Title of Invention

NOVEL POLYMORPHS OF GABAPENTIN

Abstract

The present invention relates to a new industrial feasible process for the preparation of Gabapentin Form-IV by reacting 1,1-cyclohexane diacetic acid monoamide with alkali hypo halite followed by acidification with acids in presence of an organic solvent, extracting the liberated acid salt into that solvent followed by addition of an ante solvent to crystallize the Gabapentin acid salts. The separated salt is then suspending in organic solvent(s) and pH is adjusted with a base(s), followed by separation of Gabapentin Form-IV, which is further converted to Gabapentin Form-II.

Full Text

Field of the Invention: The present invention relates to a novel crystalline Gabapentin Form-IV, process for its preparation and its use in the preparation of Gabapentin Form-II. Background of the Invention: Gabapentin (i.e. 1-aminomethyl-l-cyclohexaneacetic acid), of the formula is the active principle mainly used for the treatment of convulsive type cerebral disorders, such as epilepsy, hypokinesia including fainting and other brain trauma and in general, it is deemed to produce an improvement in the cerebral functions. Commercially available Gabapentin is crystalline and exhibits various polymorphic forms such as monohydrate, Form-II and Form-Ill characterized by their typical IR and X-ray diffraction patterns. Several processes for the preparation of Gabapentin are reported in literature. US Patent No. 4,024,175 and US Patent No. 4,087,544 disclose preparations starting from cyclohexane"l,l-diacetic acid. They also discloses an acid salt Gabapentin hydrochloride hydrate in a stiochiometric ratio of 4:4:1 and a sodium salt of Gabapentin hydrate in stiochiometric ratio of 2:1. US Patent No 4,894,476 and US Patent No. 4,960,931 disclose methods for the conversion of hydrochloride salt into crystalline monohydrate by eluting the aqueous solution through a basic ion-exchange resin, producing a slurry from the elute, adding an alcohol to the slurry and isolating the final product by centrifuging followed by drying. U.S.Patent Application No. 2003/ 0009055, US Patent No. 6,528,682, US Patent No.6, 054,482, PCT Publication WO 02 34,709, EP 1,174,418, and US Patent no. 5,091,567, describe processes that yield Gabapentin via the conversion the hydrochloride by neutralization using ion-exchanger, followed by distillation of eluted aqueous solution and crystallization. The PCT Publication WO 02 44123 discloses a process for the preparation of Gabapentin by dissolving Gabapentin hydrochloride in a solvent followed by addition of an amine, which allows the removal of insoluble amine hydrochloride salt leaving Gabapentin in solution, which is isolated, by concentration and crystallization. Industrial implementation of such processes is difficult as large volumes of ion-exchange columns and distillation of water under vacuum at low temperature is involved. Other processes disclosed in US Patents 5,132,451; 5,095,148; 5,091,567; 5,068,413 involve hydrogenation of the nitrile intermediate to yield the free amino acid. PCT Publication WO 98 28,255 discloses a novel polymorph Form-Ill, its preparation from Gabapentin hydrochloride and a process for the conversion of Form-Ill to Gabapentin Form-II. The process involves dissolution of Gabapentin hydrochloride salt in an organic solvent, removal of inorganics by Alteration, distillation of solvent under vacuum at temperature below 35oC, addition of a second solvent, neutralization with a base at 20'oC - 25oC, followed by isolation of the Form-Ill. The Form-Ill is slurried in methanol for an extended period of about 14 hrs at 25 oC or recrystallized from methanol to yield Gabapentin Form-II. Our CO pending Indian Patent Application No 327/MAS/2003 discloses a process for conversion of Gabapentin hydrochloride into Gabapentin Form-II directly without the formation of Form-Ill. Another co pending Indian Patent Application No 330/MAS/2003 discloses the process for the formation of novel Gabapentin hemisulfate hemihydrate salt and its conversion to Gabapentin Form-II directly. The method of conversion of hydrochloride salt to Form-II via Form-Ill disclosed in PCT Publication WO 98 28,255 involves elaborate process steps use of diverse solvents in a multi-step sequence, making the process industrially unacceptable. There is a long felt need in the pharmaceutical industry to develop technically and commercially attractive processes for the preparation of Gabapentin Form-II. Summary of the invention: The main object of the present invention is to provide a new techno-economically economically viable process for the preparation of Gabapentin Form-II. Another object of the invention