WO2010023694A2

WO2010023694A2 - Crystalline forms of gabapentin and process thereof

Info

Publication number: WO2010023694A2
Application number: PCT/IN2009/000480
Authority: WO
Inventors: Nagarajan Kuppuswamy; Rajender Pershad Gupta; Arulselvan Mariadas
Original assignee: Hikal Ltd
Priority date: 2008-09-01
Filing date: 2009-09-01
Publication date: 2010-03-04
Also published as: WO2010023694A3

Abstract

The present invention relates to crystalline forms of gabapentin and processes for preparing the same. The present invention particularly relates to crystalline forms of gabapentin form II and Form IIB. The invention also relates to gabapentin form IA and form IB. The gabapentin forms IA and IB are hydrated forma that contain about 20% of water by weight which corresponds to hemipentahydrate. The present invention also relates to the process for preparing these crystalline forms of gabapentin.

Description

CRYSTALLINE FORMS OF GABAPENTIN AND PROCESS THEREOF Field of the invention

The present invention relates to gabapentin. Particularly, the present invention relates to new crystalline forms of gabapentin and processes for preparing the same. Background and prior art

Gabapentin or 1 -amino methyl cyclohexane- 1 -acetic acid having formula 1, has been developed as a drug having anti convulsive properties.

Formula 1

US 4024175, US 408754 and DE 2460891 disclose this compound, process of its preparation and uses thereof. These cited patents describe various processes for the preparation of Gabapentin and similar compounds of the general formula 2 given below

Formula 2

wherein Ri is a hydrogen atom or a lower alkyl radical and 'n' is an integer with a value of 4 to 6 and their pharmaceutically acceptable salts. The processes disclosed in these patents are based on known methods used for the preparation of primary amines. Specifically, they involve Curtius reaction of cycloalkane diacetic acid monoesters, Hoffmann reaction of cycloalkane diacetic acid monoamides or Lossen Rearrangement of I- carboxymethylcycloalkane acetohydroxamic acid sulphonate esters.

In US 4152326, N-(p-toluenesulphonyloxy)-lJ -cyclohexancdiaceticacid imide was heated with 10% aqueous sodium hydroxide solution (Lossen Rearrangement) at 100° C and the resultant solution was acidified with concentrated hydrochloric acid and evaporated to dryness. The residue was digested with ethanol, filtered and the filtrate was evaporated in vacuum to give gabapentin benzene-sulphonate. Treatment of this material with the basic ion exchanger, IR-45, in the -OH form gave gabapentin. In the ensuing years, there have been patents disclosing other routes which involve the hydrolysis of 2-azaspiro (4,5) decan-3-one of the formula 3, known conveniently as gabalactam, first isolated by Sircar (J.Ind.Chem.Soc, 1928,5,549; Chem. Abstracts, 1929, 23, 818) with 1 :1 hydrochloric acid

Formula 3

In US 5068413 and EP 414263 A2, gabalactam was mixed with 1 :1 hydrochloric acid and boiled under reflux at 108° C for 6 hours, cooled and diluted with water. The mixture was extracted with methylene chloride to remove un-dissolved lactam. The aqueous solution was evaporated to dryness in vacuum and the residue was washed with acetone to give gabapentin hydrochloride as the insoluble part.

In WO 9914184Al, gabalactam of formula 3 was hydrolyzed with a mixture of 6N hydrochloric acid and dioxane at reflux for 4 hours. The resultant solution was evaporated to dryness and the residue was crystallized from methanol-ethyl acetate-heptane to afford gabapentin hydrochloride.

In US 4956473, the lactam of formula 3 having an extra carbethoxy groups has been synthesized and hydrolyzed with 1 : 1 hydrochloric acid with concomitant removal of the carbethoxy group to afford gabapentin hydrochloride.

In US 4958044, a solution of (1-cyanocyclohexyl) malonic acid dimethyl ester in ethanol was hydrogenated at 10 bars of hydrogen pressure and 90ºC on 3g Raney Nickel for 4.5 hours. The solution was filtered and the filtrate evaporated to give 2-aza-(4-methoxy- carbonyl) spiro (4,5) decan-3-one (carbethoxy gabalactam). This was mixed with 20% hydrochloric acid and stirred under reflux for 24 hours. The solution was evaporated to dryness and the residue worked up to give gabapentin hydrochloride. Other methods to synthesize gabapentin directly without the intervention of gabalactam or gabapentin hydrochloride have also been described. In US 5095148, US 5135455, US 5136091, US 5149870 & CA 203017, (1-cyano cyclohexyl) acetic acid benzyl ester was hydrogenated in methanol using 5% Rhodium on carbon catalyst at 10 bars of hydrogen pressure for 23 hours at room temperature. Filtration of the mixture, concentrating the filtrate and diluting with ethanol gave a 27% yield of gabapentin. In EP 414262B1, 1-cyano cyclohexene acetic acid was hydrogenated on Raney nickel to produce gabapentin. In US 6294690, benzonitrile was subjected to Birch reduction with lithium and liquid ammonia and the reduction intermediates trapped with ethyl bromo acetate. The resultant product was hydrolysed to (l-cyanocyclohexa-2,5-dienyl) acetic acid which was hydrogenated in methanolic ammonium hydroxide for 3.5 hrs at 5OºC and 50 psi hydrogen pressure and on 5% palladium charcoal catalyst. The mixture was filtered and the filtrate was concentrated to give crude gabapentin.

