Supercritical fluid and near critical gas extraction of organic solvents from formed articles

Abstract: Disclosed is a method of removing residual organic solvents from formed compressed articles such as tablets comprised of subjecting the organic solvent laden compressed article to a supercritical fluid or near critical gas whereby residual solvent is transferred from the solvent laden solid article to the supercritical fluid or near critical gas and separating the residual solvent depleted compressed article from the solvent enriched supercritical fluid or near critical gas.

Description: The invention relates to a process for the extraction of residual solvent from a formed compressed coated pharmaceutical tablet. The process itself consists of exposing the tablet to an inert phase of a fluid under supercritical conditions. The solvent is transferred from the formed compressed tablet to the inert phase. Many processes for the removal of volatile solvents from bulk masses are known. Air drying is often unsatisfactory for various reasons. As solvent poor dry air passes over a solvent rich area, a fraction of the solvent evaporates when the equilibrium is established. As the solvent enriched air is removed (by normal air currents or otherwise), it is replaced with additional solvent poor air and more solvent is given up. The process continues until equilibrium is reached and all or most of the solvent has been removed. Under certain conditions (i.e. high solvent volatility, minimal solvent/substrate affinity, high diffusion rates, etc.) such a process may take place rapidly within minutes, while in other cases this solvent loss is inhibited due to low solvent volatility, strong solvent/substrate binding, or low diffusion rates. In many cases the evaporation rate is unacceptably low. Many alternative processes and improvements are known. For example, heat is applied to accelerate the evaporation rate, pressure reductions are applied as well as combinations thereof. Liquid solvent exchange (leaching) is also used. In this process the solid material containing the residual solvent is exposed to another liquid which has less solubility for the solid material from which the residual solvent is to be removed, but a greater solubility for the residual solvent. The residual solvent is then transferred from the solid material to the other liquid and the liquid enriched in solvent is then separated from the solid material. The removal of solvent can be extremely difficult from a formed compressed article such as uncoated or coated tablets. The removal from coated tablets requires the complete evaporation from the film coating and the covered compressed tablet core. The increasing demand for extremely low solvent content in pharmaceutical dosage forms such as coated tablets may mandate that none of the foregoing conventional solvent removal processes is satisfactory. The extraction of residual solvents by exposure of the pharmaceutical tablet to be made solvent free to an inert phase of a fluid under supercritical conditions is another known process that has been applied to solids such as bulk masses. Especially in the food industry this method has been applied to remove caffeine from green coffee or nicotine and liquid admixtures from tobacco. This method is applicable wherever esthetic qualities associated with the solvent free article, such as shape, color, surface characteristics or physical appearance are of little concern. According to EP-A-206 685 and DE-A-3 545 913, extraction methods are known from formed compressed articles defined in EP-A as "molded product" and in DE-A as "Rohlinge". Those solid articles are unrelated with pharmaceutical tablets. It has not been attempted before to expose solid articles such as formed compressed pharmaceutical tablets, which also contain residual solvent, to fluids under supercritical conditions. It is an object of the present invention to provide an improved process to remove residual solvent from a formed compressed coated pharmaceutical tablet without significantly altering or deteriorating the appearance and/or stability of that tablet as well as pharmacological properties thereof such as release rates. It is a further object of the invention to recover any residual solvent from the solid tablet. The present invention relates to a process for extracting residual solvent from a formed compressed coated pharmaceutical tablet which consists of exposing the tablet to an inert phase of a fluid under supercritical conditions, transferring a portion of the residual solvent