Title of Invention	A NEW PROCESS FOR PREPARING GABAPENTIN POLYMORPH II
Abstract	Novel processes for preparing gabapentin polymorph II are disclosed herein which involve the treatment of gabapentin hydrochloride with base such as aqueous l°-alkyl amine, diisopropylethyl amine and aqueous sodium hydroxide followed by purification from aqueous acetone.

Full Text

FORM 2 The PATENTS ACT, 1970 (39 of 1970) Complete Specification "PROCESSES FOR PREPARING PURE GABAPENTIN POLYMORPH II WITH LOW CHLORIDE CONTENT" 20 MAY 2004 CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satelite Cross Road, Amedabad-380 015, Gujarat The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed: FIELD OF INVENTION The present invention relates to a process for the preparation of pure gabapentin polymorph II. More particularly, the present invention relates to a process for the preparation of pure gabapentin polymorph II with low chloride content" BACKGROUND OF THE INVENTION Gabapentin chemically known as (l-aminomethyl)-l-cycloexaneacetic acid having the structural formula (I) is useful in therapy of certain cerebral disorders such as certain forms of epilepsy, faintness attacks, hypokinesis and cranial traumas. A number of processes for preparation of gabapentin are reported in the literature starting from cyclohexyl-l,l-diacetic acid. (eg. US 4024175, US 4152326, US 5319135, US 5091567, US 4956473). All the preparations result in formation of gabapentin hydrochloride, which is then transformed to free gabapentin. US patent 6054482 discloses that Gabapentin on storage produces corresponding lactam compound, which is toxic. It also teaches that for having good stability of gabapentin, lactam content should be as low as possible, preferably below 0.5% w/w and anion of mineral acid preferably below 20 ppm. WO 01/97782 also disclose that gabapentin having pH in the range of 6.8-7.3, more preferably in the range of 7.0-7.2, is stable in the pharmaceutical formulations. US 4894476, US-4960931, US 6054482, WO-00/01660, WO 02/34709 and EP 340677 disclose an improved method for converting the hydrochloride salt of gabapentin into the free gabapentin, which involves passing a deionized water solution of the salt from ion exchange resin column, eluting with deionized water, producing a slurry 2 from the elute, adding an alcohol to the slurry, centrifuging and drying the slurry to obtain free gabapentin. The methods of obtaining Gabapentin described in above prior arts are industrially impractical and comprise the use of ion exchange columns for a lengthy period to lower the level of chloride ions to the desired level. Moreover due to high water solubility of gabapentin, large water volumes have to be evaporated off at low temperature to recover the said compound. Operating at low temperature to prevent the formation of corresponding lactam makes the process difficult from the industrial point of view. WO-00/58268 describes a new method for getting Gabapentin from its hydrochloride salt. Adjustment of pH to an isoelectric point of the solution of gabapentin hydrochloride in water and passing the said aqueous solution through a membrane, which is highly selective for organic compounds with molecular weight higher than 150 and poor selective to inorganic monovalent ions to separate the solution into an aqueous permeate containing chloride ions and a retentate containing gabapentin substantially free from chloride ions and concentrating the retentate by evaporation under reduced pressure and precipitating gabapentin by addition of an alcohol. US 6255526, WO 02/44123, WO 01/97612, WO 98/28255 disclose the use of an organic amine to remove chloride ion such as tributylamine dicyclohexylamine, diisopropylamine, trihexylamine etc. in various organic solvents. The procedure disclosed herein avoids the use of ion exchange columns and membrane systems. SUMMARY OF THE INVENTION The present invention relates to novel and industrially efficient methods for obtaining pure gabapentin polymorph-II from gabapentin hydrochloride. The methods provide gabapentin hydrochloride with chloride content between 20- 200 ppm and corresponding lactam less than 0.05%. It is industrially and economically desirable that the product must be isolated without the operations such as ion-exchange resins, reverse osmosis, semipermeable membranes etc. Accordingly, the first method of the present invention relates to an improved method for obtaining pure gabapentin polymorph II, which comprises: 3 a) neutralization