WO2009037718A2

WO2009037718A2 - Process for preparing 3-(2-(dimethylamino)ethyl)-n- methyl-1h-indole-5-methanesulfonamide and product thereof

Info

Publication number: WO2009037718A2
Application number: PCT/IN2008/000592
Authority: WO
Inventors: O. D. Tyagi; Purendhar Koilkonda; Jitendra Sharma; R. V. N. Vikas Chandradev; R. Sridhar; Saswata Lahiri; A. V. Mouneshwar
Original assignee: Matrix Laboratories Ltd
Current assignee: Mylan Laboratories Ltd
Priority date: 2007-09-17
Filing date: 2008-09-16
Publication date: 2009-03-26
Anticipated expiration: 2010-03-17
Also published as: WO2009037718A8; WO2009037718A3

Abstract

The present invention relates to an improved process for the preparation of 3-(2- (dimethylamino) ethyl)-N-methyl- 1 H-indole-5-methanesulfonamide (sumatriptan) acid addition salt and the base having enhanced yield and purity. Further the present invention also provides a novel crystalline sumatriptan base.

Description

PROCESS FORPREPARING3-(2-(PIMETHYLAMONO)ETHYL)-N- METHYL-1H-IND0LE-5-METHANESULFONAMIDE AND PRODUCT

THEREOF FIELD OF THE INVENTION

This invention, in general relates to a process for preparing an indole derivative. More particularly, but without restriction to the particular embodiments herein after described in accordance with the best mode of practice, the present invention provides an improved process for the preparation of 3-(2- (dimethylamono)ethyl)-N-methyl-lH-indole-5-methanesulfonamide (sumatriptan) acid addition salts, a crystalline form of sumatriptan base and product thereof.

BACKGROUND OF THE INVENTION

The indole derivatives are used in the treatment of migraine. It has been suggested that the pain of migraine may be associated with excessive dilatation of the cranial vasculature.

The indole derivatives are selective 5HT₁-IUCe receptors agonists and exhibit selective vasoconstrictor activity, which have been described in the art as useful in the treatment of migraine. The selection of indole molecule compound having two specific substituents, namely the methylaminosulphonylmethyl group at the 5-position of the indole molecule and the N,N-dimethylaminoethyl substituent at the 3 -position, wherein said compound having a combination has highly advantageous properties for the treatment of migraine, which is having the following structure:

Various prior arts disclose the process for preparation of sumatriptan; however, the processes used in prior arts are different with each other using different processes.

US Pat No. 5,037,845 filed on August 01, 1985, was granted on August 06, 1991 and assigned to Glaxo Group Limited. In this Patent, process for the preparation of sumatriptan is disclosed, wherein 4,4-dimethoxy-N,N-dimethylbutanamine is reacted with 4-hydrazino-N-methylbenzenemethane sulfonamide hydrochloride followed by work up to get 4-[2-[4-(dimethylamino)butylidene]hydrazine]-N-methyl benzenemethane sulphonamide, which is subjected to cyclization reaction in the presence of polyphosphate ester in a chloroform. After completion of the reaction, reaction mass is diluted with water and then the reaction mass pH is adjusted 10.0 to 11.0 and product is extracted into chloroform. Chloroform layer is concentrated under reduced pressure to give the residue, which is subjected to column chromatography purification to give sumatriptan oil. It is further subjected to crystallization to give sumatriptan base.

Sumatriptan acid addition salt Pure Sumatriptan Base Sumatriptan Base

Scheme- A

The above isolated sumatriptan base is recrystallised from isopropyl alcohol to give crystalline sumatriptan base, which is further treated with acid in solvent medium to give sumatriptan acid addition salts (Scheme-A).

The prior art process required chlorinated solvents such as chloroform and sumatriptan is purified through column chromatography. Further, the obtained oil base is subjected to crystallization in different solvents to give the crystalline sumatriptan base. This process involves the column purification, which is not commercially feasible, in addition to this, process needed more time cycle.

WO 2006/054311 publication reveals the process for the preparation of sumatriptan, wherein 4, 4-dimethoxy-N, N-dimethylbutanamine is reacted with 4- hydrazino-N-methyl benzene methanesulfonamide hydrochloride in diluted hydrochloric acid. After completion of the condensation reaction, the reaction mass pH is adjusted to 9.0-9.5 with sodium carbonate, the resulting solution is extracted with chloroform and -the organic layer is concentrated to give the residue.

The residue is diluted with fresh chloroform. Ethylpolyphosphate is added to the above solution. After completion of the cyclization, reaction mass is subjected to acid base, followed by workup and product is extracted into ethyl acetate. Ethyl acetate layer is dried and concentrated under reduced pressure to give the crude sumatriptan base. The crude sumatriptan base is subjected to repeated crystallizations in different solvents like acetonitrile and methanol to give the pure sumatriptan base, which is further converted into acid addition salts by conventional method. The said prior art process needed more number of solvents like chloroform, ethyl acetate, acetonitrile and methanol for reaction and crystallization of sumatriptan base. The sumatriptan base is subjected to repeated crystallizations in different solvents. It needs number of solvents for reaction and recrystallisation of sumatriptan. The recovery and reuse of the solvents in the same process requires more time cycle in the plant level. Finally, it leads to additional cost on the final product.

