at 100 MPa pressure (TST1), Tensile strength < 150 MPa pressure (TST2), Tensile strength at 250 MPa pressure (TST9): refe to powder compressibility Kollitab DC 87 L creates high strength tablets at broad compression forces. Expedite your formulation using ZoomLab!
5. Handling and Safety 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. The current version of the product specification is available on BASF WorldAccount and MyProductWorld or from your local BASF sales representative. Refer to the individual document quality and regulatory product information (QRP)), available on BASF WorldAccount, RegXcellence and from your local BASF sales representative. The QRPI document covers all relevant information includ- ing retest periods and storage conditions. Refer to the individual document quality and regulatory product information (QRP)), available on BASF WorldAccount, RegXcellence and from your local BASF sales representative. The QRPI document covers all relevant information includ- ing retest periods and storage conditions. 8. PRD and Article Numbers PRD-No. Product name Article numbers Packaging Image 30765743 Kollitab DC 87 L 50711206 1kg non-GMP sample 50708787 20 kg Commercial article 2.5 L Plastic Bottle 60 L Cardboard Box with PE liner  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 i a supply contract or other written agreement between you and BASF: (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: ia eh ari assis ac) A Sad aaah as OS TER AATANE Spi MMS ARSE a a a a aa te (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 a appropriate
echnical Information = Registered trademark of BASF in many countries.
1. Introduction Kollicoat Smartseal 100 P is a powdery grade of a film forming polymer 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 100 P can be used in aqueous and solvent based film coating processes. It is obtained from the polymer dispersion Kollicoat Smartseal 30 D. Kollicoat Smartseal 30 D has a separate Technical Information Sheet which can be found on BASF WorldAccount. 2. Technical properties Description 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. 2.0% macrogol cetostearyl ether and 2.5% sodium lauryl sulfate. It is white and has a pleasant characteristic odor. Trivial name Methyl methacrylate and diethylaminoethy! methacrylate copolymer 7:3. CAS number 27027-16-3 Molecular weight The weight average molecular weight (M,,) of the polymer is approx. 200 000 Dalton (method: size exclusion chromatography (SEC) coupled with light scattering). Glas Transition Temperature (T,) Ee ee Ne (method: differential scanning calorimetry (DSC)) The polymer of Kollicoat Smartseal 100 P is brittle. Therefore, a plasticizer is needed. Minimum film forming temperature (MFFT Approx. 57 C SLC ene ee (method: heating block system) The MFFT only applies to aqueous coating. The polymer of Kollicoat Smartseal 100 P is very lipophilic. This means that water cannot act as a plasticizer during aqueous film coating and a plasticizer is needed for lowering the MFFT.
Solubility Water: Kollicoat Smartseal 100 P is insoluble in water at neutral and basic pH values. Below pH 5.5 it becomes water soluble. Kollicoat Smartseal 100 P is insoluble in water at neutral and basic pH values. Below pH 5.5 it becomes water soluble. Organic solvents: Kollicoat Smartseal 100 P is soluble in acetone. Acetone solutions can be diluted with isopropanol in a ratio up to 1:2. The polymer is insoluble in pure isopropanol. Organic solvents: Kollicoat Smartseal 100 P is soluble in acetone. Acetone solutions can be diluted with isopropanol in a ratio up to 1:2. The polymer is insoluble in pure isopropanol. MEE Ie ae SAE a ar a Kollicoat Smartseal 100 P is soluble in acetone. Acetone solutions can be diluted with isopropanol in a ratio up to 1:2. The polymer is insoluble in pure isopropanol. Kollicoat Smartseal 100 P can be redispersed into water by employing organic acids. For more details please see page 7. 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 100 P 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 in the copolymer structure. 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 jum isolated polymer films at different pH values (films obtained from Kollicoat Smartseal 30 D).
Moisture Protection Film coatings with low water vapor permeability can delay the moisture uptake of sensitive dosage forms. As Kollicoat Smartseal 100 P 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 pum isolated polymer films (obtained from Kollicoat Smartseal 30 D). The moisture barrier properties of isolated films obtained from Kollicoat Smartseal 100 P 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 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 tum isolated polymer films (obtained from Kollicoat Smartseal 30 D).
4. Application and Processing Selection of a plasticizer Selection of a plasticizer Kollicoat Smartseal 100 P is a brittle polymer. Therefore, dried polymer films need a plasticizer for preventing crackings and for retaining film functionality. When applying Kollicoat Smartseal 100 P in aqueous coating a plasticizer is also needed to reduce the high minimum film forming temperature (MFFT) of the polymer from ~ 57 C to temperature regions where film coatings experiments are typically carried out. This is necessary as the polymer is very lipophilic and dispersion water has no plasticizing effect. (the minimum film forming temperature is not applicable to organic coating where the polymer is fully dissolved). Recommended plasticizer concentration (w/w based on the polymer): Recommended plasticizer concentration (w/w based on the polymer): e 13-15% for aqueous coating 10-12% for organic coating The following plasticizers are suitable for Kollicoat Smartseal 100 P: Acetyltributyl citrate (ATBC) Triethyl citrate (TEC) e Dibutyl sebacate (DBS) e 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 pr to use. Reason is that both plasticizers have shown to hydrolyse into acids and thus impa functionality when dispersions are stored overnight. When using ATBC or DBS in aqueous coating, the use of 2% docusate sodium is recommender to facilitate plasticizer incorporation. The following plasticizers are suitable for Kollicoat Smartseal 100 P: With the impact on the glass transition temperature, plasticizers also impact the mechanical properties of the films. Figure 4 shows that the recommended plasticizer concentration of 13 - 15% (w/w based on the polymer) increases the elongation at break to approximately 100%. Figure 4: Impact of plasticizers on the mechanical properties of isolated polymer films o1 Kollicoat Smartseal.