of gabapentin hydrochloride in aqueous acetone with the help of aqueous l°-alkyl amine solution. The l°-alkyl amine is selected from the group of methylamine, ethylamine or propylamine, preferably 20-70% aqueous ethylamine solution is used, most preferably 70% ethylamine solution used. b) neutralization is carried out upto the isoelectric point of gabapentin to obtain a slurry, which is filtered to obtain gabapentin and most of the salt as well as impurities are removed with mother liquor. c) the gabapentin thus obtained is crystallized from aqueous acetone, which is then dissolved in deionized water to obtain clear solution. d) gabapentin is recovered from the clear solution by removal of water under reduced pressure to afford mass, which on treatment with aqueous acetone provides pure gabapentin. The pure gabapentin thus obtained possesses chloride content less than 100 ppm, HPLC purity more than 99.8% and lactam content less than 0.008%. X-ray powder diffractogram confirms that the gabapentin thus obtained is indeed polymorph II of gabapentin. Alternatively, a second method to prepare pure gabapentin polymorph II comprises neutralization of gabapentin hydrochloride in aqueous solution with the help of organic base like diisopropylethyl amine to adjust pH between the range 7.15 to 7.25. The precipitated gabapentin is separated from the suspension by filtration. The product is obtained as solid and impurities as well as corresponding salts of amine are removed with mother liquor. The product thus obtained is treated with aqueous acetone under reflux condition, followed by cooling and subsequent filtration affords pure gabapentin. The techniques described above for obtaining pure gabapentin are advantageous over other prior arts, which involve the large volumes handling and carrying out tedious operation with ion-exchange resins, reverse osmosis and semi-permeable membranes. The use of ion-exchange resins has disadvantages having higher initial investment, handling large volume operation and regeneration of ion-exchange column, operation procedure is complicated as well as uneconomical. The membrane technology has also disadvantages, amongst that the major disadvantage is 4 that the membrane is susceptible to fouling, which is often caused by precipitation of suspended and dissolved solids that plug the membrane's pores. Furthermore the process by which gabapentin polymorph II is produced needs to be one, which is suitable to large-scale preparation. Additionally, it is desirable that the product should be in such form, which is readily filterable solid and the impurity as well as salts must be easily removable along with mother liquor. The processes described herein above have three major advantages: 1. critical operations like large-scale volume handling, use of ion-exchange resins, reverse osmosis as well as use of semipermeable membrane are successfully eliminated. 2. the two processes described herein have remarkable advantages over the prior art described in WO 02/44123, therein the process described the recovery of the product from mother liquor, which is not an efficient process to remove process related impurities as well as corresponding salts. Whereas, processes described herein gives the product after neutralization of gabapentin hydrochloride as a solid, during the filtration salts as well as process related impurities are easily removed with the mother liquor. 3. the amines utilized herein are aqueous l°-alkyl amines and diisopropylethylamine as such for neutralizing gabapentin hydrochloride, which are not / mentioned in prior arts and amines employed in above two process are economical and readily available in large quantities. Moreover the corresponding acid neutralized salts of the amine are highly soluble in water as well as in aqueous solvent media. Alternatively a third method can also be employed to prepare pure gabapentin. The process disclosed herein is unique in terms of neutralization of gabapentin hydrochloride which is carried out with the help of alkali metal hydroxide, carbonate and hydrogen carbonate, preferably sodium hydroxide and adopting simple operations as noted below 1.) The gabapentin, obtained after complete removal of water is treated with methanol to remove substantial amount of salts and process 5 related impurities. The operation allows removal of major amount of salts upon filtration. 