WO 2000/039074 describes the synthesis of gabapentin by hydrogenation of 1- nitromethylcyclohexyl acetic acid benzyl or diphenylmethyl ester. US 2005/0148792 report the formation of ethyl- 1-formylcyclohexane acetate by alkylation of the enamine of cyclohexanecarboxaldehyde with ethylbromoacetate. Hydrolysis of ethyl- 1-formylcyclohexane acetate to 1-formylcyclohexane acetic acid and reductive amination with ammonia leads to gabapentin. Alternatively, conversion to the oxime followed by catalytic hydrogenation affords gabapentin. If ester is used instead of the free acid in the above exercises, gabalactam is formed which is hydrolyzed to gabapentin hydrochloride. The preparation of gabapentin by reduction of 1-oximinomethylcyclohexane acetic acid is also claimed in WO 02/074727.

CN 1297885 provides a preparative process for 1 ,1-cyclohexyloxalic acid amide as an important intermediate for gabapentin. Gabapentin hydrochloride has been obtained in WO 2004/031 126 directly from cyclohexane-l ,l-diacetic acid imide by treatment with sodium hypochlorite followed by with HCl.

By far the most widely used procedure for the preparation of gabapentin appears to be the removal of acid from its acid addition salt, particularly HCl from its hydrochloride salt. This has been accomplished in various ways, neutralization with various bases in different solvents and diverse conditions, the bases being mostly amines but a few using aqueous sodium hydroxide. In other processes, solutions of the hydrochloride are passed through various ion exchange resins, mostly basic and some acidic, all of which except for four processes use a basic ion exchange resin (US 402 4175, US 4894476, US 4960931 & US 6054482; CA 1085420; EP 340677, EP 414263, WO 9914184 & 0001660) wherein the hydrochloride was mostly dissolved in water or some times in water and an alcohol.

In US 4024175, gabapentin was obtained from its hydrochloride by treatment with a basic ion exchanger and crystallization from ethanol-ether. No experimental details are given in this patent. In US 4894476, US 4960931, US 6054482, and EP 340677, a solution of gabapentin hydrochloride in deionized water was poured onto a column of Amberlite IRA-68 in the OH form and the column was eluted with deionized water. The eluate was concentrated on a rotovap at about 29-31ºC in vacuum to slurry. The slurry was mixed with isopropanol and cooled to give gabapentin monohydrate. This is further crystallized from methanol- isopropanol to give anhydrous gabapentin.

In CA 1085420, gabapentin benzenesulphonate salt was converted to gabapentin by passing through Amberlite IR 45.

In EP 414263, gabapentin hydrochloride was converted to gabapentin by deionising with the ion exchange resin IRA 68.

In WO 0001660, a solution of gabapentin hydrochloride in water was passed over Relite EXAlO resin and the eluate was concentrated under vacuum. The concentrate was treated with 2-methoxy ethanol and a mixture of water and 2-methoxy ethanol was distilled out. Isopropanol was added to the resultant suspension; the mixture was heated to 6OºC for 30 minutes and cooled. After 2 hours at -5 to -10ºC, the precipitate was filtered to give gabapentin.

Among the exceptions, in one case de-ionisation has been carried out in methanol. Thus in EP 1174418 Al and WO 200064857, deionisation of a solution of gabapentin hydrochloride in methanol was achieved by passing through a weakly basic ion exchange resin BAYER MP-2. The methanolic eluate was concentrated by low-pressure distillation below 3OºC to give a dense suspension which was dissolved in methanol- water at 65ºC cooled and treated with isopropanol to give pharmaceutical grade gabapentin.

In WO2006/09028, gabalactam was hydrolysed with aqueous hydrobromic acid to precipitate gabapentin hydrobromide which was neutralized in an alcoholic solution with an ion exchange resin.

In another process reported in WO 00/58268, an aqueous solution of gabapentin hydrochloride was neutralized with IM NaOH to a pH of 7.14 and subjected to dia filtration at about 22ºC, using a nano filtration multiplayer composite membrane having high selectivity for organic compounds with molecular weight higher than 150 and low selectivity to inorganic monovalent ions. The resultant solution was concentrated under reduced pressure below 35ºC and gabapentin was precipitated by isopropanol and crystallized from methanol.

In a process presented in WO 02/34709, gabapentin hydrochloride, obtained as a solution in n-butanol was poured over strong cationic resin (IMAC HP 1/10). After washing the column with water, gabapentin was eluted with aqueous ammonia. The ammoniacal solution was evaporated below 4OºC to a thick residue, which was heated with methanol and then stirred with isopropanol. The mixture was filtered to give gabapentin.

In WO 03089403 gabapentin sodium salt was precipitated directly from the Hoffmann degradation solution and converted to its hydrochloride in isopropanol which was then deionised by treating with a weak resin to give gabapentin.

In a process described in US 6255,526 Bl , gabapentin hydrochloride was suspended in ethyl acetate and stirred with tri-n-butyl amine at 25ºC for 2 hours. The precipitated gabapentin was collected by filtration and stirred with methanol at 25ºC for 14 hours and filtered off.