Addition of an antioxidant Kollicoat Smartseal 100 P based films always require an antioxidant to stabilize the amino ester moiety of the polymer. Without plasticizer, yellowing and a delayec dissolution may occur. The recommendation is to use 1.0 2.5% of the lipophilic antioxidant butylated hydroxytoluene (BHT) based on polymer weight. In aqueous coating, hydrophilic antioxidants like sodium carbonate can be usec alternatively. Curing Curing is recommended for coatings obtained by means of aqueous coating with redispersed Kollicoat Smartseal 100 P. This assures 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. The effect of curing is stronger for tablets. Granules may not require curing. Coatings obtained from organic coating with Kollicoat Smartseal 100 P do not require curing. Curing for longer time allows to reduce temperatures. The effect of curing is stronger for tablets. Granules may not require curing. Coatings obtained from organic coating with Kollicoat Smartseal 100 P do n require curing. Anti-tacking agents An anti-tacking agent is always needed when working with Kollicoat Smartseal 100 P to prevent sticking. Sticking was found to be more pronounced for Kollicoat Smartseal 100 P in aqueous coating than in organic coating. It is recommended to use talcum as anti-tacking agent 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 The preparation process is different for aqueous and organic coating. Whereas Kollicoat Smartseal 100 P can directly be dissolved in acetone for organic coating, partial neutralization with weak acids is required to redisperse it into water for aqueous coating. Organic coating Organic coating Step 1: Dissolve Kollicoat Smartseal 100 P in acetone while stirring. 2p 2: Add isopropanol! to the fully dissolved acetone solution until the targeted mixture is reached. The maximum is a 1:2 mixture of acetone/isopropanol. Recommended is 1:1. 2p 3: Add plasticizer and BHT to the organic solution and stir until both are fully dissolved. Step 4: Add pigments to the organic solution of step 2. Figure 5: Preparation of the coating suspension for organic coating. Aqueous coating For aqueous coating, Kollicoat Smartseal 100 P needs to be redispersed into water. Redispersion requires partial neutralization of the amino-functional groups in the polymer by employing weak acids. For the redispersion succinic acid is recommend. Alternatively, adipic acid or malonic acid can be used. AavUIU Udll US UotU. Succinic acid (Mw = 118.09 g/mol) Adipic acid (Mw = 146.14 g/mol) e Malonic acid (Mw = 104.66 g/mol) Succinic acid (Mw = 118.09 g/mol) Adipic acid (Mw = 146.14 g/mol) Malonic acid (Mw = 104.66 g/mol) The acid shall be added in about 8 mo!% relative to the amount of amino-functional groups. The calculation can be done the following way: 100 g Kollicoat Smartseal 100 P contain about 40 g of the amino-functional monomer DEAEMA (Mw = 185.27 g/mol), which equals 0.22 mol. 8% of this are 0.0173 mol. This means: nar 1NN 7A Kallinnat Qmartecaal 1NN D N N17 mal af tha arid naad tn hoe andand The acid shall be added in about 8 mol% relative to the amount of amino-functional groups. The calculation can be done the following way: 100 g Kollicoat Smartseal 100 P contain about 40 g of the amino-functional monome DEAEMA (Mw = 185.27 g/mol), which equals 0.22 mol. 8% of this are 0.0173 mol. Thi means: per 100 g Kollicoat Smartseal 100 P, 0.017 mol of the acid need to be added. This reveals for the recommended acids: e Succinic acid: 2.04 g succinic acid per 100 g Kollicoat Smartseal 100 P Adipic acid: 2.53 g per 100 g polymer Malonic acid: 1.81 g per 100 g polymer his reveals for the recommended acids: Succinic acid: 2.04 g succinic acid per 100 g Kollicoat Smartseal 100 P Adipic acid: 2.53 g per 100 g polymer - Malonic acid: 1.81 g per 100 g polymer
Figure 6: Preparation of the coating suspension for aqueous coating. Cleaning recommendations As the polymer is readily soluble below pH 5.5, weak acids are suitable for cleaning off residues of Kollicoat Smartseal 100 P 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 100 P 10.2 Acetyltributyl citrate (ATBC) 1.5 (15% rel. to polymer) Butylated hydroxytoluene (BHT) 0.3 (2.5% rel. to polymer) Succinic acid 8.0 mol% (based on monomer DEAEMA) Talcum 8.0 (50.0% rel. to polymer) Water 80 Total 100 Solid content in the spray suspension 20
Figure 7: Release from caffeine tablets in dependency of weight gain and curing.
Caffeine granules (aqueous coating) Substrate caffeine granules 0.2/0.5 ym. Composition of spray suspension Ingredients Content [%] Kollicoat Smartseal 100 P 11.9 Acetyltributyl citrate (ATBC) 1.8 (15% rel to polymer) Butylated hydroxytoluene (BHT) 0.3 (2.5% rel. to polymer) Succinic acid 8.0 mol% (based on monomer DEAEMA) Talcum 6.0 (50% rel. to polymer) Water 80 Total 100 Solid content in the spray suspension 20 Total 100 Solid content in the spray suspension 20 Process parameters Parameter Value Machine Glatt GPCG 3.1 Spray set-up Bottom spray, 25 cm Wurster 7 column Batch size 1.33 kg Inlet air temperature 55 C Product temperature 31-35 C Nozzle diameter 1.0 mm Spray rate ~ 20 g/min Spray pressure 1.5 bar Inlet air 88 - 100 m/h Final drying ~ 45 C product temperature Curing 2h @ 60 C Weight gain 15, 20, 25, 30% Process parameters
Figure 9: Release at pH 6.8 from caffeine granules with different weight gains (all tablets cured).
Caffeine granules (organic coating) Substrate caffeine granules 0.2/0.5 ym Composition of spray suspension Ingredients Content [%] Kollicoat Smartseal 100 P 8.9 Acetyltributyl citrate (ATBC) 0.9 (10% rel. to polymer) Butylated hydroxytoluene (BHT) 0.2 (2.5% rel. to polymer) Acetone 45 lsopropanol 45 Total 100 Solid content in the spray suspension 10 Minr thn nnatnn nepnpnnac tan nraniiinc wuyarrn KRIARA-CA walt 404, miner taliniim After the coating process the granules were blended with 1% micro talcurr (Micro Talk 50) to avoid sticking. Process parameters Parameter Value Machine Glatt GPCG 3.1 Spray set-up Bottom spray, 25 cm Wurster 7 column Batch size 1.3 kg Inlet air temperature 25 C Product temperature 31-36 C Nozzle diameter 1.0mm Spray rate 17 - 20 g/min Spray pressure 1.5 bar Inlet air 90 - 110 m/h Final drying ~ 45 C product temperature Weight gain 15, 20, 25, 30% 100 a Figure 10: Release from caffeine granules with different weight gains at pH 1.1 and pH 6.8.
