HK1071352A - New anhydrous crystalline forms of gabapentin - Google Patents

Description

Novel anhydrous crystalline form of gabapentin

Cross Reference to Related Applications

This application claims the benefit of application serial No. 60/328,375, 10, 9/2001, which is incorporated herein by reference.

Technical Field

The present invention relates to a novel anhydrous crystalline form of gabapentin which is prepared from gabapentin monohydrate.

Background

Gabapentin is a common name used to identify the compound (1-aminomethyl) -1-cyclohexaneacetic acid

It can be used for treating certain cerebral dysfunctions such as certain forms of epilepsy, debilitating attacks (facial attacks), hypokinesia, and cranial trauma. U.S. Pat. nos. 4,024,175 and 4,087,544 encompass the compounds and their uses. They also disclose an acid salt, namely gabapentin hydrochloride hydrate in a ratio of 4: 1 and gabapentin sodium salt hydrate in a ratio of 2: 1. U.S. patent No. 4,894,476 describes gabapentin monohydrate and methods for its preparation. These patents are incorporated herein by reference.

Summary of The Invention

The present invention provides novel crystalline forms of gabapentin, dehydrated form a and dehydrated form B. These new crystalline forms are prepared from gabapentin monohydrate. Dehydrating said gabapentin monohydrate in an environment wherein the water activity is maintained at a temperature of less than about 0.8 to about 0.9, or heating at a temperature of about 50 to 175 ℃ to form said crystalline gabapentin dehydrated form a. This crystalline form is then converted to the more stable crystalline form of gabapentin, anhydrate form B, by standing at room temperature.

The present invention also provides an improved process for the preparation of the pure crystalline form of the therapeutic agent gabapentin. The process does not require the use of organic solvents such as methanol, as described earlier in the process for the preparation of gabapentin and its monohydrate. The method has the advantages of fast processing and preparation, higher safety, less solvent treatment and less yield loss during recrystallization.

Brief Description of Drawings

FIG. 1 shows 4 crystalline forms of gabapentin¹³C-ssNMR spectrum.

Figure 2 shows an X-ray powder diffraction pattern of crystalline gabapentin anhydrate.

Figure 3 shows an X-ray powder diffraction pattern of crystalline gabapentin monohydrate.

Figure 4 shows an X-ray powder diffraction pattern of crystalline gabapentin dehydrate a.

Figure 5 shows an X-ray powder diffraction pattern of crystalline gabapentin dehydrate B.

Description of The Preferred Embodiment

The present invention provides novel crystalline forms of gabapentin, dehydrated form a and dehydrated form B. The present invention also includes improvements in the preparation of gabapentin monohydrate, a precursor of the novel crystalline anhydrate of the present invention. Initially, gabapentin monohydrate was reported in us patent 4,894,476 as a new crystalline form for therapeutic purposes, and a process for purifying commercial gabapentin (an anhydrous form) by reconverting the monohydrate to gabapentin was also reported.

The present invention is based on the following findings: it is known that gabapentin in anhydrous form can only be crystallized from solvents or solvent mixtures having a water activity of less than about 0.8 to about 0.9, and that gabapentin monohydrate can only be crystallized from water or solvent mixtures having a water activity of greater than about 0.8 to about 0.9. Gabapentin monohydrate can be prepared by: gabapentin is suspended in a solvent or solvent mixture having a water activity of at least about 0.8 to about 0.9, the resulting monohydrate is crystallized and the product is collected on a suction filter. The solvent mixture comprises a water-miscible solvent such as an alcohol, preferably a lower alkanol such as methanol or ethanol.

Gabapentin dehydrate a can be prepared from gabapentin monohydrate when the water activity of the immediate environment surrounding the monohydrate is less than about 0.85, i.e., less than about 0.8 to about 0.9. (in the vapour phase this means that its relative humidity is less than 85%). This may be accomplished by using a vacuum, a desiccant, and/or using heat.

For example, anhydrate a is produced from the monohydrate at low temperatures (subambient) provided that its relative humidity is less than about 85% (water activity less than 0.85).

Typically, once the monohydrate is formed, drying the monohydrate at a temperature of about 50-175 ℃ or at a temperature below the melting point of gabapentin will form dehydrated form a. The heating process may be carried out until a constant weight of dehydrated form a is obtained. Typically, heating may be between about 70-100 ℃, for example at about 80 ℃ for about 3 hours.