US 7071356 teach removal of hydrogen chloride from gabapentin hydrochloride by treatment with ethylene oxide.

It can be seen from the above prior art literature, the process for the preparation of gabapentin is to access gabapentin hydrochloride by a suitable method and then subjecting it to ion exchange treatment. This process leads to the formation of gabapentin, mostly an aqueous solution, which is then evaporated. This process has to be conducted at a low temperature of 25 to 4OºC and a high vacuum in the range of 1 to 2 torr as otherwise lactamisation results leading to contamination of the resulting product. Water, having a low vapour pressure, the process of evaporation will be tedious and time consuming. In addition the use of a high vacuum for such long lengths of time will consume much energy. Hence the process becomes cost-inefficient and user un-friendly and therefore not be suitable for industrial applications.

It is obvious that an ideal process for getting gabapentin from the salt would be one wherein an aqueous solution of the salt such as hydrochloride is dissolved in water and neutralized with a base such as aqueous sodium hydroxide; gabapentin should be preferably precipitated and filtered off.

In devising an industrially viable process for converting gabapentin hydrochloride to gabapentin, one has to ensure that the final product passes stringent pharmacopoeial specifications. In addition there have been many patents/patent applications on the characteristics of gabapentin obtained from certain processes which are listed below; Polymorph Patent/Patent Application

Form II Considered to be the form disclosed in pioneer patent

Form I Gabapentin monohydrate US 4894476 & 4960931 Form III US 6255526

New anhydrous form US '6521787

Dehydrates A and B US 2003/0092933

Form IV WO 2004/106281 & WO 2004/11034 US 6054482 claims that only by using the ion exchange method, gabapentin hydrochloride will give the pure amino acid with less than 0.5% of residual gabalactam and 20ppm of chloride. Above these levels, the storage stability of gabapentin is adversely affected, with build up of toxic gabalactam to undesirable levels.

Another important aspect to be considered while developing a process for the preparation of gabapentin from its hydrochloride is the purity of Gabapentin which is to be used in its pharmaceutical formulations. This aspect, which is a recent development, is concerned with the stringent specifications proposed by the Pharmaceutical Forum. Some of the important specifications stipulated and which are relevant to the present invention, are the following: 1. Chloride content NMT I OO ppm

2. Gabalactam content less than 0.1 %

3. Impurity with RF 0.5 relative to gabapentin less than 0.-2%

4. Any other individual impurity less than 0.1%

5. Total impurities less than 0.5%, excluding the impurity mentioned in item 3

The specifications of individual formulators are even more stringent with limits wherein the limitation of gabalactam should be less than 0.05% and impurity with RF 0.5 relative to gabapentin is less than 0.1%. In US 6518456, gabapentin hydrochloride was dissolved in water and treated with aqueous NaOH to a pH of 7.1 -7.2, followed by filtration of gabapentin and crystallization from water or aqueous ethanol. The method is cumbersome.

In the Indian Patent No. 186285, a process for the preparation of gabapentin has been disclosed which produces a substantially pure gabapentin. The process describes isolation of substantially pure 1 -(aminomethyl) cyclohexaneacetic acid directly from an aqueous solution of its acid addition salt. The acid addition salt used was an addition product of l-(aminomethyl)cyclohexaneacetic acid with a mineral acid selected from hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, or with an organic acid selected from Ci to Ci₂ aliphatic carboxylic acid, Ci to C₇ aliphatic sulphonic acid, aryl sulphonic acid and a polycarboxylic acid. The said process comprised of: adding a base to an aqueous solution of the l-(aminomethyl)cyclohexaneacetic acid addition salt to adjust the pH in the range of 6.7 to 8 to precipitate l-(aminomethyl)cyclohexaneacetic acid, followed by washing the precipitated l-(aminomethyl)cyclohexaneacetic acid with a water miscible organic solvent, and drying the precipitated l-(aminomethyl)cyclohexaneacetic acid to obtain substantially pure l-(aminomethyl)cyclohexaneacetic acid which contains less than 0.2% 2-azaspiro[4,5]decan-3-one (gabalactam). The base employed in the process was an alkali or alkaline earth metal hydroxide or carbonate.

The preferred base is an alkali metal hydroxide. More preferably the base is sodium hydroxide. During the treatment with hydroxide base in the process, the pH is adjusted from an acidic pH to a pH in the range of 6.7 to 8, preferably in the range of 7.2 to 7.8. The adjustment of pH with hydroxide base is carried out at temperature between 0 to 5OºC, preferably between 10 to 4OºC and more preferably between 15 to 25°C. After adjusting the pH the reaction mixture is allowed to stand for sufficient time ranging from 1 to 12 hour for ^' efficient crystallization of l-(aminomethyl)cyclohexaneacetic acid. The crystallized 1- (aminomethyl) cyclohexaneacetic acid is washed with a water-miscible organic solvent, preferably acetone and dried to obtain substantially pure anhydrous l -(aminomethyl) cyclohexaneacetic acid.

