WO2004110342A2

WO2004110342A2 - Novel polymorph of gabapentin and its conversion to gabapentin form-ii

Info

Publication number: WO2004110342A2
Application number: PCT/IN2004/000163
Authority: WO
Inventors: Chava Satyanarayana; Gorantla Seeta Ramanjaneyulu; Indukuri Venkata Sunil Kumar
Original assignee: Matrix Laboratories Ltd
Priority date: 2003-06-12
Filing date: 2004-06-11
Publication date: 2004-12-23
Also published as: WO2004110342A3

Abstract

The present invention relates to Gabapentin, a useful agent for anti-convulsing. New form of Gabapentin Form-IV, a process for its preparation, and its conversion to Form-II by slurrying it in ethanol at a specified temperature.

Description

Novel polymorph of Gabapentin and its conversion to Gabapentin Form-II

The present invention relates to a novel crystalline form of Gabapentin, process for its preparation and its use in the preparation of Gabapentin Form-II.

Gabapentin (i.e. 1-aminomethyl-l-cyclohexaneacetic acid), is the active principle mainly

Gabapentin 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 Patents 4,024,175 and 4,087,544 discloses preparations starting from cyclohexane-1,1- 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 Patents 4,894,476 and 4,960,931 discloses 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. US Patent Application 2003/ 0009055, US Patents 6,528,682; 6,054,482; PCT Publication WO 02 /34,709, European patent 1,174,418, and US Patent 5,091,567, described 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 involves 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 filtration, distillation of solvent under vacuum at temperature below 35⁰C, addition of a second solvent, neutralization with a base at 20⁰C - 25⁰C₅ followed by isolation of the Form-Ill. The Form-Ill is slurried in methanol for an extended period of about 14 hrs at 25⁰C or • recrystallized from methanol to yield Gabapentin Form-II.

A 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.

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 60⁰C to about 65⁰C in different solvents. Further it is found that it 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 hypohalite 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 salt is then suspended in organic solvent(s), removed the inorganics and neutralized with base(s) in a specified temperature range, cooled to ambient temperature, followed by separation of Gabapentin Form-IV. Gabapentin Form-IV is further converted to Gabapentin Form-II by slurrying in ethanol at a specified temperature. The process scheme is represented below.

Ethaπol

Amide derivative Gabapentinhemisulfatehemihydrate Gabapentin Form-IV Gabapentin Form-I! or Gabapentin Hydrochloride

Fig. 1 X-ray diffraction pattern of the^' Gabapentin Form -IV

Fig. 2 FTIR spectrum of the Gabapentin Form - IV Fig. 3 X-ray diffraction pattern of the Gabapentin Form-II Fig. 4 FTIR spectrum of the Gabapentin Form -II

Fig. 5 X-ray diffraction pattern of the Gabapentin Form-Ill

Fig. 6 FTIR spectrum of the Gabapentin Form-Ill

The process of this invention comprising the steps of:

^■ Reacting 1,1-cyclohexane diacetic acid mono amide with alkali hypo halite solution, acidification with acid(s) in presence of organic solvent(s)

^■ Extracting the formed Gabapentin acid salt(s) into organic layer

^■ Separating the organic layer, drying over dehydrating agents ■ Adding ante solvent(s), followed by optional cooling to precipitate the

Gabapentin acid salt(s) and its isolation

^■ Dissolving Gabapentin acid salts in short chain alcohol

^■ Adjusting pH of the solution 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 in a specified temperature range

■ Separating 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 hemisulphate hemihydrate 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 (US. 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 -10⁰C to about 5⁰C, the preferred range being about -5⁰C to about 5⁰C. Acidification of the reaction mass to a pH of about 2.0 and preferably below 2.0 in the range of about 1.0 to about 1.5 is carried out with acids preferably with hydrochloric acid or sulphuric acid in presence of an organic solvent in a temperature range of about 15⁰C to about 25⁰C. The preferred organic solvent is n-butanol.

The reaction mixture is 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 anhydrous sodium sulphate and magnesium sulphate.

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 and their mixtures thereof.

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 25⁰C₅ stirred for about for sometime to get a clear solution. The temperature of the clear solution is raised above 60⁰C preferably between 60⁰C to 65⁰C, and pH is adjusted with base, the preferred ones being triethyl amine and di isopropyl ethylamine. Gradual cooling to about 10⁰C to 25⁰C, preferably between 20⁰C - 25⁰C, 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 45⁰C - 50⁰C.