2.) Gabapentin thus obtained on repeated treatment of aqueous acetone having 16-17% (w/v) moisture content, significantly affords gabapentin having chloride content 140 ppm and lactam content 0.02% with HPLC purity 99.96%. DETAILED DESCRIPTION The invention will now be described in detail. The preparation of pure gabapentin polymorph - II along with low chloride and low lactam contents as well as with high HPLC purity is illustrated by three methods employing gabapentin hydrochloride as a starting material. First method: a) Gabapentin hydrochloride is suspended in a mixture of 1 volume of acetone and 0.5 volumes of deionized water as that of gabapentin hydrochloride, the suspension is treated with 70% (w/w) aqueous ethylamine solution to bring pH between 7.15 to 7.25. b) The solids are filtered and washed twice with 0.25 volumes of acetone as that of gabapentin hydrochloride. c) Wet cake thus obtained is suspended in 3.6 volume of 16-17% (w/v) aqueous acetone as that of gabapentin hydrochloride d) The suspension is heated to reflux and then cooled to 25 to 35 °C. e) The solids are filtered and then washed twice with 0.3 volumes of acetone as that of gabapentin hydrochloride. f) Wet cake thus obtained is dissolved in 1.85 volumes of water as that of gabapentin hydrochloride at 40 to 50° C, resulting a clear solution, which is treated with 2.3% (w/w) activated carbon as that of gabapentin hydrochloride and is filtered through hyflow supercel bed to get clear aqueous solution of gabapentin. g) Aqueous solution thus obtained is subjected to distillation at reduced pressure to remove water, resulting a thick slurry. h) The slurry thus obtained is cooled to 40 to 45 °C temperature and is mixed with 2.30 volumes of acetone as that of gabapentin hydrochloride 6 and finally water content in the slurry is adjusted between 8-12 % (w/v) with deionized water, i) The slurry is heated to reflux for 30 minutes and is then cooled to 25 to 35°C temperature, j) Pure gabapentin is filtered and is then washed twice with 0.23 volumes of acetone as that of gabapentin hydrochloride, k) The wet cake is dried at 40 to 45 °C temperature under reduced pressure to give pure gabapentin polymorph II. Second method: a) Gabapentin hydrochloride is dissolved in 3 volumes of deionized water at 25 to 35 °C temperature to get clear solution. b) The pH of solution is adjusted in the range of 7.15-7.25 with diisopropylethylamine resulting in the precipitation of gabapentin at 25 to 35 °C temperature. c) The solid thus obtained is filtered and washed twice with 0.5 volumes of acetone as that of gabapentin hydrochloride. d) The wet cake thus obtained is suspended in 2.52 volumes of 16-17 % (w/v) of aqueous acetone, as that of gabapentin hydrochloride. e) The suspension is then heated to reflux for 30 minutes and is cooled to 25 to 35 °C temperature. f) The solid is filtered to obtain a wet cake, which is washed twice with 0.3 volumes of acetone, as that of gabapentin hydrochloride. g) The wet cake is dried at 40 to 45°C temperature under reduced pressure to give pure gabapentin polymorph II. Third method: a) Gabapentin hydrochloride is dissolved in 3-5 volumes of deionized water, preferably 3 volumes of deionized water and is treated with aqueous sodium hydroxide solution to bring pH between 7.15 to 7.25 which is treated with activated carbon and is filtered through hyflow supercel bed to get the clear solution. b) Clear solution thus obtained is distilled under reduced pressure to remove water, affording the slurry, in which 1 volume of acetone as that 7 of gabapentin hydrochloride is added, and subsequently acetone is distilled out. This operation of acetone mixing and subsequent distillation is repeated thrice to remove water completely. c) Solid thus obtained is mixed with 2 volumes of acetone as that of gabapentin hydrochloride and the slurry is filtered and washed with acetone. Gabapentin thus obtained contains 16 to 17% chloride content. The solid is dried at 40 to 50 °C temperature under reduced pressure. d) The solid thus obtained is treated with 6.82 volumes of methanol as that of gabapentin hydrochloride at 50 to 55°C temperature. It is then filtered through hyflow supercel bed and is washed twice with 0.23 volumes of methanol as that of gabapentin hydrochloride. e) The mother liquor containing gabapentin is subjected to distillation under reduced pressure to remove methanol. f) The residual methanol in slurry is removed azeotropically with acetone by carrying out distillation at 60-65°C. g) The solid material is mixed with 1.96 volume of acetone as that of gabapentin hydrochloride and is then filtered. h) The filtered solid is heated to reflux with 4.71 volumes of 16-17% (w/v) of aqueous acetone as that of gabapentin hydrochloride and cooled to 25-30°C temperature, the solid is filtered. The same operation is repeated thrice and finally the obtained product is dried at 40 to 45°C temperature under reduced pressure to obtain pure gabapentin polymorph II. 8 Major objectives of the present embodiment: 1. Distillation of large volume of water is avoided. 