WO2009015685A1

WO2009015685A1 - Method for preparing polymorph form ii of gabapentin

Info

Publication number: WO2009015685A1
Application number: PCT/EP2007/057768
Authority: WO
Inventors: Maria Carmen Burgarolas Montero
Original assignee: Medichem, S.A.
Priority date: 2007-07-27
Filing date: 2007-07-27
Publication date: 2009-02-05
Also published as: EP2183211A1

Abstract

Method for preparing polymorph form II of gabapentin. This invention refers to an improved method for preparing polymorph Form II of gabapentin, and to the utility thereof as a starting product for the preparation of the marketed pharmaceutical speciality.

Description

METHOD FOR PREPARING POLYMORPH FORM II OF GABAPENTIN

FIELD OF THE INVENTION

The present invention may be included in the pharmaceutical field. Specifically, this invention refers to an improved method for preparing polymorph Form II of gabapentin.

BACKGROUND OF THE INVENTION

Gabapentin, [l-(aminomethyl)cyclohexyl] acetic acid is an anticonvulsant having the chemical structure:

Anticonvulsants are used to control seizure disorders. In this regard, gabapentin has been successfully used to treat and/or control seizures associated with cerebral diseases including, for example, epilepsy. Gabapentin has also been used to manage postherpetic neuralgia (i.e., the pain after "shingles") and it may also be useful for mood stabilization and treating anxiety. Although gabapentin is related to the brain chemical gamma amino butyric acid (GABA), its exact mechanism of action remains unknown.

Gabapentin is known to exist in at least three polymorphic forms that differ from each other based primarily on their crystal structure and associated water content:

• Form I is the monohydrate (gabapentin hydrate).

• Form II is anhydrous gabapentin, and is the form present in the marketed pharmaceutical speciality.

• Form III is another form of anhydrous gabapentin. The different forms of gabapentin can be readily distinguished based upon their IR spectra and x-ray diffraction patterns as discussed in U.S. Patent No. 6,255,526 and PCT Application No. PCT/YS97/23164 (Publication No. WO 98/28255).

A number of conventional methods are known for preparing gabapentin. Some of these methodologies are summarized in WO 2004/101489. Such methods include, for example, preparing gabapentin from cyclohexyl-l,l-diacetic acid via formation of the gabapentin hydrochloride ("gabapentin HCl") salt. Gabapentin HCl is then converted to gabapentin.

Further, U.S. Patent No. 6,054,482 discloses that in order to ensure the storage stability not only of the gabapentin active material but also of the corresponding pharmaceutical forms of preparation, the active gabapentin should be produced containing less than 20 ppm of an anion of a mineral acid, e.g. chloride ion.

Patent application WO 98/28255 discloses a method of converting gabapentin hydrochloride to gabapentin form II. The method comprises neutralizing gabapentin hydrochloride with an amine in different solvents so as to obtain a precipitate, which is gabapentin form III. Finally, it is necessary to reprocess said gabapentin form III by slurrying or crystallizing it in methanol, to be able to prepare the marketed gabapentin form II. This application is silent about the final chloride content of the obtained gabapentin form II, and it presents the disadvantage that the method disclosed there passes through polymorphic form III of gabapentin, which is different from the marketed form II, and hence needs to be transformed to gabapentin form II. Further, gabapentin form II as obtained, it could be contaminated with non-desirable form III.

WO2004/093779 reports the preparation of gabapentin form II by neutralizing a gabapentin hydrochloride solution in a short chain alcohol, preferably ethanol, with a base, preferably triethylamine or diisopropylethylamine, at temperatures of about 70 ⁰C, followed by slow cooling, to isolate gabapentin Form II. Said gabapentin Form II is further purified. However, the gabapentin form II finally obtained contains an amount of chloride ions in the range of about 20-100 ppm, an amount which can not ensure the stability of the product.

US 7151193 Bl also discloses a method for obtaining gabapentin form II directly from gabapentin hydrochloride by dissolving gabapentin hydrochloride in dry ethanol, filtering off the insoluble inorganic salts, then adding the filtered solution with tertiary amines, preferably the so-called "Hϋnig base" (N-ethyl-diisopropylamine), and a small amount of water. Upon cooling the resulting solution and seeding with gabapentin form II, the desired polymorph precipitates with content in chloride ions not higher than 200- 250 ppm. Further, the chlorine ions content may be reduced below 100 ppm by treatment with a mixture of ethanol and water. However, a content of chloride ions below 100 ppm is not a certainty for the storage stability of the gabapentin, stability than can only be assumed when the content of chloride ions is less than 20 ppm. Further, this method comprises large operational procedures which may be industrial impractical and technically unnecessary.