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. 8. 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. PEELE TP CEE GRAIN SEE) EAE NE AEA ETN RET ERE LS FNAME: PREGA RG tr REL NNR NSS Wee Rw Nes 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. 10. PRD and Article numbers 10. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30585559 Kollicoat Smartseal 100 P 50341064 15 kg cardboard box with PE liner 15 kg cardboard box with PE liner BASFs commercial product number. 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 Poloxamer Ph. Eur., Poloxamer USP/NF Poloxamer for Pharmaceutical Use March 2020 WF-No. DAWF-2019-0855 = 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 407 Geismar succeeding the word Kolliphor indicates a poloxamer with ca. 70% m/m PEO (P 407; 7x10= 70%) and approximately average molecular weight of PPO o 4000 ((P 407; 40x100= 4000) 2. Technical properties Structural formula The Kolliphor P 407 Geismar is a block copolymer that is a synthetic copolymer of ethylene oxide and propylene oxide represented by the following chemical structure: CH, HO -E CH,- CH,- 0 Hf CH, - CH= OH} CH,-CH,-O+ H Where the a and b blocks have the following values: Kolliphor Poloxamer P 407 407 101 56 Appearance Kolliphor P 407 Geismar is produced as a white to almost white prill/powder. CAS Number Molecular Weight The average molecular weight for Kolliphor P 407 Geismar is 10000 to 14600 g/mol. The product contains nominally 95 to 105 ethylene oxide units and 54 to 60 propylene oxide units, with a rough concentration of oxyethylene of 71.5 to 74.9 % based on the current monograph specification. An example of the molecular weight distribution for Kolliphor P 407 Geismar is shown below in Figure 1. Fig. 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 407 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 at 10, 15 and 20 % w/w: Fig. 2: Complex dynamic viscosity of aqueous Kolliphor P 407 Geismar-gels as a function o temperature. The dynamic viscosity of Kolliphor P 407 Geismar gels may be affected by the addition of electrolytes, moisturizers, alcohols and surfactants. Figure 3 demonstrate the influence of sodium chloride and potassium chloride in a 20% Kolliphor P 407 Geismar-gel. The addition of electrolytes at concentrations of around 1% increases the viscosity with little or no impact on the sol-gel transition temperature. Higher concentrations demonstrate a reduced gelling temperature with increased dynamic viscosity readings. Low pH values affect the sol-gel transition temperature and the viscosity. Fig. 3: Pour point of 25% aqueous Kolliphor P 407 Geismar gels at different NaC! or KCI - levels (temp. 25 C)
The HLB value of Kolliphor P 407 Geismar is approximately 22. Critical Micelle Concentration (CMC) The critical micelle concentration for Kolliphor P 407 Geismar is published as 2.8 - 10 mol/L @ 37 C (34.2 mg/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 407 Geismai as a function of concentration is shown below in Figure 4 (37 C). Fig. 4: Surface tension of Kolliphor 407 Geismar as a function of concentration. The micelle size is approximately 10-15 nm in diameter; this is shown in Figure 5 belov as determined via laser diffraction: Fig. 5: Micelle size of Kolliphor P407 Geismar determined via laser diffraction.
Solubility Kolliphor P 407 Geismar is highly soluble in water. Note that Kolliphor P 407 Geismar is significantly easier to dissolve in cold water. Particle Size Kolliphor P 407 Geismar exhibits spherical prill particles of a mean diameter o 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 ir Figure 6. Fig. 6: Scanning electron microscope image (SEM) of Kolliphor P 407 Geismar Cloud Point The cloud point for Kolliphor P 407 Geismar is >100 C for a 1% and a 10% aqueous solution. Density The true density of Kolliphor P 407 Geismar is approximately 1.06 g/cm The bulk density of Kolliphor P 407 Geismar is approximately 0.50 g/cm. The tapped density of Kolliphor P 407 Geismar is approximately 0.60 g/cm
Moisture Sorption The uptake of moisture for Kolliphor P 407 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: Fig. 7: Moisture sorption of Kolliphor P 407 Geismar. BHT Poloxamers, and specifically Kolliphor P 407 Geismar utilize 50-125 ppm BHT as an antioxidant the protects the quality and performance of the P 407 in the multitude 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. Example Use Levels Indication Concentration (w/w%) Gelling agent Suspension stabilizer Tableting Wetting Agent Emulsifier Foaming agent Plasticizer (matrix) 15 to 50 0.1 to5 1 to 10 0.01 to 5 1to5 1to3 5 to 15 Solubilization Kolliphor P 407 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.
5. 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 407 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 lsopropylmyristate Tack reducer 2 Glycerol Solvent 5 B Kolliphor P 407 Geismar Poloxamer 407 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 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. 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 Kollpiiat= Pao? Poloxamer 407 Gelling agent 18 Deionized Water Solvent 42 D_ Kollicream 3 C Cocoyl Caprylocaprate Emollient 10 Kolliphor P 407 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 407 Geismar and Kollicream 3 C have been shown tc be very mild, in vitro and in vivo.
6. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 7. Retest date and storage condition Please refer to Quality & Regulatory Product Information (QRPI). 8. Stability 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 30631538 Kolliphor P 407 Geismar 50424592 0.5 kg Plastic bottle 50424310 90 kg fibre 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.
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.

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 Polyethylene Glycol USP/NF, FCC, Macrocols Ph. Eur., Macrogol 300 JP Liquid polyethylene glycols for the pharmaceutical industry Liquid polyethylene glycols for the pharmaceutical industry October 2018 WF-No. 136619 = Registered trademark of BASF in many countries.
1. Technical properties Description Kollisolv? PEG 300 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 The number in the name of the product indicates its average molecular weight. CAS-number Hygroscopicity At room temperature and 80% r. h. approx. 55% of increase of weight was noted over a period of 42 days. Molecular weight The average molecular weight is 300 g/mol. Solubility Kollisolv@ PEG 300 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 300 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 The low-molecular weight liquid polyethylene glycols Kollisolv? PEG 300 is excellent solvent for a large number of substances that do not readily dissolve in water. Its widely used as solvent and solubilising agent for active substances and excipients in liquid and semi-solid preparations. It is the ability of PEGs to form complexes with active substances that is responsible for their excellent solvent power. However, equilibrium constants for complex formation vary considerably from one substance to another, and certain drugs such as Penicillin G and Bacitracin can even become inactivated. The effect of the polyethylene glycol on the efficacy and absorption of a drug must therefore always be determined in tests. With regard to incompatible substances, please see the remarks in the European Pharmacopoeia, Vol. II/3, Monographs M1, Macrogol 300, p. 3. Polyethylene glycols can also be used to adjust the viscosity of liquid pharmaceutical preparations and ointments, to modify their absorption properties and to stabilise the preparation. In the manufacture of soft gelatin capsules, liquid macrogol can be used as carrier for dissolved or suspended drugs. Mixtures of solid and liquid polyethylene glycols can be used as water-soluble bases for ointments, suppositories and ovula. For burns from chlorophenols or chlorocresols, a mixture of two parts Kollisolv? PEG 300 and one part ethanol is recommended. 4. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 5. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRP)). 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 9. PRD and Article numbers PRD-No. Product name Article Numbers Packaging 30554046 _ Kollisolv? PEG 300 50251695 130 kg Plastic drums 50259796 0.5 kg Plastic bottle 50548771 130 kg Plastic drums BASFs commercial product number. 10. Publications 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.