The Gabapentin Form-IV is converted into Form-II by suspending in ethanol, raising the temperature to about 60⁰C - 65⁰C₅ maintaining the temperature for sometime followed by gradual cooling with stirring for about 1-2 hrs at temperature 20⁰C - 25⁰C. Gabapentin Form-II formed as the final product is separated, and dried to obtain the material of pharmaceutically acceptable quality.

Table 1. FTIR PEAKS OF GABAPENTIN FORM-IV, FORM-I, FORM-II AND FORM-HI

XRD PEAKS OF GABAPENTIN FORM-IV, FORM-I, FORM-H AND FORM-HI

The invention is now illustrated by a few non-limiting examples.

Example -I

Stage -1: Preparation of Gabapentin hydrochloride Sodium hydroxide (51 g) is dissolved in sodium hypochlorite solution (6.25%, 625 g) and cooled to 10⁰C. The solution is stirred for 10 - 15 min and further cooled to -5⁰C. In a separate flask, 1,1-cyclohexane diacetic acid monoamide (100 g) is dissolved in 4N Sodium hydroxide solution (150 ml) at 15⁰C - 20⁰C. The amide solution is slowly added to the sodium hypochlorite solution at temperature -5⁰C to -3⁰C. The solution is then maintained at about O⁰C for 2 hrs. The temperature is gradually raised to 20⁰C - 25⁰C and maintained at this temperature for 4 hrs. Sodium metabisulphite solution (5 g 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 20⁰C - 25⁰C, n-Butanol (200 ml) is added, 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 g). 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 5⁰C and stirred for 1 hr. The product is filtered, washed with di isopropyl ether (50 ml) and dried at 45⁰C - 50⁰C to constant weight and finally crystallized from tert. butanol - di isopropyl ether to get the pure hydrochloride.

The dry wt of the hydrochloride salt is 80.0 g corresponding to a yield of 75.0%

Stage - 2: Preparation of Gabapentin Form-IV from Gabapentin hydrochloride

Gabapentin hydrochloride salt (100 g) prepared in stage 1 is suspended in n-propanol

(1000 ml) and stirred at room temperature and filtered the solution to remove insolubles. The filtrate is slowly heated to 60⁰C - 65⁰C and the pH is adjusted to 7.2 by slow addition of di isopropyl ethylamine solution (180 ml in 180 ml of n-propanol). The reaction mass is gradually cooled to 20⁰C - 25⁰C over 30 min. The product is filtered, washed with n- propanol (50 ml) and dried at 45⁰C - 50⁰C to constant weight.

Dry wt of the Gabapentin form-IV is 49.5 g (Yield: 62%). XRD and IR is used to characterize the product (table 1)

Stage -3: Conversion of Gabapentin Form-IV to Gabapentin Form-II

Gabapentin Form-IV (40 g) prepared in stage 2 is suspended in ethanol (280 ml) and the temperature is raised to 65⁰C 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 50⁰C - 55⁰C to constant weight.

The dry weight of the Gabapentin Form-II is 36 g corresponding to a yield of 90%.

XRD and IR of this product matched those reported for Form- II Example-H

Stage -1: Preparation of Gabapentin hemisulphate hemihydrate Sodium hypochlorite solution (6.25%, 625 g) is cooled to 10⁰C and sodium hydroxide flakes (51 g) is dissolved in it by stirring for about 10 - 15 min and further cooled to -5⁰C. In a separate flaskl, 1-cyclohexane diacetic acid monoamide (100 g) is dissolved in 4N sodium hydroxide solution (150 ml) at 15⁰C - 20⁰C. The amide solution is slowly added to sodium hypochlorite solution at temperature -5⁰C to -3⁰C and then maintained at about O⁰C for 2 hrs. The temperature is then slowly raised to 20⁰C - 25⁰C and maintained for 4 hrs at 20⁰C - 25⁰C. Sodium metabisulphite solution (5 g in 10 ml water) is then added. The reaction mass is filtered to remove un-dissolved material. pH of the filtrate is adjusted to 9.0 by the addition of 1:1 dilute sulphuric acid at temperature of 20⁰C - 25⁰C. 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 g). 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 5⁰C and further cooled to about O⁰C - 5⁰C with constant stirring for 1 hr. The product is filtered, washed with di isopropyl ether (50 ml) and dried at 45⁰C - 50⁰C to constant weight.