WO2004/101489 and EP1347951B1 describe the direct formation of gabapentin form II from gabapentin hydrochloride via neutralizing the gabapentin hydrochloride with an amine in water. However the water must be distilled off under reduced pressure, which may represent an important drawback when scaling-up the reaction. These applications are silent about the chloride content of the obtained gabapentin, which may be an important feature to ensure the stability of the product. DESCRIPTION OF THE INVENTION

Brief description of the invention

This invention refers to an improved method, method of the invention, for preparing polymorph Form II of gabapentin, and to the utility thereof as a starting product for the preparation of the marketed pharmaceutical speciality. The method of the invention comprises obtaining gabapentin Form II directly from gabapentin hydrochloride by using an amine base, which is suitable for industrial implementation, which affords gabapentin Form II containing chloride amounts lower than 20 ppm.

Therefore, the objective technical problem solved by the present invention refers to a simple, effective and economic method for obtaining gabapentin form II:

• directly from gabapentin hydrochloride and, therefore, avoiding intermediate steps in which the gabapentin form II is contaminated with other unwanted forms of gabapentin;

• containing chloride amounts not greater than 20 ppm and, therefore, ensuring the stability of the gabapentin form II which can be used directly as a starting product for the preparation of the marketed pharmaceutical speciality.

Although the State of the Art discloses different methods for producing gabapentin, none of said methods disclose the preparation of gabapentin directly from gabapentin hydrochloride, by using an amine base, which is suitable for industrial implementation, which affords gabapentin Form II containing chloride amounts not greater than 20 ppm which can be used directly as a starting product for the preparation of the marketed pharmaceutical speciality. So, the technical effect achieved by the present invention could not be easily or obviously materialized by any skilled person in the art who can deduce the solution proposed herein from the prior art and do it without any inventive ability. Therefore the present invention can be considered as involving inventive step.

Description of the figures

Figure 1. Infrared (IR) spectrum of Gabapentin Polymorph Form II.

Detailed description of the invention

The present invention provides a simple, effective and economic method for obtaining gabapentin form II directly from gabapentin hydrochloride using an amine base, which may be suitable for industrial implementation, which affords gabapentin Form II containing chloride amounts not greater than 20 ppm, and which hence can be used directly as a starting product for the preparation of marketed pharmaceutical speciality.

The method of the invention exposes that by (I) neutralizing gabapentin hydrochloride in a mixture of an organic solvent and water wherein the % content of water is between 5 and 30% with an amine, and (II) crystallizing the obtained product, gabapentin Form II containing chloride amounts not greater than 20 ppm is obtained.

Therefore, the first embodiment of the present invention refers to a method for producing gabapentin Form II containing chloride amounts not greater than 20 ppm, said method comprising: (I) combining gabapentin hydrochloride and a mixture of an organic solvent and water wherein the percentage content of water is between 5 and 30%, to form a suspension, (II) adjusting the pH of the suspension to 4.0-5.0 with an amine, to obtain a solution, (III) seeding the solution with gabapentin Form II, (IV) adjusting the pH of the suspension to 7.4-8.0 with an amine, to obtain a suspension, (V) isolating crude gabapentin Form II from the suspension, optionally (VI) suspending the crude gabapentin Form II in a mixture of an organic solvent and water wherein the % content of water is between 5 and 30% and isolating crude gabapentin Form II from the suspension, (VII) crystallizing crude gabapentin Form II, and (VIII) isolating gabapentin Form II containing chloride amounts not greater than 20 ppm.

In a preferred embodiment the method of the invention is characterized in that the percentage content of water in step (I) is preferably between 15 and 20%, and more preferably about 15%.

In another preferred embodiment the method of the invention is characterized in that the organic solvent of step (I) is selected from the group comprised by: ethanol, isopropanol or acetone, more preferably acetone.

In another preferred embodiment the method of the invention is characterized in that the volume of the mixture of an organic solvent and water of step (I) per Kg of gabapentin hydrochloride is about 3 L to about 8 L per Kg of gabapentin hydrochloride, preferably about 4.5 L to about 6 L per Kg of gabapentin hydrochloride.

In another preferred embodiment the method of the invention is characterized in that the pH of the suspension of step (II) is adjusted to about 4.5-5.0, more preferably to about 4.8.