2. Use of expensive amine e.g. tributylamine, cyclohexylamine etc. as mentioned in the prior arts is eliminated. 3. Commercially available base[s] such as 70% aqueous solution of ethylamine 40% methylamine aqueous and sodium hydroxide and diisopropylethylamine etc. are used. 4. Acetone as a solvent used in the process is recovered and recycled. 5. Gabapentin is recovered as a solid in method-1 & 2, removing corresponding salts and impurities with mother liquor. 6. Method-3 is modified in such a way that it doesn't require any ion-exchange columns and reverse osmosis. The present invention is illustrated by the following examples, which are not intended to limit the effective scope of the claims. Consequently, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as claimed. The present invention has been described in terms of its specific embodiments and certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention. The following examples will further illustrate the invention without, however, limiting it thereto. Example 1: a.) In a solution of 50 ml deionized water and 100 ml acetone, 100 g of gabapentin hydrochloride is added under stirring. To this suspension, 70% w/w aqueous solution of ethylamine is added till pH of the reaction mass approaches between 7.15 to 7.25. The reaction mass is then stirred for 30 min by maintaining temperature 25-30°C. Reaction mass is filtered and washed twice with 25 ml of acetone. The weight of suck dried gabapentin is 60 g. b.) Gabapentin obtained in above stage (60 g) is suspended in mixture of 300 ml acetone and 60 ml deionized water under stirring for 30 min. The reaction mass is refluxed for 30 min., then cooled to 25-30°C and it is 9 stirred for 30 min. by maintaining the same temperature. The solid mass is filtered and provided two 30 ml acetone wash to afford 46.3 g wet product. c.) The wet cake obtained in above step (46.3 g) is dissolved under stirring with 185 ml of deionized water at 40-45°C temperature to get a clear solution. To this solution 2.3 g activated carbon is added and stirred for 30 min at 40-45°C. The charcolized solution is then filtered through hyflow supercel bed and washed twice with 23 ml deionized water. The filtrates are combined and water is removed under reduced pressure below 70°C. 231 ml acetone is mixed with residue remained in the reaction vessel and if required water content is adjusted with deionized water between 8-12%. It is then heated to reflux for 30 min and cooled up to 25-30°C under stirring. Solid thus obtained is filtered and washed twice with 23 ml acetone and subsequent drying under reduced pressure at 45-50°C afforded 44 g of product. HPLC purity: 99.94 % Chloride: 25 ppm Lactam: 0.008 % X-ray powder diffractogram confirms the product to be polymorph II. [Figure-1] Example 2: 5.0 g Gabapentin hydrochloride is dissolved in 15 ml deionized water at 25-30°C and pH of the solution is adjusted between 7.15 to 7.25 by addition of diisopropylethylamine to precipitate free gabapentin. The suspension is stirred for further 30 minutes at the same temperature. Solid gabapentin is filtered from the suspension and washed twice with 2.5 ml of acetone to afford 3.1 g wet gabapentin. The wet cake is then suspended under stirring in mixture of 10.5 ml acetone and 2.1 ml deionized water. The suspension is heated up to 55-60°C for 30 min, which is cooled to 25-30°C. Solid gabapentin obtained upon filtration at the same temperature and washed 10 twice with 1.5 ml of acetone. Finally it is dried between 45-50°C under reduced pressure to afford 1.8 g gabapentin. HPLC purity: 99.92% Lactam = 0.005% Chloride: 93.5 ppm X-ray powder diffractogram confirms the product to be polymorph II. [Figure-2] Example 3: (a) 107 grams of Gabapentin hydrochloride is dissolved in 321 ml of deionized water under stirring. 