Title of Invention	IMPROVED PROCESSES FOR THE CONVERSION OF GABAPENTIN HYDROCHLORIDE INTO GABAPENTIN POLYMORPHIC FORMS II OR III
Abstract	The present invention relates to a process for the conversion of gabapentin hydrochloride into gabapentin polymorphic Forms II or III by use of gaseous alkylamine and the choice of a specific solvent.

Full Text

Field of Invention; The present invention relates to an improved process for the conversion of gabapentin hydrochloride into gabapentin. The invention more particularly, relates to an improved process for the conversion of gabapentin hydrochloride salt to gabapentin polymorphic forms II or III. Background of the Invention ; Gabapentin is chemically, l-(amino methyl)-l-cyclohexaneacetic acid, having the chemical formula I structure (The Merck Index, 13* Edn., page 767, No.4342): Gabapentin is therapeutically useful in treating epilepsy and various other cerebral disorders. It was first described by Warner-Lambert Co. in the US patent no 4,024,175 Several processes for the preparation of gabapentin are reported in the literature. US Patent 4024175 only indicates in one of the examples that "by treatment with a basic ion exchanger and crystallization from ethanol/ether, there is obtained pure 1-aminomethyl-1-cyclohexane acetic acid...", without any further details or claims. US Patent 5091567 claims the conversion of the gabapentin hydrochloride salt to gabapentin base by passing over a column filled with a weakly basic anion exchanger, without giving any further details about the preferred ion exchanger or how to achieve this (see example 10 in this patent). US Patent 4894476 discloses a hydrated form of gabapentin which is prepared by liberating the free gabapentin base from its hydrochloride salt by pouring the salt solution onto a column of ion exchange resin like amberoid IRA-68, eluting with deionizer water and further work up to recover the hydrated form. PCT patent WO-02 / 34709 describes the use of strong cation exchange resins like IMAC HPl 110, IRA 120 etc., for converting the gabapentin hydrochloride to gabapentin base. The process requires a double elution, first to remove anions and then the captions. These processes generally result in obtaining "Form 11" which is commercially marketed. Column chromatography is not convenient for application on an industrial scale. It requires long time and results in a large volume of aqueous solution to be evaporated at low temperature, which makes the process uneconomical. Diafiltration technique for the separation of salt from gabapentin is described in the PCX patent WO 00/58268 (equivalent to the U.S. Patent 6,576,790). The technique uses a Nan filtration multilayer composite membrane having selectivity for organic compounds with molecular weight higher than 150 and low selectivity to inorganic ions. The drawbacks of this process is that these membranes are not easily available and are also expensive. Further, special reactors are required for carrying out the process . A process for the conversion of gabapentin hydrochloride to free gabapentin is described in the PCT patent no WO 98/28255. In this process gabapentin hydrochloride is dissolved in a solvent such as ethyl acetate, in which free gabapentin is insoluble. Alkyl amine such as tributylamine, is added to the solution resulting in the precipitation of free gabapentin, which is insoluble. Alkyl amine hydrochloride formed in the reaction being soluble will remain in solution. Free gabapentin is recovered by filtration. There are several drawbacks in the process as described in PCT patent no WO 98/28255. Since gabapentin precipitates directly from the solvent, it is obtained as a polymorph, which is different from the commercially marketed polymorph (form II). An additional step involving treatment with methanol is required to convert the new polymorph (called form III by the inventors) into commercially marketed form II. The alkyl amine used is selected from the group consisting of triethylamine, tributylamine, tripropylamine, trihexylamine, diethyl amine, ethanolamine, and benzyl amine as described in the patent WO- No 98/28255. All these amines are nonvolatile liquids