In another preferred embodiment the method of the invention is characterized in that the amine of step (II) is a secondary or tertiary alkyl amine, preferably a secondary amine, more preferably diethylamine.

In another preferred embodiment the method of the invention is characterized in that the seeding with gabapentin form II of step (III) is performed with an amount of 0.22% of gabapentin form II with respect to the initial amount of gabapentin hydrochloride, preferably an amount of about 0.14% of gabapentin form II with respect to the initial amount of gabapentin hydrochloride.

In another preferred embodiment the method of the invention is characterized in that the pH of the suspension of step (IV) is adjusted to 7.2-8.4, preferably to 7.4-8.0 and more preferably to about 7.8.

In another preferred embodiment the method of the invention is characterized in that the amine of step (IV) is a secondary or tertiary alkyl amine, preferably a secondary amine, more preferably diethylamine. Preferably, the amine of step (IV) may be the same amine as step (II). The suspension obtained in step (IV) is stirred at 20-25 ⁰C for between 1-16 hours, preferably 2 hours. The resulting suspension is further cooled to 0- 5 ⁰C and stirred at this temperature for between 1-16 hours, preferably 2 hours.

In another preferred embodiment the method of the invention is characterized in that the isolation of the crude gabapentin Form II from the suspension of step (V) comprises filtering the suspension and washing the obtained solid at least twice with an organic solvent, preferably acetone.

In another preferred embodiment the method of the invention is characterized in that the percentage content of water in step (VI) is preferably between 15 and 20%, more preferably about 15%.

In another preferred embodiment the method of the invention is characterized in that the organic solvent of step (VI) is acetone.

The suspension obtained in step (VI) is heated at 30-40 ⁰C and stirred at this temperature for between 1-3 hours, preferably 1 hour. Afterwards, the resulting suspension is cooled to 20-25 ⁰C and stirred at this temperature for between 1-16 hours, preferably 2 hours. The resulting suspension is further cooled to 0-5 ⁰C and stirred at this temperature for between 1-16 hours, preferably 2 hours.

In another preferred embodiment the method of the invention is characterized in that the isolation of the crude gabapentin Form II from the suspension of step (VI) comprises filtering the suspension and washing the obtained solid at least twice with an organic solvent, preferably acetone.

In another preferred embodiment the method of the invention is characterized in that the crystallization of step (VII) comprises dissolving wet gabapentin in a mixture of methanol and water, and precipitating gabapentin with isopropanol.

The invention further includes a method for preparing gabapentin Form II of high purity, wherein the gabapentin Form II is more than approximately 98.8% pure when analyzed by high performance chromatography (HPLC), and more preferably wherein the gabapentin Form II is more than approximately 99.7% pure when analyzed by HPLC.

Another aspect of the invention includes gabapentin Form II having less than approximately 20 ppm of residual chloride ions, as measured by ionic chromatography.

Another aspect of the invention includes gabapentin Form II which can be used directly as a starting product for the preparation of marketed pharmaceutical specialty of gabapentin.

The invention will now be described with reference to the following examples given for illustration purposes only which are non- limitative. Specific Examples

General Experimental Conditions

HPLC Method

The chromatographic separation was carried out in a μBondapack C 18, 10 μm, 30O x 3.9 mm LD column; at room temperature (20-25⁰C).

The mobile phase was prepared by mixing 550 ml of water with 350 ml of methanol and 100 ml of acetonitrile and 1 ml of pH=7.0 buffer, which was prepared from 3.52 g OfKH₂PO₄ and 7.27 g OfNa₂HPO₄ salt in 1000 ml of water adjusting the pH to 7.0 with phosphoric acid or potassium hydroxide. This mobile phase was mixed and filtered through 0.22 μm nylon filter under vacuum.

The chromatograph was equipped with a 210 nm detector and the flow rate was 1.0 ml per minute. 50 μl of the test samples, prepared dissolving the appropriate amount of sample to obtain 6.25 mg per ml of mobile phase, were injected.