from the tablet to the inert phase of the fluid and removing the inert phase enriched with solvent. The term residual solvent defines water or organic solvents that are present as contaminants in coated tablets due to the presence of those solvents in a precursory step such as preparation of wet granulates or coating from organic liquids. Due to their toxicity, the presence of residual organic solvents, such as methanol or methylene chloride, is especially undesirable. The formed compressed coated pharmaceutical tablets are obtainable according to standard pharmacological methods such as so-called wet granulation. Especially preferred are coated tablets known in the art under the term oral osmotic system. Most preferably, the formed compressed coated pharmaceutical tablet is a film coated tablet. The most preferred type of such tablet is a film coated tablet of the type known as Oral Osmotic System (®Oros: Alza Corp.). Such systems are known according to U.S. Patent Specifications 4 326 525, 4 439 195, 4 455 143 or 3 916 899. Some of those dosage forms are commercially available. Preferably, the film coating in the coated tablets is selected from cellulose ethers and esters such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, cellulose acetates including cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, gelatin, pharmaceutical glaze, polyethylene glycol, polyvinyl acetate phthalate, sucrose, carnauba wax, microcrystalline wax, acrylic and/or methacrylic ester and acrylic and/or methacrylic acid copolymers, other vinylic polymers and copolymers such as polyvinylpyrrolidone, with or without plasticizers typically selected from castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono- and di-acetylated monoglycerides, polyethylene glycol, propylene glycol, and triacetin, citrate esters, phthalate esters, mineral oil and vegetable oils, and further with or without coloring agents, and more preferably cellulose ethers, cellulose acetates, vinyl polymers, acrylic esters and copolymers, polyglycols, with or without coloring agents, and most preferably cellulose ethers, cellulose acetates, polyglycols, acrylic esters and copolymers with or without coloring agents. These coating agents are applied to the tablet cores from organic solutions according to methods known in pharmaceutical technology, e.g. spraying methods, e.g. in a fluid bed or in a spray pan. An inert phase of a fluid under supercritical conditions contains a pure component or mixture of components, above its critical temperature and critical pressure. For a pure component, there is one specific temperature above which the application of pressure will not yield a condensed (liquid or solid) phase. That temperature defines the critical temperature for that component. The pressure at the critical temperature which will first produce a condensed phase is referred to as the critical pressure. The critical temperature and critical pressure define the critical point. While the critical point is unique for each pure component, the critical point of a mixture is dependent on the composition of the mixture and varies with the molar fraction of each component. Fluids under supercritical conditions exhibit properties similar to both liquids and gases. For example, so-called supercritical fluids have densities and solvating power similar in magnitude to those observed in liquids while exhibiting diffusion rates associated with gases. Another property associated with supercritical fluids is that small changes in temperature and/or pressure result in considerable changes in properties such as density or solvating potential. These properties are varied by varying temperature and/or pressure. A suitable so-called supercritical fluid is inert to the coated pharmaceutical tablet from which the solvent is removed. The fluid is especially inert to the active agent present in the tablet and also inert to the additives and carrier materials as contained therein. It is mandatory that no significant chemical reactions occur with any of the ingredients of the tablet. Physical appearance such as shape, hardness, friability or color is preserved during the process. A suitable so-called supercritical fluid is any liquid or gas which can be subjected to an elevation of temperature and/or pressure above its critical point without decomposing and which such temperature and pressure will not adversely affect or decompose the solid article. Typical supercritical fluids with their critical temperatures and pressures include, but are not limited to: a) ammonia (132.5°C, 