at ambient temperature and difficult to remove when present in excess, requiring repeated extractions. Gabapentin also has a free carboxylic acid group, which can form salt with excess amine. Such salts are not desirable in the final product. Objectives of the present invention ; It is the main objective of the present invention to provide an industrially useful process for the conversion of gabapentin hydrochloride to gabapentin in commercially marketable form of polymorph (Form II) directly in a single step. Another objective of the present invention is to provide an improved process for the conversion of gabapentin hydrochloride to gabapentin avoiding the use of an additional step and provides gabapentin directly in commercially marketable form of polymorph (Form II) in a single step. Still another objective of the present invention is to provide an improved process for the conversion of gabapentin hydrochloride to gabapentin using a solvent such as methanol in which both gabapentin hydrochloride and gabapentin are soluble Yet another objective of the present invention is to provide an improved process for the conversion of gabapentin hydrochloride to gabapentin using gaseous alkyl amines, excess of which is removed easily by heat or flushing during the process, Another objective of the present invention is to provide an improved process for the conversion of gabapentin hydrochloride to gabapentin polymorphic form III. Accordingly, the present invention provides an improved process for the conversion of gabapentin hydrochloride to gabapentin crystalline polymorphic forms which comprises (i) dissolving gabapentin hydrochloride in methanol in which free gabapentin is also soluble. (ii) passing gaseous alkyl amine to the resulting solution of step (i) till the pH is neutral at ambient temperature and (iii) removing the methanol employing low pressure, and washing the residue with a solvent in which the alkyl amine hydrochloride formed in the reaction is soluble, to yield gabapentin crystalline polymorphic forms. The alkyl amine which may be used in step (ii) may be selected from dimethylamine or trimethylamine. The solvent used in step (iii) may be selected from methanol, isopropanol, chloroform or isoamyl alcohol. It was noted that when methanol or isopropanol or chloroform was used as solvent to remove the alkylamine hydrochloride from the residue, gabapentin crystalline polymorphic form II with characteristic x-ray diffractogram as described in publications cited earlier, was formed. On the other hand using isoamyl alcohol as solvent for washing the residue to remove the alkylamine hydrochloride formed in the reaction, surprisingly it was found that gabapentin crystalline polymorphic form III, with the characteristics described in the patent literature cited earlier, was obtained. Thus the process as per the present invention is elegant, in facilitating the preparation of either form II or form III of gabapentin, simply by changing the solvent at the step of final recovery. The alkyl amine which may be used in step (ii) may be selected from dimethylamine or trimethylamine. Gabapentin hydrochloride can be prepared by one of the methods described in the literature, for example, US patent 4,024,175 or 4,152,326. It is dissolved in methanol in which free gabapentin is also soluble. The selection of the solvent is important, because if the free gabapentin is not soluble the polymorphic form obtained will be different from that of the commercially marketed form and an additional step will be required to convert the product into commercially marketable form. The second step of the present invention comprises passing alkylamine, which is in the gaseous form at ambient temperature to the solution of gabapentin hydrochloride. Alkylamines, which are gaseous at ambient temperature, are methylamine, dimethylamine and trimethylamine. Preferred alkylamines are dimethylamine and trimethylamine because their hydrochloride salts are soluble in a number of organic solvents such as methanol, isopropanol, isoamyl alcohol, chloroform, etc. These alkylamines being highly reactive, convert gabapentin hydrochloride to gabapentin rapidly. When the