Ionic Chromatography Method

The chromatographic separation was carried out in a Waters IC-Pak Anion HC, 10 μm, 150 x 4.6 mm LD column; at 35⁰C for detector temperature and 3O⁰C for column temperature. The mobile phase was prepared by mixing 20 ml of 1.3 mM borate- gluconate solution with 500 ml of HPLC grade water and 120 ml of acetonitrile, and diluting this mixture to a 1000 ml with HPLC grade water. This mobile phase was mixed and filtered through 0.45 μm aqueous/organic membrane under vacuum and stored in a plastic container. The approximate conductivity of the mobile phase is about 280μS cm^"1. Borate-gluconate solution was prepared from 8 g of sodium gluconate, 9 g of boric acid, 12.5 g sodium tetraborate decahydrate and 125 ml of glycerine in 500 ml of HPLC grade water. This solution was stored in a plastic container at 4⁰C and warm to ambient temperature before use.

The chromatograph was equipped with a conductivity detector (base range 500 μS, sensitivity 0.01 and polarity positive) and the flow rate was 1.5 ml per minute. 100 μl of the test samples, prepared dissolving the appropriate amount of dry sample to obtain 100 mg per ml of mobile phase, were injected.

Example 1: Preparation of "[l-(aminomethyl)cyclohexyl]acetic acid" Gabapentin.

In a 250 ml round bottomed flask were charged 31.12 g of wet Gabapentin Hydrochloride (30 g of dry product, 0.144 moles, 1.0 molar equivalent, according to the loss on drying data), 153 ml of Acetone and 27 ml of deionised water (equivalent to a mixture of acetone / H₂O (85:15, v:v)). The mixture was stirred at 20-25⁰C for 15 minutes until a homogeneous white suspension was formed.

The pH of the resulting suspension was adjusted to 7.4-8.0 with Diethylamine at 20- 3O⁰C (15 ml, 10.61 g, 1.004 molar equivalents of amine were needed). Between pH 4.28-4.90 a clear or almost clear solution was obtained. At pH 4.90 it was seeded with the desired polymorphic form of gabapentin Form II. Reaction mixture was stirred for 15 minutes (initial pH actual value 7.68, final pH actual value 7.89 after stirring).

The suspension obtained was heated at 30-40⁰C, stirred at this temperature for 1 hour, cooled at 20-25⁰C, stirred at this temperature for 2 hours, cooled at 0-5⁰C, stirred at this temperature for 2 additional hours and filtered, washing the solid twice with acetone to give 23.59 g of wet Gabapentin (21.83 g of dry product, according to the loss on drying data). Yield: 88.27%.

The following analysis of the wet solid was done: IR: The IR spectrum was substantially identical to the IR shown in Fig. 1.

In a 250 ml round bottomed flask were charged the wet solid and 54.57 ml of methanol. The suspension was heated to reflux temperature (66⁰C). At this point deionised water was added until a complete or nearly complete dissolution was observed (there were needed 14.62 ml of water). Reaction mixture was cooled to 20-25⁰C, 54.57 ml of isopropanol were added in about 15-30 minutes, cooled to 0-5⁰C, stirred during 2 h at this temperature and filtered, washing the solid twice with 7.44 ml of isopropanol. After drying it at 4O⁰C under vacuum till constant weight, there were obtained 18.59 g of dry product. Yield: 85.15% (global yield from Gabapentin Hydrochloride: 75.16%)

The following analyses of the dried solid were done: HPLC (area %): 98.82%; IR: The IR spectrum was substantially identical to the IR shown in Fig. 1.; Chloride content: 18 ppm (by ionic chromatography).

Examples from 2 to 14: Preparation of "[l-(aminomethyl)cyclohexyl]acetic acid" Gabapentin

The examples below were made using the same procedure described in example 1. Results and changes over the procedure are specified in Table 1 below:

TABLE 1

Example 15: Preparation of "[l-(aminomethyl)cyclohexyl]acetic acid" Gabapentin.

In a 15 L cylindrical reactor were charged 3.044 Kg of wet Gabapentin Hydrochloride (3 Kg of dry product, 14.44 moles, 1.0 molar equivalent, according to the loss on drying data), 12.1 Kg (15.3 L) of Acetone and 2.7 Kg of deionised water (equivalent to a mixture of acetone / H₂O (85:15, v:v)). The mixture was stirred at 20-25⁰C for 15 minutes until a homogeneous white suspension was formed. The pH of the resulting suspension was adjusted to 7.4-8.0 with Diethylamine at 20- 3O⁰C (1.67 L, 1.18 Kg, 1.12 molar equivalents of amine were needed). Between pH 4.20-4.90 a clear or almost clear solution was obtained. At pH 4.8±0.1 it was seeded with the desired polymorphic form of gabapentin Form II. Reaction mixture was stirred for 15 minutes (initial pH actual value 7.73, final pH actual value 7.77 after stirring).