116,21 bar), sulfur hexafluoride (45.6°C, 38.94 bar), argon (-122.3°C, 49.58 bar), carbon dioxide (31°C, 75.31 bar), deuterium (-234.8°C, 16.94 bar) helium (-267.9°C, 2.33 bar), hydrogen (239.9°C, 13.22 bar), krypton (-63.8°C, 56.10 bar), neon (-228.7°C, 27.79 bar), nitrogen (-147°C, 34.60 bar), nitrous oxide (36.5°C, 59.91 bar), and xenon; and b) chlorodifluoromethane (96°C, 50.10 bar), fluoromethane (44.6°C, 59.91 bar), methane (-82.1°C, 47.51 bar), bromotrifluoromethane (67°C, 52.0 bar), chlorotrifluoromethane (28.85°C, 39.46 bar), dichlorodifluoromethane (111.5°C, 40.9 bar), tetrafluoromethane (-45.7°C, 43.77 bar), ethyne (35.5°C, 63.63 bar), ethene (9.9°C, 52.17 bar), fluoroethane (102.16°C, 51.24 bar), ethane (32.2°C, 49.79 bar), methylether (127°C, 54.34 bar), propadiene (120°C, 45.04 bar), propyne (127.8°C, 54.54 bar), propane (96.8°C, 43.39 bar), n-butene (146°C, 41.01 bar), i-butane (135°C, 37.19 bar), perfluoro-n-butane (113.2°C, 23.76 bar). Of these gases or liquids those having a critical temperature below 150°C are preferred, while those with a critical temperature below about 100°C are more preferred. Highly preferred are carbon dioxide, argon, helium, neon, nitrous oxide, nitrogen, and methane; more highly preferred are nitrous oxide and carbon dioxide; most highly preferred is carbon dioxide. An advantageous set of conditions for use of carbon dioxide in the present invention is at 20°C to 65°C, more preferably about 25°C to 65°C and 40 to 1000 bar, preferably about 40 to 350 bar. The length of time for which the coated tablet should be exposed to the extracting medium depends on the solvent to be extracted, the coatings of tablets which must be permeated and the extraction medium used. The extraction conditions can be maintained for a period from under 10 minutes to in excess of 24 hours to assure removal of the solvent. Preferably however, the extraction conditions are maintained from about 15 minutes to about 16 hours, more preferably from about 30 minutes to about 12 hours yet more preferably from about 4 hours to about 8 hours. Preferred solvents which are extractable from the formed compressed articles by the present invention include: water and organic compounds with a vapor pressure greater than 1 mm Hg at 20°C; more preferred are acetone, ethanol, amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, glycerin, isopropyl alcohol, methyl alcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanut oil, polyethylene glycol, polypropylene glycol, propylene glycol, sesame oil, and most preferred are methyl alcohol, methylene chloride, acetone, and water. The residual solvent remaining after treatment by the instant invention is significantly less than that which was present prior to such treatment, at least less than 50 %, preferably less than 30 %, till more preferably less than 20 % and most preferably from less than about 7 % of the residual solvent content prior to such treatment. The solvent content of the coated tablet is reduced to ranges from about 1.0 % to 0.0001 %, especially 0.01 % to 0.001 % of the weight of the article. This extremely low solvent content obtained by the method according to the present invention exceeds the requirements for pharmaceutical production as expressed by the standardized Good Manufacturing Practice (GMP). If desired, the so-called supercritical fluid enriched in the solvent can be separated from the coated tablet in a manner so as to recover the solvent therefrom. Typically, mere reduction of pressure below the critical point is all that is necessary, although any method known in the art for separating a compound from a supercritical fluid may be employed. The invention will be more clearly understood in the context of the following Examples which are exemplary only and not limiting the invention. Example 1 : 108.6 kg of metoprolol fumarate powder and 5.4 kg of hydroxypropyl methylcellulose are blended together. The mixture is then granulated with 17.9 kg of a 65/35 weight/weight (w/w) solution of SD 3A anhydrous ethanol and water in which 5.4 kg povidone has been dissolved. The wet granulation is then milled using a Fitzpatrick comminuting machine. The mixture is then regranulated with 8.7 kg of a 65/35 (w/w) solution of SD 3A anhydrous ethanol and water and remilled. The wet granules are dried for approximately 16 hours at 40°C. The dried granules are then milled and blended with 3.4 kg of magnesium stearate. The blended mixture is then compressed into 430 mg tablet cores. A 5 mg per tablet, hydroxypropyl methylcellulose coating is applied to