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
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.
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 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 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 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.
Chemical names of active ingredient  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. Articles Specification Assay Country of origin as ethyl ester Ph. Eur. 2063/2.4.29 EPA (Eicosapentaenoic acid) min. 460 mg/ DHA (Docosahexaenoic acid) min. 180 mg/ EPA & DHA min. 640 mg/ Total Omega-3 content min. 700 mg/g Description os Eee PronovaPure 460:180 EE is a light yellow fish oil ethyl ester concentrate. ST PORT IIT Tas The fish oil is obtained from anchovies, sardines and mackerels (families Engraulidae, Clupeidae, Carangidae and Scombridae). 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. 640 mg/g. For further information see separate document: Standard Specification (not for regulatory purposes). For further information see separate document: Standard Specification (not for regulatory purposes). Standards ee Produced under FSSC 22000, cGMP and HACCP principles. Product is halal certified. Produced under FSSC 22000, cGMP and HACCP principles. Product is halal certified. Composition 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). Bee mainly derived from soybean (from identity preserved, not genetically modified origin).
Applications Monographs and Regulations PronovaPure 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. Eich ail athy! acter cancentratec are accented for  PronovaPure 460:180 EE is intended for use in dietary supplements such as in soft gel capsules. Note PronovaPure 460:180 EE must be handled in accordance with the Material Safety Data Sheet. PronovaPure 460:180 EE must be handled in accordance with the Material Safety Data Sheet. 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. Stability, Storage and Handling The product is sensitive to oxygen, light and heat. It should therefore be stored in the tightly sealed, lightoroof packaging in a cool place. Once opened, it is recommended to flush the remaining contents with inert gas and use as quickly as possible. 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: between you and BAS! 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, INCLUDINC ANY IMPLIED WARRANTIES, REPRESENTATIONS OR CONDITIONS OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE SATISFACTORY QUALITY, NON-INFRINGEMENT, AND ANY REPRESENTATIONS, WARRANTIES, CONDITIONS OR GUARANTEES, ARISINC FROM STATUTE, COURSE OF DEALING OR USAGE OF TRADE and BASF HEREBY EXPRESSLY EXCLUDES AND DISCLAIMS ANY LIABILIT 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 th extent caused by BASFs sole negligence, (i) BASFs wilful misconduct, fraud or fraudulent misrepresentation or (ii) any matter in respect of whic! it would be unlawful for BASF to exclude or restrict lability 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; ) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicabl law; and @i This dos GaBar Fe Biw IRIAT SINGH BrEAAGSE HARSIN FUSE ABE He (isd Ter BiRSGRS Gt Bran RaeeuTiOSl raaeietians: 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 () death or personal injury to the extent caused by BASFs sole negligence, (i) BASFs wilful misconduct, fraud or fraudulent misrepresentation or (ii) any matter in respect of which it would be unlawful for BASF to exclude or restrict lability 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; ) BASF rejects any obligation to, and will not, automatically update this document and any information provided herein, unless required by applicable
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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 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 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.
Polyvinyl acetate and povidone based matrix sustained release excipien
Contents 1. Introduction 1.1 General 1.2 Chemical structure 1.3 Trivial name 1.1 General 2. Composition 3. Specifications and methods 3.1 Specification 3.1 Specification 3.2 IR-Spectra 3.3 Content of polyvinyl acetate 3.4 Content of povidone 3.5 Vinyl acetate 4. Properties 5. Registration 5.1 Regulatory status 5.2 Drug Master File 5.3 Use of polyvinyl acetate in drugs 5.1 Regulatory status 6. Applications 6.1 General Information 6.2 Propranolol substained release matrix tablets 6.3 Diclofenac substained release matrix tablets RA Thennhviline caihetained releace matriy tahlete 7. Storage 8. Stability 9. PRD-No. 10. Packaging
1. Introduction 1.1 General Kollidon SR is a polyvinyl acetate and povidone based matrix retarding agent. It is particularly suitable for the manufacture of pH-independent sustained-release matrix tablets by direct compression. Polyvinyl acetate is a very plastic material that forms a coherent matrix even under low compression forces. When the tablets are introduced into gastric or intestinal fluid, the water soluble povidone is leached out to form pores allowing the active ingredient to diffuse. Kollidon SR does not contain ionic groups and therefore does not show interactions with drug sub- stances. The sustained-release properties are unaffected by ions or salts. 1.2 Chemical structure 2. Compositions Kollidon SR consists of 80% polyvinyl acetate and 19% povidone Ph. Eur./USI (Kollidon 30) in a physical mixture. Approx. 0.8% of sodium laury sulfate and about 0.2% of silica are used as stabilizers. 3. Specifications and methods See separate document Standard Specification (not for regulatory purposes), available via the BASF WorldAccount platform. 3.1 Specification The IR-spectra is measured in potassium bromide and a typical spectra is give! in the following figure 1. Fig. 1: IR-spectra of Kollidon SR
3.3 Content of polyvinyl acetate Determine the saponification value using 0.5-1.0 g of Kollidon SR, add 49 ml of 0.5 mol/I ethanolic KOH and saponify for 4 h under reflux. Calculate the content of polyvinyl acetate as follows: Polyvinyl acetate in Kollidon SR (%) = Saponification value x 0.1534 3.4 Content of povidone Determine the nitrogen content in ~0.1 g of Kollidon SR according to the Ph. Eur. monograph Povidone and calculate the content of povidone as follows: The monomer vinyl acetate is determined by a HPLC method which is available on request. 4. Properties White or slightly yellowish, free-flowing powder. Description Insoluble in water (The povidone part is soluble but the polyvinyl acetate part is insoluble). It is verv soluble in N-methviovrrolidone. The average molecular weights Mw of the polyvinyl acetate part is about 450,000 That one of the povidone K 30 part it is about 50,000. The average molecular weight of Kollidon SR as mixture is expressed as K-value according to the method described in the monographs Povidone and measured in a 1% solution in Tetrahydrofuran. The typical K-value is 60 - 68. The average particle size is about 100 ~m. The glass transition temperature Tg of the anhydrous material is about 35 C. About 0.45 g/ml. Kollidon SR has outstanding flow properties with a angle of repose well below 30 . It can enhance the flowability of other components added for a tablet formulation.