10% w/v aqueous sodium hydroxide solution is added to the clear solution to adjust the pH between 7.15 to 7.25 by at 25°C to 30°C. Reaction mass is allowed to stir for further 30 minutes and 10.7 g of activated carbon is added. The solution is then allowed to stir for another 30 minutes and it is filtered through 5u filter pads, with two washes each of 53.5 ml deionized water; filtrate and washes are combined. Water is completely removed under reduced pressure below 70°C temperature. Solid gabapentin remained inside the reaction vessel, to this 107 ml of acetone is added, which is then distilled to remove moisture azeotropically. This operation is repeated for thrice to remove traces of moisture completely. Moisture free gabapentin remain inside the reaction vessel, to this 214 ml of acetone is added, which is refluxed for 30 min. Reaction mass is cooled to 25 to 30 °C and stirred for another 30 min at same temperature, followed by filtration to afford solid, which is washed twice with 53.5 ml of acetone. Solid gabapentin thus obtained is dried at 45 to 50 °C under reduced pressure. Solid product thus obtained weigh 105 g. (b) The solid product obtained in above step (105 g) is dissolved 730 ml of methanol at 50 to 55 °C. The clear solution thus obtained is filtered through hyflow supercel bed and the hyflow supercel bed is washed twice with 25 ml of hot methanol (50 to 55 °C). Filtrate is collected and 11 methanol is removed by distillation under reduced pressure. Traces of methanol are removed by azeotropic distillation with the help of acetone under reduced pressure. 210 ml acetone is added in the reaction mass under stirring and stirred for 30 min. to make homogeneous slurry. Slurry thus obtained is filtered and product is dried at 45 - 50 °C under reduced pressure to afford 84 gm product, (c) The solid product obtained in above step (84 g) is slurred in 420 ml acetone and 84 ml of deionized water, which is heated at 55-60°C for 30 min. The reaction mass is cooled to 25 to 30 °C then filtered followed by two 42 ml acetone washings. The process as described herein above is repeated thrice maintaining same water and acetone ratio as well as the volume of aqueous acetone. After the completion of final operation solid gabapentin is dried under reduced pressure between 45-50°C to afford 54.7 g of dry gabapentin. HPLC purity: 99.96% chloride: 140 ppm lactam: 0.02% X-ray powder diffractogram confirms the product to be polymorph II. [Figure-3] 12 We claim 1. A process for the manufacturing of pure gabapentin polymorph II having chloride content between 20-100 ppm and lactam less then 0.01%, which: a) treating suspension of gabapentin hydrochloride in aqueous acetone with aqueous l°-alkyl amine to adjust pH between 7.15-7.25; b) removing the solid compound from the suspension of step (a) by filtration; c) suspending the solid compound obtained in step (b) into aqueous acetone, which is then refluxed and subsequently cooled to 25-30°C, followed by filtration to obtain wet cake; d) dissolving the wet cake obtained in step (c) in deionized water at 40-45°C, which is treated with activated charcoal, followed by filtration to obtain a clear solution. e) distilling the clear solution obtained in step (d) under reduced pressure to afford solid gabapentin, which is mixed with acetone and moisture content of the mixture is adjusted between 5-25% (w/v),more preferably 8-12% (w/v). f) refluxing and then cooling the suspension of gabapentin in aqueous acetone obtained from step (e); g) filtering and drying the product from step (f) under reduced pressure, between 45-50°C to obtain pure gabapentin polymorph - II. 2 A process for the manufacturing of pure gabapentin polymorph II having chloride content between 75-125 ppm and lactam less then 0.01%, which comprises: a) dissolving Gabapentin hydrochloride in deionized water to obtain a clear solution; b) adjusting pH of the above solution between 7.15-7.25 by adding diisopropylethylamine, resulting in the precipitation of free gabapentin from the solution. c) filtering the solution from step (b) to afford free gabapentin as a solid. d) suspending the wet gabapentin obtained from step (c) in aqueous acetone; e) heating the suspension obtained in step (d) to get a clear solution; f) cooling the solution obtained from the previous step (e) to crystallize gabapentin, which is then filtered and dried under reduced pressure between 45-50°C temperature to afford pure gabapentin polymorph-II. 3. A process for the manufacturing of pure gabapentin polymorph II having chloride content between 125-200 ppm and lactam less then 0.05%, comprises the following steps: a) preparing an aqueous solution of gabapentin