The inventors tried to repeat the above-explained process by following Example 2 of Indian Patent No. 186285. The gabapentin so prepared was not within the pharmacopoeial specifications explained above and found to contain unacceptably large amount, namely more than 3% versus less than 100 ppm of chlorides and total impurity levels of more than 1.5% as against 0.5% required by pharmacopoeia. Therefore, the inventors observed that the process as disclosed and claimed in Indian Patent No. 186285 seemed to be not suitable for the preparation of gabapentin satisfying pharmacopoeial specifications mentioned above.

Systematic and sustained investigations made by the inventors with (i) various volumes of water for dissolving gabapentin hydrochloride, (ii) various strengths of neutralizing alkali, (iii) various temperatures of neutralization, (iv) different aging times of the precipitate, (v) various compositions of liquids for washing the filter cake, and (vi) different crystallization procedures resulted in developing an improved process for the preparation of gabapentin. Gabapentin thus prepared by the process developed meets the stringent pharmaceutical stipulations and also results in good yields (say 40 to 60%) with total impurity levels less than 0.5% and chloride contents less than 100 ppm as required by pharmacopoeia. In addition the inventors have reported a procedure of converting gabapentin in mother liquors to gabalactam which could be recycled to give additional gabapentin.

Accordingly the invention disclosed in PCT/IN02/00224 provided a process for the preparation of gabapentin comprising of strictly defined concentrations and quantities of gabapentin hydrochloride, aqueous alkali and water, and reaction parameters such as temperature and time. The international application reported 10 examples at the laboratory level using gabapentin hydrochloride ranging from 100 to 300 g. T he crude gabapentin obtained from neutralization had varying degrees of moisture from 12 to 17% and not being free-flowing was rather difficult to handle, particularly at production levels although it was satisfactory for other parameters. The problem appeared to arise from nonhomogenity of the reaction mass during neutralization.

It is clear from PCT/IN02/00224 that a better process is needed to give gabapentin of more uniform characteristics from the neutralization reaction. This is particularly necessary when operating on production levels. Hence efforts were made to evolve a process that would lead to gabapentin of desired uniform characteristics in commercial quantities. Summary of the invention

The present invention is directed to crystalline forms of gabapentin and processes for preparing the same. A primary aspect of the present invention relates to crystalline forms of gabapentin Form II or Form IIB and its process of preparation, said process comprising treating an aqueous solution of gabapentin hydrochloride hemihydrate with a base to reach pH about between 7.0 and 7.5 to obtain a thick mass; stirring said thick mass followed by centrifuging to obtain gabapentin hemipentahydrate of form I A or I B; and crystallizing gabapentin hemipentahydrate using methanol, isopropanol and optionally water to obtain gabapentin form II or II B.

Another aspect of the present invention relates to crystalline forms of gabapentin hemipentahydrate of form I A or I B, used in the preparation of gabapentin form II and form IIB. The gabapentin forms IA and IB are hydrated, preferred forms of gabapentin contain about 20% of water by weight and this corresponds to hemipentahydrate. This hemipentahydrate of form I A or I B is prepared by the process comprising treating an aqueous solution of gabapentin hydrochloride hemihydrate with a base to reach pH about between 7.0 and 7.5 to obtain a thick mass; stirring said thick mass followed by centrifuging. These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This Summary is provided to introduce a selection of concepts in a simplified form. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. Brief description of the drawings

The above and other features, aspects, and advantages of the subject matter will become better understood with regard to the following description, appended claims, and accompanying drawings where:

Fig. 1 shows an infrared spectrum of gabapentin form IA.

Fig. 2 shows a characteristic powder X-ray diffraction pattern of gabapentin form IA. Fig. 3 shows a differential scanning calorimetry thermogram of gabapentin form IA. Fig. 4 shows an infrared spectrum of gabapentin form IB.

Fig. 5 shows a characteristic powder X-ray diffraction pattern of gabapentin form IB.

Fig. 6 shows a differential scanning calorimetry thermogram of gabapentin form IB.

Fig. 7 shows an infrared spectrum of gabapentin form HB. Fig. 8 shows a characteristic powder X-ray diffraction pattern of gabapentin form HB. Fig. 9 shows a differential scanning calorimetry thermogram of gabapentin form HB.

Detailed description of the invention

The present disclosure provides a process for preparing gabapentin comprising treating an aqueous solution of gabapentin hydrochloride hemihydrate with a base to reach pH about between 7.0 and 7.5 to obtain a thick mass; stirring said thick mass followed by centrifuging to obtain gabapentin hemipentahydrate of form I A or I B; and crystallizing gabapentin hemipentahydrate of form I A or I B using methanol, isopropanol and optionally water to obtain gabapentin form II or II B.

An embodiment of the present disclosure provides a process for preparing gabapentin wherein crystallizing gabapentin hemipentahydrate of form I A or I B is by using methanol, isopropanol and water to obtain gabapentin form II. Another embodiment of the present disclosure provides a process for preparing gabapentin wherein crystallizing gabapentin hemipentahydrate of form I A or I B is by using methanol and isopropanol to obtain gabapentin form II B.

Another embodiment of the present disclosure provides a process for preparing gabapentin wherein the gabapentin hydrochloride hemihydrate is prepared by a process comprising; heating gabalactam with concentrated hydrochloric acid to obtain a reaction mixture; cooling and slurrying said reaction mixture in presence of a hydrocarbon solvent; and filtering and washing with acetone to obtain gabapentin hydrochloride hemihydrate.