the tablet cores by spraying a 63/37 w/w mixture of methylene chloride and methanol containing 2.5 % by weight hydroxypropyl methylcellulose. A 40 mg per tablet laminate containing 85 % cellulose acetate, 11 % hydroxypropyl methylcellulose, and the remainder being polyethylene glycol is then similarly applied using a 80/20 w/w solvent mixture of methylene chloride and methanol. The coating operations are performed in a Glatt Wurster Coater® (fluid bed). The coated tablets are then drilled to result in a bore of about 0.3 mm diameter connecting the inner tablet core with the outside atmosphere. As a result of the spray coating operation, the coated tablets contain about 0.4 % methylene chloride and 0.16 % methanol by weight. The tablets are then exposed to CO₂ at 111 bar at 60°C for 8 hours. The solvent content of the film coated tablets after extraction is about 0.005 % methylene chloride and 0.01 % methanol by weight. The experimental apparatus used is a Milton Roy Supercritical Extraction Screener which essentially consists: one - 160 ml per hour high pressure piston pump, one - 250 ml bottom feed extraction vessel with temperature controller and heating mantel, two - pressure'step down'vessel (not essential for this application), and a final dry ice trap. Various valves, pressure regulators and valves are also required to maintain the desired extraction pressure. The analysis of the solvent content is performed by gas chromatography. Example 2 : Using essentially the same method described in Example 1 to produce the tablet cores, 107.7 kg of metoprolol fumarate is granulated with 12.6 kg of povidone in a 65/35 weight/weight (w/w) solution of SD 3A anhydrous ethanol and water. After the milling and drying steps, 3.3 kg of magnesium stearate is blended with the granules and the mixture is then compressed into 190 mg tablet cores. Using essentially the same method described in Example 1 to coat the tablet cores (except only one coating is applied), a 21 mg per tablet laminate is applied containing, 84 % cellulose acetate, 8 % a 80/20 w/w solvent mixture of methylene chloride and methanol. The coated tablets are then drilled to result in a bore of about 0.3 mm diameter connecting the inner tablet core with the outside atmosphere. As a result of the spray coating operation, the coated tablets contain about 0.76 % methylene chloride and 0.44 % methanol by weight. The tablets are then exposed to CO₂ at 208 bar at 50°C for 4.5 hours in a Milton Roy Supercritical Extraction Screener. The solvent content of the film coated tablets after extraction is about 0.095 % methylene chloride and 0.11 % methanol by weight. Example 3 : Using film coated tablets prepared in the same manner as in Example 2, the methylene chloride and methanol content was reduced from approximately 0.23 % and 0.10 % by weight, respectively, to approximately 0.06 % methylene chloride and 0.05 % methanol by weight, by exposing the tablets to CO₂ at 49 bar at 21°C for 8 hours in a Milton Roy Supercritical Extraction Screener. Example 4 : 36.0 kg of dextromethorphan-hydiobromide, 6.3 kg of hydroxypropyl methylcellulose, 89.1 kg mannitol, and 1.35 kg stearic acid are blended together. The mixture is then granulated with ca. 16.0 kg of a 50/50 weight/weight (w/w) solution of SD 3A anhydrous ethanol and water in which 0.036 kg FD&C Red #3 has been dissolved. The wet granulation is then milled using a Fitzpatrick comminuting machine. The wet granules are dried for approximately 16 hours at 40°C. The dried granules are then milled and blended with 0.9 kg of magnesium stearate and 1.35 kg stearic acid. The blended mixture is then compressed into 75 mg tablet cores. A 7.2 mg per tablet coating consisting of 82 % cellulose acetate and 18 % polyethylene glycol is applied to the tablet cores by spraying a 63/37 w/w mixture of methylene chloride and methanol containing 3 % by weight dissolved solids. A 12.5 mg per tablet laminate containing 80 % dextromethorphan-hydrobromide and 20 % hydroxypropyl methylcellulose is then similarly applied using a 63/37 w/w solvent mixture of methylene chloride and methanol. A third laminate (2.2 mg per tablet) laminate containing 73 % hydroxypropyl methylcellulose and 27 % coloring agent is then similarly applied using a 63/37 w/w solvent mixture of methylene chloride and methanol. The coating operations are performed in a Glatt Wurster Coater® (fluid bed). A portion of the coated tablets are then drilled to result in a bore of about 0.3 mm diameter connecting the inner tablet core with the outside atmosphere. As a result of