The water uptake is much less than that of povidone or copovidone. Figure 2 shows the water sorption and desorption isotherms at room temperature. Fig. 2: Sorption isotherms of Kollidon SR Kollidon SR has excellent compressibility and endows tablets with enormous hardness and low friability. This is due to the combination of the very plastic polyvinyl acetate and the also strongly binding povidone. Fig. 3: Hardness-compression force profile of propranolol sustained release tablets containing 50% of Kollidon SR (2 Lots, Formulation see chapter 6.2) 5. Registration The product is a formulation of two excipients. Thus monographs for Kollidon SR do not exist. 5.1 Regulatory status For registration purposes a US-DMF was prepared. 5.2 Drug Master File Polyvinyl acetate is used in a variety of drugs for oral administration in numerous countries including Germany, France, Japan and USA. Polyvinyl acetate also is allowed in the food industry in several countries like Germany, USA and Japan. 5.3 Use of polyvinyl acetate in drugs and food
6. Applications 6.1 General Information Kollidon SR can be used for the production of the following sustained release matrix dosage forms: Tablets, pellets and granules. Different technologies to obtain such dosage forms can be applied: Direct compression, roller compaction, wet granulation and extrusion. The excellent flowability and compressibility of Kollidon SR makes this excipient particulary suitable for the manufacture of sustained release tablets obtained by direct camnreccion ISTE direct compression. The required content of Kollidon SR in the tablet depends on the solubility of the active ingredient. The following table gives an information about the usual amounts of Kollidon SR to obtain a sustained release during 12 24 hours. Solubility of the active ingredient Kollidon SR in the tablet 15 25% 25 40% 40 - 55% Very slightly soluble to practically insoluble The sustained release characteristics can be modified by varying the Kollidon SR content in the formulation. Figure 4 shows the influence of the amount of Kollidon SR on the release of caffeine as a example of a soluble active ingredient. Fig. 4: Influence of the amount of Kollidon SR on the drug release in a caffeine sustained release tablet (160 mg Caffeine) In the case of slightly soluble or practically insoluble drug substances the release can be accelerated not only by reducing the content of Kollidon SR but also by the addition of hydrophilic substances like lactose, Kollidon 30 or Kollidon CL-M which act as pore former. Interesting and important properties of sustained release matrix tablets based on Kollidon SR are the following: 1. The drug release is independent of the pH (see figure 5). 2. The drug release is independent of the ionic strength of the dissolution medium (see figure 5, addition of 2.5% of NaCl). 3. The drug release is independent of the usual compression force and tablet hardness (see figure 6).
Fig. 5: Influence of the pH and the ionic strength of the dissolution medium or the release of caffeine tablets (Caffeine + Kollidon SR 1+1) It is recommended to store the matrix tablets containing Kollidon SR at temperatures below 30 C and in tightly closed containers to avoid the uptake of humidity which could modify the release profile of formulations containing a higher percentage of Kollidon SR. In the following chapters three typical examples of soluble and practically insoluble active ingredients are given in form of sustained release tablets. Further formulations can be found in the current edition of BASF CD-ROM Generig Drug Formulations. 6.2 Propranolol Sustained Release Matrix Tablets Parts by weight [g] Composition [%] Propranolol-HCl 160.0 49.23 Kollidon SR 160.0 49.23 Silicon dioxide, colloidal 3.4 1.05 Magnesium stearate 1.6 0.49 Total 325.0 100.00 Formulation All ingredients were passed through a 0.8 mm sieve, blended for 10 min in a Turbula mixer and then pressed on a rotary press. 10 mm 330 mg 10 KN/18 KN/25 kh 170 N/235 N/250 I 0.1% See Figure 6 Jiameter Weight Compression force ardness -riability Drug release Diameter Weight Compression force Hardness Friability Drug release
Fig. 6: Propranolol sustained release tablets: Influence of the compressior force on the drug release 6.3 Diclofenac Sustained Release Matrix Tablets Diclofenac sodium Kollidon SR Aerosil 200 Magnesium stearate Formulation All ingredients are mixed, passed through a 0.8 mm sieve and pressed with a medium compression force on a rotary press. Fig. 7: Dissolution of Diclofenac sustained release tablets
6.4 Theophylline Sustained Release Matrix Tablets Parts by weight [g] Composition [%] Theophylline gran. 500.0 63.9 Kollidon SR 200.0 21.6 Ludipress LCE 225.0 24.2 Magnesium stearate 3.0 0.3 Total 928.0 100.00 Formulation All ingredients were passed through a 0.8 mm sieve, blended for 10 min in a Turbula mixer and then pressed on a rotary press. Tablet properties Fig. 8: Dissolution of theophylline sustained release tablets Store at 15 25 C, occasionally up to 30 C. 8. Stability At least 24 months in the unopened original container below 25 C. A stability report is available on request.
10. Packaging 20 kg plastic container 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 Macrogolglycerol Ricinoleate (Ph. Eur.), Polyoxyl 35 Castor Oil (USP-NF) Macrogolglycerol Ricinoleate (Ph. Eur.), August 2019 Supersedes issue dated December 2018 Last change WF-No. DAWF-2019-0819 = Registered trademark of BASF in many countries.
1. Technical properties Description Kolliphor EL is a nonionic solubiliser and emulsifier made by reacting castor oil with ethylene oxide in a molar ratio of 1 : 35. The main component of Kolliphor EL is glycerol polyethylene glycol ricinoleate. Together with fatty acid esters of polyethylene glycol, this forms the hydrophobic part of the product. The smaller hydrophylic part consists of free polyethylene glycols and ethoxylated glycerol. A diagram of the molecular formula is listed below: Kolliphor EL is a pale yellow oily liquid that is clear at temperatures above 26 C. It has a faint but characteristic odor. The hydrophilic-lipophilic balance (HLB) lies between 12 and 14. CAS-number 61791-12-6 Solubility Kolliphor EL 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 EL becomes less soluble in water at higher temperatures. Thus, aqueous solutions become turbid at a certain temperature. Kolliphor EL 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 @ 37C Dispensing It is recommended that Kolliphor EL be heated to between 50 and 60 C and lightly agitated prior to use. Kolliphor EL 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. 2. Handling Please refer to the individual Material Safety Data Sheet (MSDS) for instructions on safe and proper handling and disposal.