pH reaches 7.0 to 7.5, from the initial pH of about 1.5, addition of the amine is discontinued. At this stage the solution remains clear. The solvent is removed at a reduced pressure. Excess alkylamine, if any, will also be eliminated at this stage. The residue obtained is again dissolved in methanol and concentrated to small volume to precipitate gabapentin. It is cooled and filtered. The precipitate is washed repeatedly with small quantities of solvent in which the amine hydrochloride is soluble. The solvents preferred are isopropanol or chloroform. Methanol can also be used in small quantity and at cold temperature keeping in mind that gabapentin is soluble in methanol. Methanol removes amine hydrochlorides efficiently. Washing is repeated till the filtrate is negative to chloride as indicated by silver nitrate test. At this stage the residue is also negative to silver nitrate test. The residue is dried under vacuum. It exhibits the peaks in the X-ray diffraction diagram with 2-theta values at 6.0, 7.8, 14.9, 16.8, 20.2, 23.5, 26.7, 28.1 degrees which are characteristic of the form II. Interestingly, when isoamyl alcohol is used as solvent to remove dimethylamine hydrochloride, the material obtained is found to be of different polymorph, named as Form III. The X-ray diffraction pattern and infra-red spectra of this polymorph are same as that of the novel form mentioned in PCT patent WO 98/28255. The embodiments of the present invention are further described in the following examples, which are not intended in any way to limit the scope of the present invention. Example-1 10.0 g of gabapentin hydrochloride were dissolved in 100 mL dry methanol. Dimethylamine gas was bubbled into the solution till the pH was 7 to 7.5. After stirring for 30 minutes, most of the solvent was removed under reduced pressure, the thick slurry was filtered to obtain 11.5 g precipitate. The precipitate was suspended in 15 mL dry methanol, stirred for 10 minutes and filtered. The process was repeated till the filtrate was negative to chloride as shown by AgN03 test. The residue was dried under vacuum to obtain 3.6 g of gabapentin. From the pooled filtrate a second crop of 0.9 g pure material can be obtained. Total yield: 4.5 g (54.6 %), m.p: 160-161°C, purity by HPLC: 99.1%. It displayed characteristic X-ray diffraction pattern with 2-theta values at 6.0, 7.8, 14.9, 16.8, 20.2, 23.5, 26.7, and 28.1 degrees and characteristic infra-red absorption peaks at 708.6, 749.0, 890.6, 927.9, 976.1, 1165.1, 1300.1, 1420.2, 1474.9, 1543.4, and 1614.9 cm"". These X-ray diffraction pattern and infra-red peaks are characteristics of form II. Example-2 10.0 g of gabapentin hydrochloride were dissolved in 100 mL dry methanol. Dimethylamine gas was bubbled into the solution till pH was 7 to 7.5. After stirring for 30 minutes, most of the solvent was removed under reduced pressure, the thick slurry was filtered to obtain 11.5 g precipitate. The precipitate was suspended in 15 mL dry isopropanol, stirred for 10 minutes and filtered. The process was repeated till the filtrate was negative to chloride as shown by AgNOs test. The residue was dried under vacuum to obtain 4.2 g of gabapentin. From the pooled filtrate a second crop of 0.8 g pure material can be obtained. Total yield: 5.0 g (60.6 %), m.p: 160-162°C, purity by HPLC: 99.3 %. It displayed characteristic X-ray diffraction pattern and infra-red peaks as given in the Example-1. Example-3 10.0 g of gabapentin hydrochloride were dissolved in 100 mL dry methanol. Dimethylamine gas was bubbled into the solution till pH was 7 to 7.5. After stirring for 30 minutes, most of the solvent was removed under reduced pressure, the thick slurry was filtered to obtain 11.5 g precipitate. The precipitate was suspended in 15 mL dry isoamyl alcohol, stirred for 10 minutes and filtered. The process was repeated till the filtrate was negative to AgNO3 test. The residue was dried under vacuum to obtain 4.0 g (48.5 %) of gabapentin. m.p: 156-158°C, purity by HPLC: 99.2 %. It displayed characteristic X-ray diffraction pattern with 2-theta values at 6.02, 12.07, 24.35, 5.60, 16.84, 11.84, 17.99, and 20.64 degrees (decreasing order of