the spray coating operation, the coated tablets contain about 0.24 % methylene chloride and 0.08 % methanol by weight. Both the drilled and undrilled tablets are then exposed to CO₂ at 111 bar at 40°C for 8.0 hours in a Milton Roy Supercritical Extraction Screener. The solvent content of both the drilled and undrilled film coated tablets after is less than 0.005 % methylene chloride and 0.005 % methanol by weight. Example 5 : 102.9 kg of phenylpropanolamine-hydrochloride and 23.0 kg of hydroxypropyl methylcellulose are blended together. The mixture is then granulated with ca. 17.8 kg of a 67/33 weight/weight (w/w) solution of SD 3A anhydrous ethanol and water. The wet granulation is then milled using a Fitzpatrick comminuting machine. The wet granules are dried for approximately 16 hours at 40°C. The dried granules are then milled and blended with 1.3 kg stearic acid. The blended mixture is then compressed into 80 mg tablet cores. A 6.5 mg per tablet coating consisting of 90 % cellulose acetate and 10 % hydroxypropyl methylcellulose is applied to the tablet cores by spraying a 63/37 w/w mixture of methylene chloride and methanol containing 3 % by weight dissolved solids. A 12.5 mg per tablet laminate containing 80 % phenylpropanolamine-hydrochloride and 20 % hydroxypropyl methylcellulose is then similarly applied using a 63/37 w/w solvent mixture of methylene chloride and methanol. A third laminate (2.3 mg per tablet) laminate containing 70 % hydroxypropyl methylcellulose and 30 % coloring agent is then similarly applied using a 63/37 w/w solvent mixture of methylene chloride and methanol. The coating operations are performed in a Glatt Wurster Coater® (fluid bed). A portion of the coated tablets are then drilled to result in a bore of about 0.3 mm diameter connecting the inner tablet core with the outside atmosphere. As a result of the spray coating operation, the drilled coated tablets contain about 0.65 % methylene chloride and 0.61 % methanol by weight and the undrilled coated tablets contain about 0.74 % methylene chloride and 0.71 % methanol by weight. Both the drilled and undrilled tablets are then exposed to N₂O at 111 bar at 40°C for 8.0 hours in a Milton Roy Supercritical Extraction Screener. The methylene chloride content of both the drilled and undrilled film coated tablets after extraction is less than 0.01 % methylene chloride by weight. The methanol content of the drilled and undrilled film coated tablets after extraction is reduced to approximately 0.28 % and 0.30 % by weight, respectively. Example 6 : Using film coated tablets prepared in the same manner as in Example 5, the drilled coated tablets contain about 0.55 % methylene chloride and 0.52 % methanol by weight and the undrilled coated tablets contain about 0.62 % methylene chloride and 0.59 % methanol by weight. Both the drilled and undrilled tablets are then exposed to CO₂ at 111 bar at 50°C for 8.0 hours in a Milton Roy Supercritical Extraction Screener. The solvent content of both the drilled and undrilled film coated tablets after extraction is reduced to approximately 0.01 % methylene chloride and 0.18 % methanol by weight.

Claims: A process for extracting residual solvent from a formed compressed coated pharmaceutical tablet which consists of exposing the tablet to an inert phase of a fluid under supercritical conditions, transferring a portion of the residual solvent from the tablet to the inert phase of the fluid and removing the inert phase enriched with solvent. A process according to claim 1, characterised in that a film coated tablet is applied. A process according to claim 2, characterised in that the film coated tablet is an oral osmotic system. A process according to claim 3, characterised in that the film coating is selected from cellulose esters. A process according to claim 3 or 4, characterised in that the oral osmotic system contains containing metoprolol fumarate, dextromethorphan hydrobromide, or phenylpropanolamine hydrochloride. A process according to any one of claims 1 to 5, characterised in that an organic solvent is extracted as residual solvent. A process according to claim 6, characterised in that methylene chloride and/or methanol is extracted as residual solvent. A process according to any one of claims 1 to 7, characterised in that carbon dioxide or nitrous oxide is used as fluid.

Inventors: CLEVENGER JAMES M, HEIT LAWRENCE B, CLEVENGER, JAMES M., HEIT, LAWRENCE B.
Applicants: CIBA GEIGY AG, CIBA-GEIGY AG
Application year: 1990
Main classification: B01D11
IPC codes: A61K9, B01J3, B01J8, B01D11, B01J15