3. Example application Kolliphor EL is recommended as a solubilizer and emulsifier in many different branches of industry. It is particularly suitable for the production of liquid preparations. Kolliphor EL is the industry standard pharmaceutical surfactant used primarily as a solubilizer and emulsifier. Most notably the product is used in the following types of formulations (common concentration show): Kolliphor EL is the industry standard pharmaceutical surfactant used primarily as ; solubilizer and emulsifier. Most notably the product is used in the following types of formulations (commot concentration show): CMe eee ee eee Softgel Capsules 600 mg per dose Ophthalmics up to 5 % w/w Oral Solutions and Suspensions 0.5 45% Topicals 4% w/w In softgel applications, Kolliphor EL is soluble in PEG 400 (Kollisolv? PEG 400) up to 50% w/w. Kolliphor EL is fully miscible in aqueous formulations. For Parenteral Applications, please see Kolliphor ELP. 10picalS 47% W/W In softgel applications, Kolliphor EL is soluble in PEG 400 (Kollisolv? PEG 400) t to 50% w/w. Kolliphor EL is fully miscible in aqueous formulations. For Parenteral Applications, please see Kolliphor ELP. Solubilization and Bioavailability Enhancement Kolliphor EL 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 EL digests slightly faster than Kolliphor RH 40 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) This example shows high concentrations of Kolliphor EL, this will result in moderate droplet sizes upon self-emulsification (120 nm) and slow digestion. Ethanol may be used in place of water to increase drug content. Compound Content Kolliphor EL 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 smaller oil droplets (85 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 %
Important note The fine dispersion of compounds that can be achieved with the aid of Kolliphor EL improves their absorption characteristics and efficacy. Kolliphor EL 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 EL preparations are used in practice, it is advisable to subject them to thorough pharmacological tests. Kolliphor EL 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 EL 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 EL or simila solubilizers have displayed anaphylactic reactions in isolated cases involving exceptione circumstances. Anaphylactic reactions have occasionally been observed in humans after injections containing Kolliphor EL. For this reason, the health authorities in the Federal Republic of Germany and the UK, for instance, have laid down that the conten of polyethoxylated castor oil in injections for parenteral administration to humans mus 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 fo human use must pay particular attention. No side effects of this kind have been observed after oral administration of preparations containing Kolliphor EL.
4. Safety data sheet Safety data sheets are available on request and are sent with every consignment. 5. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). For current specification, please speak to your local BASF sales or technical representative. The toxicological abstracts are available on request. 8. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30554032 Kolliphor EL 50539398 0.5 kg Plastic bottle 50259799 0.5 kg Plastic bottle 50251533 60 kg Steel drum BASFs commercial product number. http://pharmaceutical.basf.com/en.html his document, or any answers or Information proviaed nerein by BAor, 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 Supersedes issue dated November 2008 ) = Registered trademark of BASF in many countries. Ph. Eur., USP
1. Medical indication Dexpanthenol increases the healing of wounds, stimulates the epithelization, anc has anti-inflammatory properties, which is why it is applied locally. The substance is applied orally (with other vitamins) as food supplement, or as therapeutic supportive for the treatment of inflammation of the oral cavity and the throat (lozenges). Furthermore, Dexpanthenol is applied parenterally in combination with other vitamins for the prophylaxis or therapy of malnutrition and drastic lack of vitamins, disorders of the vitamin absorption from the gastrointestinal tract, and vitamin-consuming diseases. In addition, such injectable vitamin preparations with Dexpanthenol are used for completing parenteral nutrition. Pharmaceutical formulations which are available on the market include: Topical formulations (local application) Creams, gels, ointments, solutions and foam spray (skin) e Eye drops, gels, and ointments Nose sprays and gels e Ear drops Mouth sprays Oral dosage forms Tablets and lozenges Soft gelatin capsules Oral solutions e Syrups e Injectables Injection solutions for i.m. and i.v. application Infusion solutions Dexpanthenol is an active pharmaceutical ingredient for topical, oral, and injectable application. Application Dexpanthenol is the corresponding alcohol to Pantothenic acid (Pantoyl-B-alanine, Vitamin B,). Pharmacology Pantothenic acid is a compound of Coenzyme A, which is a cofactor for a number of biochemical and enzyme-catalyzed reactions for the transfer of acetyl groups: Composition and decomposition of fatty acids, oxidative metabolism of carbo- hydrates, biosynthesis of steroids etc. Coenzyme A is a food compound and is hydrolyzed in the intestines to Pantothenic acid. Dexpanthenol and D-Pantothenic acid are absorbed rapidly and completely from the small intestines. In the blood, Pantothenic acid is bound to plasma proteins. Inside the cells, Pantothenic acid is transformed to coenzyme A. The substance is eliminated via the kidneys. Pharmacokinetics
2. Chemical information Synonyms Panthenol, Pantotheny! alcohol Structural formula Molecular formula Molar mass Dexpanthenol Ph.Eur. is a colorless to slightly yellowish, viscous liquid or semi- crystalline substance. See separate documentation: Q&R PI (not for regulatory purposes) available at BASFs WorldAccount: https://worldaccount.basf.com (registered access). See separate document: Standard Specification (not for regulatory purposes) available via BASFs WorldAccount: https://worldaccount.basf.com (registered access). Meets current Ph. Eur. and USP monographs. CEP is available and can be issued to customers on request. EDMF and JDMF are available upon request and when necessary 5. Regulatory status Meets current Ph. Eur. and USP monographs. CEP is available and can be issued to customers on request. EDMF and JDMF are available upon request and when necessary Dexpanthenol Ph.Eur. should be stored in the original container or in airtight, well- filled containers, and protected from light and humidity.
7. Formulations Dexpanthenol is very hygroscopic and can thus be easily dissolved in water for the production of liquid or semi-solid formulations. The following example is given for a gel-cream: Dexpanthenol Gel-Cream (5%) 1. Formulation . Formulation Dexpanthenol Ph.Eur. (BASF) . Liquid paraffin........ Lutrol E 400 (BASF) Lutrol F 127 (BASF)... . Manufacturing Dissolve Dexpanthenol Ph.Eur. and Lutrol E 400 in water, add and stir while heating to 60 70 C. Add Lutrol F 127 slowly a is dissolved. Cool to room temperature while stirring continous bubbles disappear. . Properties of the gel Soft turbid gel-cream. . Physical stability (3 months, 40 C) RIn phannga nf tho annooaranna and vioenncity Dexpanthenol Ph.Eur. (BASF) wo... eee 5g Liquid paraffin Lutrol E 400 (BASF). Lutrol F 127 (BASF) . 2. Manufacturing No change of the appearance and viscosity. 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 Protective coating providing a moisture barrier and taste masking. March 2019 Supersedes issue dated February 2012 Last change WF-No. 136874 = Registered trademark of BASF in many countries
1. Introduction Kollicoat Protect is a coating based on Kollicoat IR (polyvinyl alcohol-polyethylene glycol graft copolymer) that is very readily soluble in water. It is used primarily as a protective coating in the manufacture of film coatings that dissolve in the gastric juices (instant-release coatings). The protection may consist in a barrier against water vapor, for taste masking formulations, or prevention of incompatibilities between ingredients. 2. Technical properties Description Kollicoat Protect is a white to off-white, free-flowing powder. The recipe is based mainly on the highly flexible film former Kollicoat IR, which has the following structure. Structural formula Composition Polyvinyl alcohol-polyethylene glycol graft copolymet Polyvinyl alcohol-polyethylene glycol graft copolymer 55 65% Polyvinyl alcohol 35 45% Silicon dioxide 0.1 -0.3% CAS-number 96734-39-3 + 9002-89-5 + 7631-86-9 Chemical nature Owing to the special spray-drying process for Kollicoat Protect, the polymers are embedded in one another to such an extent that they cannot separate. The powder has good flowability and dissolves rapidly in water. Physicochemical properties The aqueous solution has a relatively low viscosity and can be readily prepared. Film formation The aqueous solution is poured on to a glass plate. The water evaporates, leaving a. flexible film.