Yet another embodiment of the present disclosure provides a process for preparing gabapentin wherein the base is selected from a group consisting of alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides and alkaline earth metal carbonates.

Further an embodiment of the present disclosure provides a process for preparing gabapentin wherein the base is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. Another embodiment of the present disclosure provides a process for preparing gabapentin wherein the pH is 7.25.

Still another embodiment of the present disclosure provides a process for preparing gabapentin wherein gabapentin (on dry basis): methanol: isopropanol: water are in the ratio 1 : 3.5 to 5.0: 4.0 to 6.0: 0.3 to 0.5 (w/v/v/v) respectively. Yet another embodiment of the present disclosure provides a process for preparing gabapentin wherein gabapentin (on dry basis): methanol: isopropanol are in the ratio 1 : 4.5 to 5.5: 5.5 to 6.5 (w/v/v) respectively.

Further embodiment of the present disclosure provides a process for preparing gabapentin wherein the hydrocarbon solvent is selected from toluene, xylene, hexane, heptane or isooctane.

In an embodiment of the present disclosure, it provides a crystalline form of gabapentin form IA, which is gabapentin hemipentahydrate characterized by peaks in powder X-ray diffraction pattern at 6.09, 6.16, 12.21, 18.32, 24.35, 24.45, 26.18, 28.20, 32.12, 34.83, 38.20, 43.42 ± 1 degrees two-theta and bands in the IR spectrum at 1653.66, 1556.27, 1454.06, 1399.10, 1290.14, 1265.07, 1208.18, 1174.44, 1156.12, 1116.58, 1088.62, 1025.94, 967.13, 926.63, 878.42, 848.53, 788.74, 721.25, 650.86, 575.65, 554.43, 512.97, 474.44, 445.48, and 430.05 ± 2 cm-1. Further embodiment of the present disclosure provides a crystalline form of gabapentin form IA which is further characterized by a thermal analysis result indicative of melting point of 171.50± 2ºC.

Yet another embodiment of the present disclosure provides a crystalline form of gabapentin form IA which is further characterized by a thermal analysis result, wherein the result is a differential scanning calorimetry thermogram taken at a heating rate of

10°C/minute in a closed pan that exhibits a melting endotherm with a maximum at 171.50±

2ºC.

Still another embodiment of the present disclosure provides a crystalline form of gabapentin form IA which is further characterized by a thermal analysis result, wherein the result is a differential scanning calorimetry thermogram taken at a heating rate of

10°C/minute in a closed pan that exhibits a melting endotherm with a magnitude of 21 1.8 joules per gram.

An embodiment of the present invention is to provide a crystalline form of gabapentin form IB, which is gabapentin hemipentahydrate, characterized by peaks in' powder X-ray diffraction pattern at 6.21, 12.28, 18.38, 24.52, 26.30, 28.28, 31.60, 32.26,

34.37, 34.92 and 43.47 ± 1 degrees two-theta and bands in the IR spectrum at 1642.09,

1584.24, 1532.17, 1509.99, 1460.81, 1418.39, 1399.10, 1334.50, 1291.1 1, 1275.68,

1230.36, 1209.15, 1177.33, 1 157.08, 1 1 14.65, 1089.58, 1043.30, 1025.94, 971.95, 925.66, 883.24, 848.53, 787.78, 758.85, 704.86, 649.89, 616.15, 568.90, 507.19, and 441.62 ± 2 cm-

I

. The crystalline form of gabapentin form IB is further characterized by a thermal analysis result indicative of melting point of 68.18± 2ºC.

The crystalline form of gabapentin form IB is further characterized by a thermal analysis result, wherein the result is a differential scanning calorimetry thermogram taken at a heating rate of 10°C/minute in a closed pan that exhibits a melting endotherm with a maximum at 68.18± 2ºC.

The crystalline form of gabapentin form IB is further characterized by a thermal analysis result, wherein the result is a differential scanning calorimetry thermogram taken at a heating rate of 10°C/minute in a closed pan that exhibits a melting endotherm with a magnitude of 70.07 joules per gram.

Gabapentin hydrochloride hemihydrate required for the preparation of gabapentin hemipentahydrate is prepared from gabalactam according to the Applicant's co-pending Indian Patent Application No, 1845/CHE/2005. The processes are uniquely suited to manufacture ton quantities.

Approximately 800Kg (3695 mol) of gabapentin hydrochloride hemihydrate prepared by hydrolysis of gabalactam with concentrated hydrochloric acid is charged to a glass-lined reactor and dissolved in about 1.5 parts by volume of purified water. The resulting solution is cooled by chilled water to 5-15ºC and kept stirred while a solution of about 0.175 parts of caustic soda flakes in approximately 0.250 parts by volume of purified water and cooled to 25 to 3OºC is pumped into the glass lined reactor slowly, keeping the temperature below 15ºC. The resulting mass is kept intimately mixed under recirculation through a slurry pump. The addition is carried out for about 4 hours and the mixture reaches a final pH of 7.25. It is kept stirred at 9ºC for 1 hour and centrifuged in a baglifting SS centrifuge at 900 rpm in three lots with a final spin drying for a minimum of 20 minutes for each lot. The three lots of free flowing hydrated gabapentin are collected to give about 600Kg containing about 20% moisture, corresponding to gabapentin hemipentahydrate, representing about 480 Kg of the anhydrous material.