is to explore other forms of Gabapentin, their characteristic features and process for their inter-form transformations. During the present investigations, it has surprisingly been found that a novel crystalline form now designated as Form-IV is formed when neutralization of Gabapentin acid salts is done appropriately with base(s) in the temperature range of about 20oC to about 75oC in different solvent,. Further it is found that is possible to convert Form-IV directly to Form-II. Thus in accordance of this invention, 1,1-Cyclohexane diacetic acid monoamide is reacted with alkali hypo halite followed by acidification with acids in presence of an organic solvent to extract the liberated acid salts into the solvent. An ante solvent is added to crystallize the Gabapentin acid salts. The separated salts is then suspending in organic solvent(s) and neutralized with base(s) in a specified temperature range, cooled to ambient temperature, followed by separation of Gabapentin form-IV for further conversion to Gabapentin form-II by slurring in ethanol at specified temperature. The process scheme is represented below. Brief description of the drawings: Fig. 1 shows a representative x-ray diffraction diagram of Gabapentin form -IV Fig. 2 shows a representative FTIR spectrum of the Gabapentin form - IV Fig. 3 shows a representative x-ray diffraction diagram of Gabapentin form-II Fig. 4 shows a representative FTIR spectrum of the Gabapentin form -II Fig. 5 shows a representative x-ray diffraction diagram of Gabapentin form-Ill Fig. 6 shows a representative FTIR spectrum of the Gabapentin form-Ill Detailed description of the Invention: The process of this invention comprising the steps of: - Reaction of 1,1-cyclohexane diacetic acid mono amide with alkali hypo halite solution, acidification with acid(s) in presence of solvent(s) - Extraction of the formed Gabapentin acid salt(s) into organic layer - Separation of the organic layer, drying over dehydrating agents - Addition of ante solvent(s), followed by optional cooling to precipitate the Gabapentin acid salt(s) and its isolation - Dissolution of Gabapentin acid salts in short chain alcohol - pH adjustment of the solution with base(s) in a specified temperature range - Cooling the reaction mass to precipitate Gabapentin form-IV Separation of the formed Gabapentin form-IV - Conversion of the form-IV into form-II by slurring in ethanol in a specified temperature range - Separation of Gabapentin form-II followed by drying The isolated Gabapentin acid salts are characterized by chemical analysis to be Gabapentin hydrochloride hydrate in stiochiometric the ratio of 4:4:1 and Gabapentin sulphate hydrate in the stiochiometric ratio of 2:1:1 depending on the acid used. The novel Gabapentin Form IV characterized by XRD and IR as a new form not reported so far. The 1,1-cyclohexane diacetic acid mono amide used as starting material is prepared as per the literature (U.S.Patent No. 4,024,175). For the reaction of 1,1-cyclohexane diacetic acid mono amide with alkali hypo halite, the preferred alkali hypo halite is sodium hypochlorite solution. The reaction is carried out in a temperature range of about -10oCto about 5oC, the preferred range being about -5oC to about 5oC. Acidification of the reaction mass to a pH of about 2 and preferably below 2 in the range of about 1.0 to about 1.5 is carried out with acid preferably with hydrochloric acid or sulphuric acid in presence of an organic solvent in a temperature range of about 15oC to about 25 oC. The preferred solvent is n-butanol. The reaction mass was allowed to settle and the organic layer is separated. The aqueous layer is extracted few times with the solvent. The combined extract is dried over dehydrating agents selected from materials such as anhydrous sodium sulphate, magnesium sulphate, etc. The dried organic layer is treated with ante solvent, optionally cooled to precipitate the acid salt(s). The ante solvent is selected from hydrocarbons, aromatic hydrocarbons, alkyl ketones, alkyl ethers, the preferred solvent being hexane, toluene, acetone, di isopropyl ether or their mixtures. The precipitated salt(s) is separated by conventional methods such as filtration, centrifugation and dried to constant weight. The Gabapentin salt(s) is dissolved in short chain alcohol, preferred alcohol being ethanol, n-propanol, n-butanol at about 200C to about 25 oC, stirred for about for sometime to get a clear solution. The temperature of the solution is raised above 60oC preferably between about 60oC to about 65 oC, and pH is adjusted a base the preferred ones being diethyl amine and di isopropyl ethyl amine. Gradual cooling to about 10oC to 25 oC, preferably between 20oC 25oC, results