Properties of aqueous solutions Viscosity of aqueous Kollicoat Protect solutions as a function of polymer concentratior (at 23 C). Viscosity of a Kollicoat Protect solution as a function of temperature. Viscosity of various Kollicoat Protect spray suspensions (20% w/w, 25 C).
Surface tension The surface tension of a 15% Kollicoat Protect solution is very low (42.3 mN/m). Good wetting and spreadability are therefore achieved even on lipophilic surfaces. Film properties Kollicoat Protect forms transparent, highly flexible films that dissolve very rapidly in water. Kollicoat Protect films are not tacky and can be readily printed. Elongation at break of various moisture-barrier films (23 C, 58% r. h.) Adhesiveness Kollicoat Protect film coatings adhere extremely well to tablet surfaces of varying lipophilic character. Coating engravings The very low viscosity and excellent wetting and spreading properties ensure that even fine engravings are uniformly coated and no bridging occurs.
3. Example application Applications Kollicoat Protect can be used in all applications where a readily soluble, flexible coating is required. fo TeQuirea. e Instant-release coating e Protection against moisture Taste masking e As a subcoating Improves appearance, makes tablet easier to swallow, gives distinctive colorit protects active ingredients (prevents interaction) e Binder e As a binder Processing notes Because of the high flexibility of Kollicoat Protect films, it is not necessary to adda plasticizer. Foam may form when Kollicoat Protect is incorporated into water, to an extent that depends on the mixing conditions. Foam formation can be minimized by adding 0.1% Simethicon 30% emulsion or 0.75% Labrasol (supplied by Gattefosse). A spray solution is conveniently prepared as follows: A Spray solution ls conveniently prepared as follows: a.) Spray solution with water-soluble dye: Stir the Kollicoat Protect and water-soluble dye into water and dissolve. The mixer speed should be adjusted so that little or no foam is produced. After stirring for 30 min, the spray solution is ready for further processing. b.) Spray suspension containing pigments and/or lakes: Film-forming solution Stir Kollicoat Protect into the specified quantity of water and dissolve. Pigment suspension Stir the insoluble components, such as talc, titanium dioxide, kaolin, lakes or color pigments, into the appropriate quantity of water and homogenize with high-shear mixer, e.g. Ultra-Turrax. Spray suspension Stir the pigment suspension into the film-forming solution. Stir the pigment suspension into the film-forming solution. The coating can be applied on all the usual coaters, e.g. horizontal drum coaters, fluidized bed coaters, immersion sword coaters and coating pans, under the usual conditions for aqueous solutions. The following conditions have produced good results in numerous trials: Inlet air temperature 50 - 80 C Outlet air temperature 30 - 50 C Atomizing pressure 3-5 bar Temperature of spray Suspension 20-70C Temperature of spray suspension
Cleaning The product can very easily be cleaned off equipment with warm or cold water. Typical recipes Aspirin moisture-protected film-coated tablets Composition of spray solution The formulation is designed for 6 kg tablets (tablet weight 300 mg, diameter 9 mm) Spray suspension Kollicoat Protect Talc Titanium dioxide Water Weight [g] Proportion [%] 125.40 12 62.25) 5 3 ireco 3 836.00 80 1045.00 100 Machine parameters Coating machine Batch size Inlet air temperature Outlet air temperature Product temperature Inlet air flow Outlet air flow Atomizing pressure Forming air pressure Number of spray nozzles Spraying rate Spraying time Final drying Quantity applied Accela-Cota drum coater (24 inch) 6 kg 60 C 36 C 35 C 210 m%/h 410 m%/h 2 bar 1.4 bar 1 30 g/min 35 min 60 C/4 min 5 mg/cm? solids Tablet properties Appearance Hardness Friability Disintegration time Core Film-coated tablet white white 67N 7ON 0% 0% 3:17 [min:s] 3:58 [min:s]
Vitamin C moisture-protected film-coated tablets Composition of spray suspension The formulation is designed for 1 kg tablets (tablet weight 300 mg, diameter 8.5 mm) Polymer suspension Weight [g] Proportion [%] Kollicoat Protect 16.8 12.0 Water 82.6 59.0 Pigment suspension Talc a0) 5.0 Titanium dioxide 4.2 3.0 Sicovit Yellow 10 1.4 1.0 Water 28.0 20.0 140.0 100.0 Machine parameters Coating machine Hi-Coater (Freund Industrial Co.) Batch size 1kg Inlet air temperature 54-57 C Outlet air temperature 34 - 35 C Atomizing pressure 1.5 bar Number of spray nozzles 1 Spraying rate 5.2 5.4 g/min Spraying time 29 min Final drying 8 min (outlet air temp. 34 - 40 C) Quantity applied 3.15% Tablet properties Appearance Hardness Friability Disintegration time Core Film-coated tablet white yellow 150 N 181N 0% 0% 5:18 [mins] 5:45 [min:s] The formulation is designed for 1 kg tablets (tablet weight 300 mg, diameter 8.5 mm)
Comparison of polymer formulations Comparison of polymer formulations
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. Retest date and storage conditions Please refer to Quality & Regulatory Product Information (QRPI). 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 abstract is available on request. 9. PRD and Article numbers PRD-No. Product name Article numbers Packaging 30235579 Kollicoat Protect 50391593 25 kg Plastic drums Packaging 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.