The collective experience of several batches of gabapentin hemipentahydrate thus manufactured shows that the gabapentin so produced has fixed characteristics, containing about 20.35% moisture, corresponding to a hemipentahydrate (calcd. 20.8%), with a standard deviation of 1.23%. Thus the production exercises surprisingly gave a consistent but differently hydrated gabapentin designated as gabapentin form IA, from the one reported in PCT/IN02/00224 which lacked consistency conspicuously. The gabalactam content of the gabapentin hemipentahydrate by the present process at this technical stage itself is very low with an average of 0.0372% and a standard deviation of 0.0157%, already well within the pharmacopoeial limit of gabapentin API. The chloride content in this campaign is on the average 0.936% with a standard deviation of 0.199%. Figures 1 , 2 and 3 represent the IR, XRPD, and DSC of a standard batch of gabapentin hemipentahydrate and Table 1 shows the 2Θ values and d-spacings.

The gabapentin hemipentahydrate also precipitates in another free flowing crystalline form, designated as gabapentin form IB, characterized by IR, XRPD, and DSC shown in figures 4, 5 and 6 with Table 2 showing the 2Θ values and d-spacings,

The gabapentin formulations use only the anhydrous amino acid having the polymeric form II. Gabapentin hemipentahydrate (gabapentin form IA or IB) on crystallization from methanol and isopropanol yields a new polymeric form, designated as gabapentin form HB, characterized by IR, XRPD, and DSC shown in figures 7, 8 and 9 with Table 3 showing the 2Θ values and d-spacings.

Further, Gabapentin hemipentahydrate (gabapentin form IA or IB) on crystallization by dissolution in methanol containing defined amounts of additional water followed by isopropanol gave gabapentin form II, characterized by IR, XRPD, and DSC.

Yet another embodiment of the present invention provides a crystalline form of gabapentin form IIB characterized by peaks in powder X-ray diffraction pattern at 6.07, 7.84, 12.14, 15.01 , 15.95, 16.39, 16.95, 17.58, 18.16, 18.85, 19.67, 20.76, 24.50, 25 12, 26.46, 28.16, 28.87, 30.14, 30.73, 31.46, 33.28, 34.77, 36.20, 36.76, and 37.11 ± 1 degrees two-theta and bands in the IR spectrum at 1644.02, 1583.27, 1533.13, 1462.74, 1399.10, 1335.46, 1291.11, 1231.33, 1208.18, 1177.33, 1157.08. 1115.62, 1089.58, 1043.30, 1024.98, 970.98, 925.66, 883.24, 848.53, 788.74, 758.85, 703.89, 675.93, 647.97, 615.18, 576.61, 511.04, 457.05, and 437.76 ± 2 cm^-1.

The crystalline form of gabapentin form IIB is further characterized by a thermal analysis result indicative of melting point of 175.78± 2ºC.

The crystalline form of gabapentin form IIB is further characterized by a thermal analysis result, wherein the result is a differential scanning calorimetry thermogram taken at a heating rate of 10°C/minute in a closed pan that exhibits a melting endotherm with a maximum at 175.78± 2°C.

The crystalline form of gabapentin form IIB is further characterized by a thermal analysis result, wherein the result is a differential scanning calorimetry thermogram taken at a heating rate of 10°C/minute in a closed pan that exhibits a melting endotherm with a magnitude of 328.2 joules per gram.

EXAMPLES

The process steps of the present invention are described in the following examples, which are only illustrative in nature and should not be construed as limiting the scope of the invention in any manner. Example 1

Synthesis of gabalactam from cyclohexane-l,l-diacetic acid through hypobromite route a) A round-bottomed flask equipped with stirrer, thermometer and heating arrangement and scrubber for scrubbing carbon dioxide and ammonia is charged with 1,1- cyclohexane diacetic acid (diacid-200g, 1.00 mol) and urea (6Og, 1.00 mol). The mixture is slowly heated so as to attain a temperature of 90-95ºC when it changes to a molten mass. At this stage evolution of ammonia and carbon dioxide is noticed; the stirrer is started now and the homogeneously stirring mixture is heated to 14OºC slowly and steadily over a period of 30-40 minutes. Once the desired temperature is reached, the material is kept stirring at that temperature for a period of 1-2 hours or until the evolution of gases has ceased. The reaction mixture is allowed to cool down to 14OºC. If it is cooled further the imide (Formula 4) is obtained as a solid of 96% purity. If the melt is dropped into water the imide (Formula 4) is precipitated and can be filtered off, purity 99% and m.p. 169-170ºC.

Formula 4 b) In another flask equipped with stirrer and cooling facility is charged caustic lye (48%, 40Og, 22.2 mol) and heated to 5OºC. The reaction mixture obtained above from the condensation of diacid with urea is added to the caustic lye over a period of 1 hr so as to maintain the temperature below 65ºC. Once the addition is complete the mixture is stirred vigorously for another 1 hour and cooled to room temperature or 30 ºC. c) In another round bottomed flask caustic lye (300ml) and water (800 ml) are taken and cooled to 0-5ºC. The reaction mixture is stirred well and bromine (165g, 1.03 mol) is added slowly keeping the temperature of the reaction below 5ºC, Once the bromine addition is completed, the reaction mixture is stirred at this temperature for another 30- 45 min. d) To the hypobromite solution as obtained in step (c), is added the solution obtained in step (b) over a period of 2-3 hours maintaining the temperature of the reaction below 5ºC. Once the addition is complete, the reaction mass is stirred for another 1 hour.