When left to stand at room temperature, gabapentin dehydrate form a was found to convert to the more stable crystalline form, dehydrate form B. The material may, for example, be left to stand in an inert environment or in a sealed container. The ratio of conversion of anhydrate a to B is directly related to the purity of the starting material gabapentin anhydrate a.

The moisture content of the reported form is less than 0.5% by weight, while gabapentin monohydrate contains about 9% by weight water.

These new crystalline forms are characterized by their unique X-ray powder diffraction patterns and by their respective solid states¹³Characteristic chemical shifts in the C NMR spectrum.

Tables 1-4 below compare two new crystalline forms of gabapentin dehydrate a and anhydrate B with known anhydrous crystalline forms of gabapentin and gabapentin monohydrate.

TABLE 1 PXRD data for gabapentin
			2-θ	d*	Strength of
7.9	11.1	100
			15.0	5.9	33
16.9	5.2	22
			20.4	4.4	18
23.6	3.8	15
			25.7	3.5	13
27.0	3.3	23

TABLE 2 PXRD data for gabapentin monohydrate
			2-θ	d*	Strength of
6.1	14.5	100
			12.2	7.3	50
18.3	4.8	23
			24.4	3.6	10

TABLE 3 PXRD data for gabapentin dehydrate A
			2-θ	d*	Strength of
6.2	14.2	100
			12.5	7.1	18
16.1	5.5	18
			18.8	4.7	21
19.2	4.6	22
			25.1	3.5	21
26.1	3.4	11

TABLE 4 gabapentinPXRD data for dehydrate B
			2-θ	d(*)	Strength of
6.0	14.8	53
			7.7	11.4	27
16.8	5.3	100
			18.0	4.9	40
20.6	4.3	17
			24.3	3.65	13

X-ray (PXRD) data were obtained using a Rigaku Ultima + X-ray powder diffractometer equipped with a copper target operated at 40kV/40mA to generate X-rays with a wavelength of 1.542 angstroms. The deflection slit and the scattering slit are set to 1 °. The receiving slit is set to 0.3 mm. The diffractometer was equipped with a Rigaku ASC-6A sample changer. The preparation of the sample comprises: a sufficient amount of sample was poured to fill the sample plate and its surface was scraped smooth without compacting the sample. The sample was continuously scanned from 4 ° to 40 ° 2- θ at a rate of 5 °/min under ambient conditions. The PXRD data for these 4 forms are shown in tables 1-4 above. These data are data for peaks with intensities of at least 10% of the most intense peak intensity, rounded off from the original data, with an accuracy of about ± 0.2 for 2-theta and d (*) taking into account routine experimental error.

Tables 5-8 compare the chemical shifts (in parts per million (ppm)) of gabapentin for various crystalline forms, including the novel crystalline forms of the present invention (dehydrated form a and dehydrated form B).

TABLE 5 chemical shifts (ppm) of gabapentin
	22.428.229.834.835.536.339.640.147.7179.6

TABLE 6 chemical shifts (ppm) of gabapentin monohydrate
	22.727.435.736.444.147.3178.5

TABLE 7 chemical shifts (ppm) of gabapentin dehydrate A
	22.127.033.736.237.641.051.0177.4

TABLE 8 chemical shifts (ppm) of gabapentin dehydrate B
	23.328.535.036.237.142.348.2178.3

All of¹³The C-ssNMR spectra were obtained using a Varian 400MHz NMR spectrometer with a high energy proton decoupled cross-polarization with a magic angle rotation at about 6 kHz. Chemical shifts were referenced to external hexamethylbenzene (methyl signal at 17.3 ppm). Each specimen was prepared by packaging the specimen with a packaging tool into a 7mm can silicon nitride rotor and sealing the rotor with a lid. These profiles were obtained under ambient conditions. Of these 4 forms¹³The C-ssNMR spectrum is shown in FIG. 1.

Examples

Example 1Preparation of gabapentin monohydrate

100g gabapentin dehydrate was suspended in 480mL of water and stirred for 1 hour while adding the seed monohydrate. After crystallization, the gabapentin monohydrate is isolated by suction filtration.