hydrochloride in 2-5 volumes of deionized water, preferably 3 volumes of deionized water as that of gabapentin hydrochloride taken; b) adjusting pH of the said solution between 7.15-7.25 by addition of aqueous solution of an inorganic base; 13 c) removing water from the above solution by distillation to obtain solid gabapentin; d) removing traces of water azeotropically with acetone from the solid gabapentin as obtained in step (c). e) mixing gabapentin obtained in step (d) with 3-10 volumes of methanol, preferably 6-7 volumes of methanol, as that of gabapentin hydrochloride taken, for dissolving gabapentin only; f) filtering the slurry obtained from step (e) to remove majority of salt(s) resulting in gabapentin remaining in the filtrate as a methanolic solution; g) distilling the filtrate of step (f) at 55-60°C, under reduced pressure to afford gabapentin as a solid mass; h) mixing solid gabapentin obtained in step (g) with 2-2.5 times acetone, as that of gabapentin hydrochloride taken, and filtering it to obtain gabapentin as a solid; i) refluxing the gabapentin obtained in step (h)) with 4-5 volumes of 16 to 17% (w/v) of aqueous acetone as that of gabapentin hydrochloride; cooling the solution so obtained and subsequently filtering it to obtain gabapentin; j) if desired repeating step (i) at least thrice to obtain the final product and drying final product is dried at 40 to 45°C under reduced pressure to obtain pure gabapentin polymorph-II. 4. A process as claimed in claim 1 wherein in step (a) said aqueous acetone is prepared by mixing 1 volume of acetone with 0.5 volume of deionized water as that of gabapenin hydrochloride. 5. A process as claimed in claim 1 wherein in step (b), the pH is adjusted using an aqueous organic base, preferably 1° alkyl amine comprising straight or branched carbon chain having C1-C4 carbon atoms selected from a group comprising aqueous methyl amine, aqueous ethyl amine, aqueous propylamine, most preferably aqueous ethyl amine. 6. A process as claimed in claim 1 wherein in step (b) the aqueous organic base has strength between 10-80% (w/w), preferably 40-70% (w/w), most preferably 70% (w/w). 7. A process as claimed in claim 1 wherein in step (c), 10-30 % (w/v) aqueous acetone is taken, most preferably 16-17% (w/v) aqueous acetone taken as that of gabapentin hydrochloride. 8. A process as claimed in claim 1 wherein in step (d), said wet cake is dissolved in 1-5 volumes of water, preferably 1.85-2 volumes of water as that of gabapentin hydrochloride taken. 9. A process as claimed in claim 1 wherein in step (e), 1.5-5 volume of acetone is added after removal of water under reduced pressure, preferably 2.3-2.5 volume of acetone is added as that of gabapentin hydrochloride taken. 14 10. A process as claimed in claim 2 wherein in step (a), 2-5 volume of deionized water is taken, preferably 3 volume of deionized water is taken as that of gabapentin hydrochloride. 11. A process as claimed in claim 2 wherein in step (b), pH is adjusted in between 7.15-7.25 by diisopropylethyl amine. 12. A process as claimed in claim 2 wherein in step (d), said wet cake obtained from 2(c), is suspended in 15-20 % (w/v) aqueous acetone, preferably 16-17% (w/v) aqueous acetone as that of gabapentin hydrochloride taken. 13. A process as claimed in claim 2 wherein in step (e), the suspension is heated at 45-60 °C to get clear solution, preferably 50-60°C and the solution so obtained is cooled to 10-40 °C preferably 25-30°C. 14. A process as claimed in claim 3 wherein in step (b), 5-50% (w/w) sodium hydroxide is used in pH adjustment, more preferably 10% solution of sodium hydroxide is used. 15. A process as claimed in claim 3 wherein in step (b), said inorganic base is selected from alkali metal hydroxide, carbonate or hydrogen carbonate salts, preferably sodium hydroxide is used. 16. A process as claimed in claim 3 wherein in step (c), the water is removed under reduced pressure below 70°C. A process as claimed in claim 1, 2 or 3 wherein, the product is dried under reduced pressure at 30-45°C. 15 Abstract Novel processes for preparing gabapentin polymorph II are disclosed herein which involve the treatment of gabapentin hydrochloride with base such as aqueous l°-alkyl amine, diisopropylethyl amine and aqueous sodium hydroxide followed by purification from aqueous acetone. 20 MAY 2004 16

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454-MUM-2003-DESCRIPTION(COMPLETE)-(20-5-2004).pdf

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