Slowly the temperature of the reaction mixture is raised to room temperature or up to 3OºC. The reaction mixture is heated to 80-85ºC and maintained at temperature for another 2-3 hours. The reaction mass is then cooled to 50-55ºC and toluene (33Og) is added to the mixture and stirred. The stirring is stopped and allowed to settle to separate into layers. The aqueous layer is extracted with toluene (2 times) and the organic layers are combined. Activated charcoal is added to the toluene layer and stirred at room temperature. Charcoal is removed by filtration and the organic layer is taken up for concentration under vacuum. The solvent is distilled off completely under vacuum to obtain gabalactam (Formula 3), m.p. 88-90ºC and above 99% purity (105-11Og, 68%- 72% or 0.525-0.55 w/w based on diacid input).

Example 2

Synthesis of gabalactam from cyclohexane-l,l-diacetic acid through hypochlorite route a) A 1 litre round bottomed flask equipped with stirrer, thermometer, heating arrangement and scrubber for carbon dioxide and ammonia is charged with 1 , 1 -cyclohexane diacetic acid (diacid, 20Og, 1 mol) and urea (6Og, 1 mol). The mixure is slowly heated so as to obtain a temperature of 70-95ºC when it changes to a molten mass. At this stage evolution of ammonia and carbon dioxide is noticed. The stirrer is started now and the homogeneously stirring mixture is heated slowly and steadily to 14OºC and maintained at the same temperature for 1 hour till the evolution of gases ceases. b) In another 1 litre round bottomed flask fitted with overhead stirrer, thermometer and condenser, caustic soda lye (48%, 1.1 mol) and water (40Og, 22.2 mol) are charged and the solution is heated to 5OºC. The molten mass from step (a) is slowly dropped into this solution during Vi hr and the temperature of the reaction mixture is kept at 65ºC for 2 hours. The solution is cooled to 3OºC. c) In a four-necked 3-litre flask provided with a stirrer, thermometer and condenser, caustic lye (310g, 48% 3.7 mole) and water (40Og, 22.2 mole) are charged and the flask is cooled down to -5ºC. Chlorine gas (78.1 g, 1.1 mole) is bubbled in slowly during 2 hours, maintaining the temperature at -5°C to OºC. The hypochlorite solution is stirred at the same temperature range for another Vi hour.

The solution from step (b) is now dropped in during 2 hours, maintaining the temperature at -5 to OºC. The solution is stirred for a further Vi hour. The temperature is then slowly raised to 3OºC. Then the temperature is raised to 80-85ºC and maintained at that level for 2 hours. The reaction mass is cooled to 5O-55°C and extracted with toluene (330g) by stirring together for Vi hour. The layers are separated. The aqueous layer is again heated at 80-85ºC for 2 hours, cooled to 50-55ºC and extracted with toluene (33Og) by stirring together for Vi hour. The layers are separated. The aqueous layer is heated once again at 80-85ºC for 2 hours, cooled to 50-55ºC and extracted with toluene (146g). The combined toluene layers are stirred with activated charcoal (7g) for Vi hour at 30ºC and filtered through a hyflo bed (1Og). The filtrate is washed with water (400ml) three times; the toluene layer is separated and the solvent is distilled off completely to give gabalactam (Formula 3), m.p. 88-9OºC and purity 98.2% (105-1 1Og; yield 68-

72%).

Example 3

Hydrolysis of gabalactam to gabapentin hydrochloride. A mixture of 800 Kg (5229 mol) of gabalactam and 880 litres (10120 mol) of concentrated hydrochloric acid are heated in a steam jacketed vessel at 95-100ºC for about 15 hours under vigorous stirring. The reaction mass is cooled to 70-75ºC during 6 hours. 1050 litres of toluene are charged into the vessel. The reaction mass is cooled to about 45ºC and kept at that temperature for 30 minutes. It is then filtered through a Nutsch filter using nitrogen pressure. 1600 Kg of acetone are charged to the filter and the agitated mass is heated to 30 to 35ºC for 30 min and filtered. Gabapentin hydrochloride is sucked free of water and acetone in nitrogen atmosphere. 800 Kg of gabapentin hydrochloride containing about 4.25% water of crystallization (corresponding to hemihydrate) and traces of acetone are obtained, lactam content about 0.2%.