in the precipitation of Gabapentin form-IV which is separated by conventional means, washed with the solvent and dried in the preferred temperature range of about 45oC - 50oC. The Gabapentin form-IV is converted into form-II by suspending in ethanol, raising the temperature to about 60oC- 65oC, maintaining the temperature for sometime followed by gradual cooling with stirring for about 1-2 hrs at temperature 20oC - 25oC. Gabapentin form-II formed as the final product is separated, and dried to obtain the material of pharmaceutically acceptable quality. The invention is now illustrated by a few non-limiting examples. Example -I Following the Gabapentin hydrochloride hydrate route: Stage-1: Sodium hydroxide (51 gms) is dissolved in sodium hypochlorite solution (6.25%, 625 gms) and cooled to 10 oC. The solution is stirred for 10 - 15 min and further cooled to -5 oC. In a separate flask, 1,1-cyclohexane diacetic acid monoamide (100 gms) is dissolved in 4N Sodium hydroxide solution (150 ml) at 15oC - 20 oC. The amide solution is slowly added to the sodium hypochlorite solution at temperature -5oC to -3 oC. The solution is then maintained at about 0oC for 2 hrs. The temperature is gradually raised to 20oC - 25 oC and then maintained at this temperature for 4 hrs. Sodium meta bisulphite solution (5 gms in 10 ml water) is then added to the solution. The reaction mass is filtered to remove any un- dissolved material. pH of the filtrate is adjusted to around 9.0 by the addition of hydrochloric acid at temperature 20 - 25 oC. n-Butanol (200 ml) is added and the pH is further adjusted to 1.5 with hydrochloric acid and stirred. The reaction mass is allowed to settle with the separation of the layers. The aqueous layer is extracted with n-Butanol (200 ml). The organic layer is dried over anhydrous sodium sulphate (15 gms). Di isopropyl ether (1200 ml) is slowly added to the dried organic layer at room temperature and stirred for about 1 hr.. The system is cooled to 5oC and stirred for 1 hr. The product is filtered, washed with di iso propyl ether (50 ml) and dried at 45oC - 50 oC to constant weight and finally crystalised from tert. butanol - diisopropyl ether to get the pure hydrochloride. The dry wt of the hydrochloride salt is 80.0 gms corresponding to a yield of 75.0% Stage " 2: Gabapentin hydrochloride salt (100 gms) prepared in stage 1 is suspended in n-propanol (1000 ml) and stirred at room to get clear solution. The filtrate is slowly heated to 60oC -65 oC and the pH is adjusted to 7.2 by slow addition of di isopropyl ethyl amine solution (180 ml in 180 ml of n-propanol). The reaction mass is gradually cooled to 20oC - 25oC over 30 mins. The product is filtered, washed with n-propanol (50 ml) and dried at 45 C -50oC to constant weight. Dry wt of the Gabapentin form-IV is 49.5 gms (Yield; 62%). XRD and IR is used to characterise the product (table 1) Stage-3: Gabapentin Form-IV (40 gms) prepared in stage 2 is suspended in ethanol (280 ml) and the temperature is raised to 65oC and maintained for 90 min. The reaction mass is gradually cooled to room temperature and stirred for 30mins. The product is filtered, washed with ethanol (20 ml) and dried at 50oC- 55 oC to constant weight. The dry weight of the Gabapentin form-II is 36 gms corresponding to a yield of 90%. XRD and IR of this product matched those reported for Form II Example-II Following the Gabapentin Hemisulphate hydrate route: Stage-1: Sodium hypochlorite solution (6.25%, 625 gms) is cooled to 10 oC and sodium hydroxide flakes (51 gms) is dissolved in it by stirring for about 10-15 min and cooled to -5 oC. In a separate flaskl,l-cyclohexane diacetic acid monoamide (100 gms) is dissolved in 4N sodium hydroxide solution (150 ml) at 15 oC - 20 oC. The amide solution is slowly added to sodium hypochlorite solution at temperature -5 oC to -3 oC and then maintained at about 0 oC for 2 hrs. The temperature is then slowly raised to 20 - 25 oC and maintained for 4 hrs at 20 oC - 25 oC. Sodium metabisulphite solution (5 gms in 10 ml water) is then added. The reaction mass is filtered to remove any un-dissolved material. pH of the filtrate is adjusted to 9.0 by the addition of 1:1 dilute sulphuric acid at temperature of 20 oC - 25 oC. n-Butanol (200 ml) is added and the pH is further adjusted to 1.5 with sulphuric acid. The reaction mass is stirred for 10 - 15 min. and then allowed to settle. The layers are separated. The aqueous layer is extracted with n-Butanol (200 ml). The combined extract is dried over anhydrous sodium sulphate (15 gms). Di isopropyl ether (1200 ml) is slowly added at room temperature to the dried extracted layer. The reaction mass is stirred for 1 hr and then cooled to 5 oC and