Example 2Crystalline gabapentin dehydrate forms A and B

Form A: two batches of gabapentin monohydrate (200mg and 100g) were heated at 70-80 ℃ for 3 hours to give gabapentin dehydrate form a.

The density of the new dehydrated form A was 1.156g/mL as determined by the hexane displacement method. Samples of gabapentin dehydrated form a were analyzed for moisture by Karl Fischer and gabapentin by HPLC.

The crystalline forms A and B of the anhydrate meet the specifications for water (< 0.5% w/w) and tests (98.5% -101.5% w/w on anhydrous basis).

Elemental analysis and¹h NMR confirmed the chemical composition of gabapentin dehydrate form A.

Steam sorption analysis showed that gabapentin dehydrate form a did not absorb significant amounts of water (< 0.5%) at 25 ℃ at relative humidities < 85%.

Form B: the two batches of dehydrated form a obtained above were allowed to stand. Form a was found to convert to gabapentin dehydrate form B by 20% within 1 month. Complete conversion to the dehydrated form B was found within 1 year. By passing¹³The samples of both batches were monitored by C-ssNMR until the end of the conversion, as evidenced by the disappearance of the dehydrated form A.

These two crystalline forms are characterized by their respective solid state NMR spectra and X-ray powder diffraction patterns.

The above specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended.

Claims (15)

1. A process for preparing crystalline gabapentin dehydrate form B comprising:

(a) dehydrating gabapentin monohydrate to form crystalline gabapentin dehydrated form A, and

(b) the anhydrate a is allowed to stand at room temperature to form crystalline gabapentin dehydrate form B.

2. The method of claim 1, wherein said dehydrating step (a) is performed by using vacuum, a desiccant or heat.

3. The method of claim 1, wherein the gabapentin monohydrate is dehydrated in an environment wherein the water activity remains below about 0.8 and about 0.9.

4. The process of claim 2 wherein the heating is carried out at a temperature of from about 50 ℃ to about 175 ℃.

5. The process of claim 1, wherein the dehydrated form a is left to stand in an inert environment or in a sealed container.

6. The process of claim 2, wherein gabapentin monohydrate is prepared by the steps comprising:

(a) suspending gabapentin in a solvent or solvent mixture having a water activity value of greater than about 0.8 to about 0.9;

(b) the gabapentin monohydrate is crystallized and collected on a filter.

7. The process of claim 6, wherein the solvent is water.

8. A crystalline gabapentin dehydrate form a having an X-ray powder diffraction containing at least one of the following 2-theta values measured using CuK α radiation: 18.8 or 25.1.

9. A crystalline gabapentin dehydrate form A having an X-ray powder diffraction containing the following 2-theta values measured using CuK α radiation: 18.8, 25.1 and 26.1.

10. A crystalline gabapentin dehydrate form A having an X-ray powder diffraction containing the following 2-theta values measured using CuK α radiation: 6.2, 12.5, 16.1, 18.8, 19.2, 25.1 and 26.1.

11. A crystalline gabapentin dehydrate form A characterized by a solid state methyl signal referenced to an external methyl signal at 17.3ppm of hexamethylbenzene¹³C nuclear magnetic resonance has the following chemical shifts expressed in parts per million: 22.1, 27.0, 33.7, 36.2, 37.6, 41.0, 51.0 and 177.4.

12. A crystalline gabapentin dehydrate form B having an X-ray powder diffraction containing at least one of the following 2-theta values measured using CuK α radiation: 6.0 or 16.8.

13. A crystalline gabapentin dehydrate form B having an X-ray powder diffraction containing the following 2-theta values measured using CuK α radiation: 6.0, 16.8 and 18.0.

14. A crystalline gabapentin dehydrate form B having an X-ray powder diffraction containing the following 2-theta values measured using CuK α radiation: 6.0, 7.7, 16.8, 18.0, 20.6 and 24.3.

15. A crystalline gabapentin dehydrate form B characterized by a solid state methyl signal referenced to an external methyl signal at 17.3ppm of hexamethylbenzene¹³C nuclear magnetic resonance has the following chemical shifts expressed in parts per million: 23.3, 28.5, 35.0, 36.2, 37.1, 42.3, 48.2 and 178.3.