The suspension obtained was heated at 30-40⁰C, stirred at this temperature for 1 hour, cooled at 20-25⁰C, stirred at this temperature for 2 hours, cooled at 0-5⁰C, stirred at this temperature for 2 additional hours and filtered, washing the solid twice with 1.3 Kg (1.6 L) of acetone to give 2.9 Kg of wet Gabapentin (2.15 Kg of dry product, according to the loss on drying data). Yield: 86.98%.

In a 15 L cylindrical reactor were charged the wet solid and 6.05 Kg (7.65 L) of Acetone and 1.35 Kg of deionised water (equivalent to a mixture of acetone / H₂O (85:15, v:v)). The mixture was stirred at 20-25⁰C for 15 minutes until a homogeneous white suspension was formed.

The suspension obtained was heated at 30-40⁰C, stirred at this temperature for 1 hour, cooled at 20-25⁰C, stirred at this temperature for 2 hours and filtered, washing the solid twice with 0.63 Kg (0.8 L) of acetone to give 2.45 Kg of wet Gabapentin (2.15 Kg of dry product, according to the loss on drying data). Yield: 100.00%.

The following analysis of the wet solid was done: IR: The IR spectrum was substantially identical to the IR shown in Fig. 1. In a 15 L cylindrical reactor were charged the wet solid and 4.26 Kg (5.38 L) of methanol. The suspension was heated to reflux temperature (66⁰C). At this point deionised water was added until a complete or nearly complete dissolution was observed (there were needed 1.550 Kg of water). Reaction mixture was cooled to 25- 3O⁰C, 4.21 Kg (5.36 L) of isopropanol were added in about 1.5-2 hours, cooled to 0-5⁰C in about 2 hours, stirred during about 5 hours at this temperature and filtered, washing the solid twice with 0.6 Kg (0.76 L) of isopropanol. After drying it at 4O⁰C under vacuum till constant weight, there were obtained 1.70 kg of dry product. Yield: 80.00% (global yield from Gabapentin Hydrochloride: 69.58%).

The following analyses of the dried solid were done: HPLC (area %): 98.82%; IR: The IR spectrum was substantially identical to the IR shown in Fig. 1.; Chloride content: 2 ppm (by ionic chromatography).

Example 16: Preparation of "[l-(aminomethyl)cyclohexyl]acetic acid" Gabapentin.

In a 500 ml round bottomed flask were charged 60.53 g of wet Gabapentin Hydrochloride (60 g of dry product, 0.289 moles, 1.0 molar equivalent, according to the loss on drying data), 242 g (306 ml) of Acetone and 54 g of deionised water (equivalent to a mixture of acetone / H₂O (85:15, v:v)). The mixture was stirred at 20-25⁰C for 15 minutes until a homogeneous white suspension was formed.

The pH of the resulting suspension was adjusted to 7.4-8.0 with Diethylamine at 15- 25⁰C (31.2 ml, 22.06 g, 1.044 molar equivalents of amine were needed). Between pH 4.20-4.90 a clear or almost clear solution was obtained. At pH 4.8±0.1 it was seeded with the desired polymorphic form of gabapentin Form II. Reaction mixture was stirred for 15 minutes (initial pH actual value 7.90, final pH actual value 7.96 after stirring). The suspension obtained was stirred at 20-25⁰C for 2 hours, cooled at 0-5⁰C, stirred at this temperature for 2 additional hours and filtered, washing the solid twice with 11.87 g (15 ml) of acetone to give 42.81 g of wet Gabapentin (42.51 g of dry product, according to the loss on drying data). Yield: 85.93%.

In a 500 ml round bottomed flask were charged the wet solid and 125.24g (158.33 ml) of Acetone and 27.94 g of deionised water (equivalent to a mixture of acetone / H₂O (85:15, v:v)). The mixture was stirred at 20-25⁰C for 15 minutes until a homogeneous white suspension was formed.

The suspension obtained was heated at 30-40⁰C, stirred at this temperature for 1 hour, cooled at 20-25⁰C, stirred at this temperature for 2 hours and filtered, washing the solid twice with 12.28 g (15.52 ml) of acetone to give 47.44 g of wet Gabapentin (41.39 g of dry product, according to the loss on drying data). Yield: 97.37%.