Example 4

Preparation of gabapentin hemipentahydrate from gabapentin hydrochloride hemihydrate 800 Kg (3695 mol) of gabapentin hydrochloride hemihydrate and 1200 Kg of purified water are stirred and heated at 40 to 45ºC for about thirty minutes until a clear solution is obtained. The solution is cooled to 5 to 1OºC during about 3 hours. Separately 140 Kg (3500 mol) of soda flakes are dissolved in 200 litre of purified water and the solution is cooled to about 25ºC. The caustic solution is added slowly to gabapentin hydrochloride solution during about 4 hours, keeping the temperature of the reaction mass strictly between 5 to 15ºC and the pH between 7 and 7.5. During this period gabapentin starts crystallizing out forming very soon a thick mass which is vigorously recirculated through a slurry pump. After checking that the final pH is stabilized around 7.25, the mass is maintained at about 12ºC for 1 hour. Gabapentin is centrifuged in lots in a centrifuge of 900 rpm for 20 minutes. The lots are combined to give about 600 Kg of gabapentin of form IA as a white to off- white free flowing crystalline powder. It has a water content of 20.5%, gabalactam 0.04%, chloride 1.13%, and sulphated ash 0.65%. The weight of gabapentin form IA on dry basis is 480 Kg. m.p. 163-168ºC.

Example 5

Preparation of gabapentin form IIB: Crystallization of gabapentin hemipentahydrate from methanol and isopropanol

5 g of gabapentin hemipentahydrate (gabapentin form IA or form IB) is dissolved in 20 ml of hot methanol. The solution is diluted with 25 ml of isopropanol and cooled to OºC, then gabapentin of form HB crystallizes out.

Example 6

Preparation of anhydrous gabapentin, gabapentin form II, from gabapentin hemipentahydrate

580 Kg (on dry basis) of gabapentin form IA or form IB is suspended in 2240 litre of methanol in a steam-jacketed SS kettle and treated with 232 litre of purified water. The mixture is heated with stirring at 60 to 65ºC for about 30-40 minutes until dissolution is complete. A slurry of 6 Kg of activated carbon in 20 litre of methanol is charged into the vessel and the mixture is stirred at about 6OºC. It is then filtered through a sparkler filter. 3000 litre of isopropanol is added to the filtrate and the solution is cooled to 5ºC over 10 hours. Anhydrous gabapentin of form II precipitates during this period. This is centrifuged off and dried at about 4OºC in vacuum for around 4 hours. Yield 475 Kg. Advantages of the invention

The previously described versions of the subject matter and its equivalent thereof have many advantages, including those which are described below:

1. The process of the present invention yields anhydrous gabapentin of form II consistently about 50 %; 2. The form I used in the manufacture of gabapentin API of form II yielded by the process of the present invention is free flowing, uniform, crystalline solid and therefore, can be easily handled.

Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiment contained therein.

Claims

We Claim:

1. A process for preparing gabapentin comprising: treating an aqueous solution of gabapentin hydrochloride hemihydrate with a base to reach pH about between 7.0 and 7.5 to obtain a thick mass; stirring said thick mass followed by centrifuging to obtain gabapentin hemipentahydrate of form I A or I B; and crystallizing gabapentin hemipentahydrate of form I A or I B using methanol, isopropanol and optionally water to obtain gabapentin form II or II B.

2. The process as claimed in claim 1, wherein crystallizing gabapentin hemipentahydrate of form I A or I B by using methanol, isopropanol and water to obtain gabapentin form II.

3. The process as claimed in claim 1, wherein crystallizing gabapentin hemipentahydrate of form I A or I B by using methanol and isopropanol to obtain gabapentin form II B.

4. The process as claimed in claim Y, wherein the gabapentin hydrochloride hemihydrate is prepared by a process comprising: heating gabalactam with concentrated hydrochloric acid to obtain a reaction mixture; cooling and slurrying said reaction mixture in presence of a hydrocarbon solvent; and filtering and washing with acetone to obtain gabapentin hydrochloride hemihydrate.

5. The process as claimed in claim 1, wherein said base is selected from a group consisting of alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides and alkaline earth metal carbonates.

6. The process as claimed in claim 5, wherein said base is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

7. The process as claimed in claim 1, wherein said pH is 7.25.

8. The process as claimed in claim 2, wherein gabapentin (on dry basis): methanol:

^' isopropanol: water are in the ratio 1 : 3.5 to 5.0: 4.0 to 6.0: 0.3 to 0.5 (w/v/v/v) respectively.

9. The process as claimed in claim 3, wherein gabapentin (on dry basis): methanol: isopropanol are in the ratio 1 : 4.5 to 5.5: 5.5 to 6!5 (w/v/v) respectively.

10. The process as claimed in claim 4, wherein said hydrocarbon solvent is selected from toluene, xylene, hexane, heptane or isooctane.

11. Crystalline gabapentin hemipentahydrate of form I A, characterized by peaks in powder X-ray diffraction pattern at 6.09, 6.16, 12.21, 18.32, 24.35, 24.45, 26.18, 28.20, 32.12, 34.83, 38.20, 43.42 ± 1 degrees two-theta.

12. Crystalline gabapentin hemipentahydrate of form I B, characterized by peaks in powder X-ray diffraction pattern at 6.21, 12.28, 18.38, 24.52, 26.30, 28.28, 31.60, 32.26, 34.37, 34.92 and 43.47 ± 1 degrees two-theta.

13. Crystalline Form II B of gabapentin, characterized by peaks in powder X-ray diffraction pattern at 6.07, 7.84, 12.

14, 15.01,

15.95, 16.39,

16.95,

17.58, 18.16,

18.85,

19.67,

20.76, 24.50, 25.12, 26.46, 28.16, 28.87, 30.14, 30.73, 31.46, 33.28, 34.77, 36.20, 36.76, and 37.11 ± 1 degrees two-theta.