The dry wt of Gabapentin hemisulphate hemihydrtae is 85 g corresponding to yield 73.8%.

Stage-2: Preparation of Gabapentin Form-IV from Gabapentin hemisulphate hemihydrate

The Gabapentin hemisulphate hemihydrate salt (100 g) prepared in stage- 1 is suspended in ethanol (700 ml) and stirred for 30 min. at room temperature. The insolubles are filtered and washed with ethanol (50 ml). The filtrate is heated to 60⁰C - 65⁰C and the pH of the filtrate is adjusted between 7.1 to 7.2 by slow addition of di isopropyl ethylamine solution (135 ml in 145 ml ethanol) at 60 - 65⁰C over 20 min. The reaction mass is then cooled to 20⁰C - 25⁰C over 30 min. The filtered product is washed with ethanol (50 ml) and dried at 45⁰C - 50⁰C to constant weight.

Dry wt of the Gabapentin Form-IV is 47.5 g corresponding to yield: of 63 %.

Stage -3: Conversion of Gabapentin Form-IV to Gabapentin Form-II Gabapentin Form-IV (40 g) prepared in stage- 2 is suspended in ethanol (240 ml) and the temperature is raised to 65⁰C, maintained for 90 min. at 65⁰C - 70⁰C then cooled to room temperature and stirred for 30min. at room temperature. The filtered product is washed with ethanol (25 ml) and dried at 50⁰C - 55⁰C to constant weight.

The dry weight of the Gabapentin Form-II is 36 g corresponding to yield: 90%

Claims

What is claimed is:

1. A crystalline Gabapentin Form-IV

2. A crystalline Gabapentin according to claim 1 characterized by an X-ray powder diffraction pattern having peaks at about 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 crystalline Gabapentin according to claim 1, further characterized by infra-red absorptions having peaks at 637, 707, 800, 846, 894, 985, 1086, 1196, 1235, 1289,

1302, 1376, 397, 1431, 1462, 1521, 1574 and 1622 cm-1

4. A process for preparing crystalline Gabapentin Form-IV, comprising the steps of

^■ Reacting 1,1-cyclohexane diaceticacid mono amide with alkali hypo halite , solution, acidification 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 agsnts

^■ Adding ante solveήt(s), followed by optional cooling to precipitate the Gabapentin acid salt(s) and its isolation ^■ Dissolving Gabapentin acid salts in short chain alcohol

^■ Adjusting pH of the solution with base(s) in a temperature range of about 60⁰C to about 65⁰C,

^■ Cooling the reaction mass to precipitate Gabapentin Form-IV

^■ Separating the formed Gabapentin Form-IV

5. A process for the preparation of Gabapentin Form-II comprising steps of

■ Reacting 1,1-cyclohexane diaceticacid mono amide with alkali hypo halite solution, acidification 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 ante solvent(s), followed by optional cooling to precipitate the Gabapentin acid salt(s) and its isolation

^■ Dissolving Gabapentin acid salts in a short chain alcohol

^■ Adjusting pH of the solution with base(s) in a temperature range of about 60⁰C to about 65⁰C₃

^■ 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 at a specified temperature range ^■ Separating Gabapentin Form-II followed by drying

6. A process as claimed in claim 4 and 5, wherein acidification is done with HCl and/ or sulphuric acid

7. A process as claimed in claims 4 and 5 wherein the Gabapentin acid salt formed is Gabapentin hydrochloride or Gabapentin hemisulfate hemihydrate when hydrochloric acid or sulphuric acid is used.

8. A process as claimed in claims 4 and 5, wherein the short chain alcohol is ethanol, n- propanol, n-Butanol

9. A process as claimed in claims 4 and 5, wherein the base is selected from Di isopropyl Ethylamine and tri ethylamine

10. A process as claimed in claims 4 and 5, wherein cooling is effected after pH adjustment is done to obtain Gabapentin Form- IV

11. A process as claimed in claim 5, wherein the conversion of Form-IV to Form-II is carried out at about 25⁰C to about 75⁰C in an ethanol