In a 500 ml round bottomed flask were charged the wet solid and 81.97 g (103.5 ml) of methanol. The suspension was heated to reflux temperature (66⁰C). At this point deionised water was added until a complete or nearly complete dissolution was observed (there were needed 27.75 g of water). The reaction mixture was cooled to 25-

3O⁰C, 81.25 g (103.5 ml) of isopropanol were added in about 1.5-2 hours, cooled to 0-

5⁰C in about 2 hours, stirred during about 5 hours at this temperature and filtered, washing the solid twice with 38.44 g (48.96 ml) of isopropanol. After drying it at 4O⁰C under vacuum until constant weight, there were obtained 35.69 of dry product. Yield:

86.20% (global yield from Gabapentin Hydrochloride: 72.12%) The following analyses of the dried solid were done: HPLC (area %): 99.75%; IR: The IR spectrum was substantially identical to the IR shown in Fig. 1.; Chloride content: 3 ppm (by ionic chromatography).

Claims

1. A method for producing gabapentin Form II containing chloride amounts not greater than 20 ppm, characterized in that it comprises the following steps: I. combining gabapentin hydrochloride and a mixture of an organic solvent and water wherein the percentage content of water is between 5 and 30%, to form a suspension,

II. adjusting the pH of the suspension to 4.0-5.0 with an amine, to obtain a solution, III. seeding the solution with gabapentin Form II,

IV. adjusting the pH of the suspension to 7.4-8.0 with an amine, to obtain a suspension,

V. isolating crude gabapentin Form II from the suspension,

VI. optionally, suspending the crude gabapentin Form II in a mixture of an organic solvent and water wherein the percentage content of water is between 5 and 30% and isolating crude gabapentin Form II from the suspension,

VII. crystallizing crude gabapentin Form II, and

VIII. isolating gabapentin Form II containing chloride amounts not greater than 20 ppm.

2. The method for producing gabapentin Form II, according to claim 1, characterized in that the percentage content of water in step (I) is preferably between 15 and 20%, and more preferably about 15%.

3. The method for producing gabapentin Form II, according to claim 1, characterized in that the organic solvent of step (I) is selected from the group of: ethanol, isopropanol or acetone, more preferably acetone.

4. The method for producing gabapentin Form II, according to claim 1, characterized in that in step (I) the volume of the mixture of organic solvent and water per Kg of gabapentin hydrochloride is about 3 L to about 8 L per Kg of gabapentin hydrochloride, preferably about 4.5 L to about 6 L per Kg of gabapentin hydrochloride.

5. The method for producing gabapentin Form II, according to claim 1, characterized in that the pH of the suspension of step (II) is adjusted to about 4.5-5.0, more preferably to about 4.8.

6. The method for producing gabapentin Form II, according to claim 1, characterized in that the amine of step (II) is a secondary or tertiary alkyl amine, preferably a secondary amine, more preferably diethylamine.

7. The method for producing gabapentin Form II, according to claim 1, characterized in that the seeding with gabapentin form II of step (III) is performed with an amount of 0.22% of gabapentin form II with respect to the initial amount of gabapentin hydrochloride, preferably an amount of about 0.14% of gabapentin form II with respect to the initial amount of gabapentin hydrochloride. 8. The method for producing gabapentin Form II, according to claim 1, characterized in that the pH of the suspension of step (IV) is adjusted to 7.2-8.4, preferably to 7.4-8.0 and more preferably to about 7.

8.

9. The method for producing gabapentin Form II, according to claim 1, characterized in that the amine of step (IV) is a secondary or tertiary alkyl amine, preferably a secondary amine, more preferably diethylamine.

10. The method for producing gabapentin Form II, according to claim 1, characterized in that the isolation of the crude gabapentin Form II from the suspension of step (V) comprises filtering the suspension and washing the obtained solid at least twice with an organic solvent, preferably acetone.

11. The method for producing gabapentin Form II, according to claim 1, characterized in that the percentage content of water in step (VI) is preferably between 15 and 20%, more preferably about 15%.

12. The method for producing gabapentin Form II, according to claim 1, characterized in that the organic solvent of step (VI) is acetone.

13. The method for producing gabapentin Form II, according to claim 1, characterized in that the isolation of the crude gabapentin Form II from the suspension of step (VI) comprises filtering the suspension and washing the obtained solid at least twice with an organic solvent, preferably acetone.

14. The method for producing gabapentin Form II, according to claim 1, characterized in that the crystallization of step (VII) comprises dissolving wet gabapentin in a mixture of methanol and water, and precipitating gabapentin with isopropanol.