the peak size with the peak at 6.02 degree =100 %) and characteristic infra-red absorption peaks at 708.6, 749.0, 890.6, 927.9, 976.1, 1165.1,1300.1, 1420.2, 1474.9,1543.4, and 1614.9 cm"". These X-ray diffraction pattern and infra-red peaks are characteristics of form III (the novel polymorph as described in the patent WO 98/28255). ExampIe-4 10.0 g of gabapentin hydrochloride were dissolved in 100 mL dry methanol. Dimethylamine gas was bubbled into the solution till pH was 7 to 7.5. After stirring for 30 minutes , most of the solvent was removed under reduced pressure, the thick slurry was filtered to obtain 11.5 g precipitate. The precipitate was suspended in 15 mL dry chloroform, stirred for 10 minutes and filtered. The process was repeated six times to make the final filtrate negative to AgNO3 test. The residue was dried under vacuum to obtain 6.0 g (72.8 %) of gabapentin form II m.p: 160-162° C. Purity by HPLC: 98.9 %. It displayed characteristic X-ray diffraction pattern and infra-red peaks as given in the Example-1 Example-5 10.0 g of gabapentin hydrochloride were dissolved in 100 mL dry methanol. Trimethylamine gas was bubbled into the solution till pH was 7 to 7.5. After stirring for 30 minutes, most of the solvent was removed under reduced pressure, the thick slurry was filtered to obtain 11.9 g precipitate. The precipitate was suspended in 15 mL dry isopropanol, stirred for 10 minutes and filtered. The process was repeated till the filtrate was negative to AgNO3 test. The residue was dried under vacuum to obtain 2.9 g of gabapentin. From the pooled metabolic filtrate a second crop of 0.8 g pure gabapentin Form II is obtained. Total yield: 3.7 g (45.0 %), m.p: 160-162°C. Purity by HPLC: 99.1 %. It displayed characteristic X-ray diffraction pattern and infra-red peaks as in the Example-1 Advantages of the invention ; The process is simple and can be applied commercially The process does not use ion exchange resins and tedious column chromatography. The alkyl amine used can be easily removed " The process can yield either commercially marketed form II or the form III by a simple change of solvent. We Claim ; 1. An improved process for the conversion of gabapentin hydrochloride to gabapentin crystalline polymorphic form which comprises : (i) dissolving gabapentin hydrochloride in methanol in which free gabapentin is also soluble, (ii) passing gaseous alkylamine to the resulting solution of step (i) till the pH"is neutral at ambient temperature and (iii) removing the methanol employing low pressure, stirring the residue with a solvent to remove the alkylamine hydrochloride formed in the reaction, followed by washing the residue with the said solvent, to yield gabapentin crystalline polymorphic forms. 2. An improved process as in claim 1 wherein the alkylamine used in step (ii) is selected from methylamine, dimethylamine and trimethylamine, preferably dimethylamine or trimethylamine. 3. An improved process as in claim 1, wherein in the step (iii) the solvent used to remove alkylamine hydrochloride is selected from the group consisting of methanol, isopropanol and chloroform to yield gabapentin crystalline polymorphic form characterized by its x-ray diffractogram with 2-theta values at 6.0, 7.8, 14.9, 16.8, 20.2, 23.5, 26.7 and 28.1 degrees, which is characteristic of form II. 4. An improved process as in claim 1, wherein in the step (iii) the solvent used to remove alkylamine hydrochloride is isoamyl alcohol to yield gabapentin crystalline polymorphic form characterized by its x-ray diffractogram with 2-theta values at 6.02, 12.07, 24.35, 5.60, 16.84, 11.84, 17.99 and 20.64 degrees in decreasing order of relative intensities, which is characteristic of form III.

Documents:

0127-che-2004 abstract-duplicate.pdf

0127-che-2004 abstract.pdf

0127-che-2004 claims-duplicate.pdf

0127-che-2004 claims.pdf

0127-che-2004 correspondence-others.pdf

0127-che-2004 correspondence-po.pdf

0127-che-2004 description (complete)-duplicate.pdf

0127-che-2004 description (complete).pdf

0127-che-2004 form-1.pdf

0127-che-2004 form-19.pdf

0127-che-2004 form-3.pdf

0127-che-2004 form-5.pdf

0127-che-2004 others.pdf

0127-che-2004 pct.pdf