further cooled to about 0 - 5 oC with constant stirring for 1 hr . The product is filtered, washed with di isopropyl ether (50 ml) and dried at 45°C - 50* oC to constant weight. The dry wt of hemisulphate hemihydrtae is 85 gms corresponding to yield 73.8%. Stage-2: The Gabapentin hemisulphate hemihydrate salt (100 gms) prepared in stage-1 is suspended in ethanol (700 ml) and stirred for 30 min. at room temperature. The insolubles is filtered and washed with ethanol (50 ml). The filtrate is heated to 60 oC - 65 C and the pH of the filtrate is adjusted between 7.1 to 7.2 by slow addition of di isopropyl ethyl amine solution (135 ml in 145 ml ethanol) at 60 - 65 oC over 20 min. The reaction mass is then cooled to 20 oC - 25 oC over 30 min. The filtered product is washed with ethanol (50 ml) and dried at 45 oC - 50 oC to constant weight. Dry wt of the Gabapentin form-IV is 47.5 gms corresponding to yield: of 63 %. Stage -3: Gabapentin form-IV (40 gms) prepared in stage 2 is suspended in ethanol (240 ml) and the temperature is raised to 65 oC, maintained for 90 min. at 65 oC - 70 * oC then cooled to room temperature and stirred for 30min. at room temperature. The filtered product is washed with ethanol (25 ml) and dried at 50 oC - 55 oC to constant weight. The dry weight of the Gabapentin form-II is 45 gms corresponding to yield: 90% The XRD and IR of this product matched those reported for Form II Table-l FTIR Peaks of Gabapentin Form-IV, Hydrate (Form-I), Form-II and Form-Ill WE CLAIM: 1. A process for the preparation of Gabapentin form-II comprising steps: Reacting 1,1-cyclohexane diacetic acid mono amide with alkali hypo halite solution, Acidifying the reaction mass with acid(s) in presence of solvent(s) Extracting the formed Gabapentin acid salt(s) into organic layer Separating the organic layer, drying over dehydrating agents Adding anti solvent(s) selected from hydrocarbons, aromatic hydrocarbons, alkyl ketones, alkyl ethers, followed by optional cooling to precipitate the Gabapentin acid salt(s) Isolating the Gabapentin acid salt(s) Dissolving Gabapentin acid salts in short chain alkanol Adjusting the pH with base(s) Cooling the reaction mass to precipitate Gabapentin form-IV Separating the formed Gabapentin form-IV Converting the form-IV into form-II by slurrying in ethanol Separating the Gabapentin form-II followed by drying 2. A process for the preparation of novel crystalline Gabapentin form-IV comprising the steps : - Reacting 1,1-cyclohexane diacetic acid mono amide with alkali hypo halite solution, - Acidifying the reaction mass with acid(s) in presence of solvent(s) - Extracting the formed Gabapentin acid salt(s) into organic layer - Separating the organic layer and drying over dehydrating agents - Adding anti solvent(s), followed by optional cooling to precipitate the Gabapentin acid salt(s) - Isolating the Gabapentin acid salt(s) - Dissolving Gabapentin acid salts in short chain alkanol - Adjusting the pH with base(s) - Cooling the reaction mass rapidly to precipitate Gabapentin form-IV Separating the formed Gabapentin form-IV wherein the formed Gabapentin form-IV is characterized by powder x-ray diffraction peaks at 6.3, 12.6, 16.3, 18.0, 18.8, 19.4, 21.4, 25.3, 26.3, 27.0, 30.2, 32.4, 35.7, 38.2 and 45.6 ± 0.2 degrees 2-theta. 3. The process as claimed in claim 1 and 2, wherein acidification is carried out with HCl and/or sulphuric acid in n-butanol. 4. The process according to claim 1 and 2, wherein the anti-solvent employed is selected from hexane, toluene, acetone di-isopropyl ether or their mixtures thereof 5. The process as claimed in claims 1 and 2, wherein the formed Gabapentin acid salt is Gabapentin hydrochloride or Gabapentin hemisulfate hemihydrate. 6. The process as claimed in claim 1 and 2, wherein the short chain alkanol is selected from ethanol, n-propanol and n-butanol 7. The process according to claim 1 and 2, wherein the base is selected from diisopropyl ethylamine, triethylamine 8. The process as claimed in claim 1 and 2, wherein the pH is adjusted to 6.8-7.2 at 60^C -65^C 9. The process as claimed in claim 1 and 2, wherein rapid cooling is after pH adjustment to obtain Gabapentin form IV 10. The process as claimed in claim 1, wherein the conversion of form-IV to form-II, is carried out at 25oC to 75oC in an ethanol

Documents:

0480-che-2003 abstract duplicate.pdf

0480-che-2003 claims duplicate.pdf

0480-che-2003 description(complete) duplicate.pdf

480-che-2003-abstract.pdf

480-che-2003-claims.pdf

480-che-2003-correspondnece-others.pdf

480-che-2003-correspondnece-po.pdf

480-che-2003-description(complete).pdf

480-che-2003-drawings.pdf

480-che-2003-form 1.pdf

480-che-2003-form 19.pdf

480-che-2003-form 3.pdf