L-Menthol Pharma and L-Menthol Pharma and L-Menthol flakes Pharm: L-Menthol flakes Pharma January 2013 Ph. Eur., USP, JP
1. Medical indication L-Menthol is an organic compound made synthetically or obtained from natural peppermint or other mint oils. The main form of menthol occurring in nature is L-Menthol, which is assigned the (1R,2S,5R) configuration. BASFs L-Menthol Pharma can be obtained as either a white solid mass or in form of white flakes, solid at room temperature. L-Menthol is widely used in clinical and pharmaceutical practice for oral and topical formulations. Topical applications of L-Menthol includes the treatment of local pain, pruritus and allergic dermatitis. Oral formulations include the treatment of digestive disorders, such as for example irritable bowel disease, and the use in the oral cavity due to its antiseptic and anesthetic properties. A further established application of L-Menthol is in form of inhalations for the symptomatic relief of sinusitis, rhinitis, bronchitis and similar conditions. L-Menthol is an organic compound made synthetically or obtained from natural peppermint or other mint oils. The main form of menthol occurring in nature is L-Menthol, which is assigned the (1R,2S,5R) configuration. BASFs L-Mentho! Pharma can be obtained as either a white solid mass or in form of white flakes. solid at room temperature. L-Menthol is widely used in clinical and pharmaceutical practice for oral and topical formulations. Topical applications of L-Menthol includes the treatment of local pain, pruritus and allergic dermatitis. Oral formulations include the treatment of digestive disorders, such as for example irritable bowel disease, and the use in the oral cavity due to its antiseptic and anesthetic properties. A further established application of L-Menthol is in form of inhalations for the symptomatic relief of sinusitis, rhinitis, bronchitis and similar conditions. L-Menthol is an organic compound made synthetically or obtained from natural peppermint or other mint oils. The main form of menthol occurring in nature is L-Menthol, which is assigned the (1R,2S,5R) configuration. BASFs L-Mentho! Pharma can be obtained as either a white solid mass or in form of white flakes. solid at room temperature. L-Menthol is widely used in clinical and pharmaceutical practice for oral and After oral application, L-Menthol is absorbed via the intestines and metabolized via the cytochrome P450 enzyme system, more specifically by CYP 2A6 microsomes, in the human liver. After alternating hydroxylation and oxidation reactions, it is excreted in the urine and bile as a glucuronide. Pharmacokinetics L-Menthol is an agonist to the cold-sensitive TRPM8 (Transient Receptor Potentie Melastatin Family Member 8) ion channel in sensory neurons. Natural stimulatior of TRPM8 by temperatures < 24 26 C or pharmacological stimulation by L-Menthol lead to an increase in the intracellular Ca concentration. As a result the membrane currents at the peripheral nerve endings of cold-specific non-nociceptive Ac fibers increase causing the cold perception. Inhalation of L-Menthol elicits a distinctive cooling sensation mediated through its specific interactions with TRPMB8 on trigeminal nerve endings in the nose and the upper airways providing a subjective nasal decongestant effect without any objective decongestant action. However, in addition to its sensory effects, L-Menthol has shown antimicrobial activity caused by perturbation of the lipid fraction of the plasma membrane of microorganisms. As the cooling sensation of L-Menthol is primarily linked to its activation of the TRPM8 receptor, the well-known topical analgesic and anesthetic effects appee to be mediated through blockage of voltage-gated neuronal and skeletal Na channels located in close proximity to TRPM8 receptors. In addition, L-Menthol has shown to be a selective agonist at k-opioid receptors that apart from analgesic properties may be responsible for its antipruritic action. L-Menthol has been shown to act as a potent penetration enhancer for dru: Pharmacology ae enon Ngee SENNA reg, Fi<ee can aii ow pegs errr wee shown antimicrobial activity caused by perturbation of the lipid fraction of the plasma membrane of microorganisms. As the cooling sensation of L-Menthol is primarily linked to its activation of the TRPM8 receptor, the well-known topical analgesic and anesthetic effects appear to be mediated through blockage of voltage-gated neuronal and skeletal Na channels located in close proximity to TRPM8 receptors. In addition, L-Menthol has shown to be a selective agonist at k-opioid receptors that apart from analgesic properties may be responsible for its antipruritic action. L-Menthol has been shown to act as a potent penetration enhancer for drug molecules through the epidermis of the skin due its ability to disrupt the lipid L-Menthol has been shown to act asa a potent penetration enhancer for drug molecules through the epidermis of the skin due its ability to disrupt the lipid bilayer of the stratum corneum. Literature references . Farco, J.A. and Grundmann, O. 2013, Mini-Reviews in Medicinal Chemistry Vol. 13, No. 1, Pages 124-131. . Galeotti, N. et al. 2002, Neuroscience Letters Vol. 322, Pages 145-148. . Patel, T. et al. 2007. Journal of the American Academy of Dermatology Vol. 57, No. 5, Pages 873-878. . Trombetta, D. et al 2005. Antimicrobial Agents and Chemotherapy Vol. 49, No. 6, Pages 2474-2478. Precautionary measures
2. Chemical information Levomenthol, 3-p-Menthanol, Hexahydrothymol, Menthomenthol 2-isopropyl-5-methylcyclohexanol or 5-methyl-2-(propan-2-yl)-cyclohexan-1 -ol or (1R,2S,5R)- 5-methyl-2-(1-methylethyl)-cyclohexanol Chemical name Structural formula Molecular weight 4. Retest period See separate documentation: Q&R PI (not for regulatory purposes) available at BASFs WorldAccount: https://worldaccount.basf.com (registered access). L-Menthol Pharma should be stored in the original container. Once open it shoul be closed after use. L-Menthol flakes Pharma should be stored in the original packaging protecte against higher temperatures than 25 C and against humidity. 6. Container size 180 kg steel drum with an internal lacquer. 20 kg card box with a double lining of polyethylene bags.
7. Physical and chemical properties L-Menthol Pharma: white, solid mass Appearance L-Menthol flakes Pharma: white flakes Confocal laser sc scanning microscopy picture of L-Menthol flakes Pharma (surface magnification, 20x) Macroscopic picture of L-Menthol flakes Pharma (flake size approx. 3mm to 15 mm) L-Menthol is practically insoluble in water. L-Menthol is soluble at concentrations of at least 1 g per milliliter solvent in acetone, acetonitrile, dimethylformamide (DMF), ethanol, heptane, isopropanol, methanol, propane-1,2-diol (propylene glycol), tetrahydrofuran (THF) and toluol. L-Menthol is soluble at concentrations of at least 0.3 g per ml solvent in polyethylene glycol 400 (PEG 400). L-Menthol is practically insoluble in water. L-Menthol is soluble at concentrations of at least 1 g per milliliter solvent in acetone, acetonitrile, dimethylformamide (DMF), ethanol, heptane, isopropanol, methanol, propane-1,2-diol (propylene glycol), tetrahydrofuran (THF) and toluol. L-Menthol is soluble at concentrations of at least 0.3 g per ml solvent in polyethylene glycol 400 (PEG 400). 8. Regulatory Status L-Menthol Pharma and L-Menthol flakes Pharma meet current Ph. Eur., USP, and JP monographs. See separate documentation: Q&R PI (not for regulatory purposes) available at BASFs WorldAccount: https://worldaccount.basf.com (registered access). 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 by BASF, does not 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 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.
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.