US publication No. 2007/0054953 discloses process for the preparation of sumatriptan. The crude sumatriptan is dissolved in acetone at reflux temperature, treated with carbon and filtered to give pure sumatriptan base. It is further reacted with different acids such as citric acid, ascorbic acid and oxalic acid to give corresponding sumatriptan acid addition salts.

The above isolated acid addition salts are suspended in water, then the resulting solution pH is adjusted to 9.0- 9.5 with potassium carbonate. The precipitated solid is filtered and washed with water to get sumatriptan base, which is further subjected to purification in acetone to give pure sumatriptan base, which is treated with succinic acid in alcohol solvent to give sumatriptan succinate.

According to the above process, initially crude sumatriptan base is also crystallized in a solvent, then converting sumatriptan base into acid addition salt. The sumatriptan acid addition salt is set free by treating sodium or potassium carbonate to give sumatriptan base, which is subjected to crystallization to give pure sumatriptan base. Finally sumatriptan base is converted into acid addition salts by conventional method.

The processes disclosed above according to the cited prior arts are cumbersome and involve number of purification steps and require different solvents which results in loss of yield at each purification step, thereby making the process uneconomical.

Therefore, there is unmet need to develop a simple and economical process for the preparation of sumatriptan acid addition salts and base to achieve improvement in product yield and quality.

OBJECT AND SUMMARY OF THE INVENTION

It is a principal object of the present invention to provide an improved process for the preparation of sumatriptan acid addition salts resulting in enhanced yield with high purity. It is another object of the present invention to provide a novel crystalline form of sumatriptan base.

It is yet another object of the present invention to provide a process for the preparation of novel crystalline form of sumatriptan base

The above and other objects are attained in accordance with the following embodiments of the present invention, however, the described embodiments hereinafter is in accordance with the best mode of practice and the invention is not restricted to the particular embodiments.

In accordance with preferred embodiment of the present invention, there is provided an improved process for preparing sumatriptan acid addition salts, wherein the process comprises adsorbing crude sumatriptan base on stationary phase, leaching/ treating stationary phase with acid and isolating the resultant acid addition salt of sumatriptan, wherein said stationary phase is silica gel enabling the reduction of purification steps and resulting a pure and improved yield of acid addition salt of sumatriptan. In accordance with one preferred embodiment of the present invention, there is provided an improved process for preparing sumatriptan acid addition salts, wherein the process comprises adsorbing crude sumatriptan base on stationary phase, leaching/ treating stationary phase with solvent, followed by adding acid to the solvent and isolating the resultant acid addition salt of sumatriptan, wherein said stationary phase is silica gel enabling the reduction of purification steps and resulting a pure and improved yield of acid addition salt of sumatriptan.

In accordance with one other embodiment of the present invention, there is provided a process for preparing crystalline form of sumatriptan base, the process comprises of suspending the sumatriptan acid addition salt in a water or mixture of water and water miscible organic solvents, adjusting pH of the resultant solution to basic with base and isolating the crystalline form of sumatriptan base.

In accordance with another preferred embodiment of the present invention, there is provided a process for preparing of sumatriptan base, wherein said process avoids repeated crystallizations in different solvents to obtain the sumatriptan.

In accordance with another preferred embodiment of the present invention, there is provided a process for preparing of sumatriptan base, wherein the process results in improved quality of sumatriptan without subjecting to extra purification steps.

In accordance with another preferred embodiment of the present invention, there is provided a novel crystalline sumatriptan base, wherein said crystalline form is characterized by having a X-ray powder diffraction pattern having peaks at about 9.97 (±) 0.2, 17.29 (±) 0.2, 21.68 (±) 0.2, two-theta. In accordance with yet another preferred embodiment of the present invention, there is provided a novel crystalline sumatriptan base, wherein said crystalline form is characterized by having a differential scanning calorimetry thermogram (DSC) peak at about 67 ° C, about 106 ° C and 174° C (±) 0.1% at 10° C/ minute. BRIEF DESCRIPTION OF THE DRAWINGS

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein: FIG. 1 is X-ray powder diffractogram for the sumatriptan base isolated from water.

FIG.2 is X-ray powder diffractogram for the sumatriptan base crystallized from Isopropyl alcohol.

FIG. 3 is X-ray powder diffractogram for the sumatriptan base crystallized from acetone.

FIG. 4 is X-ray powder diffractogram for the sumatriptan benzoate. FIG. 5 is X-ray powder diffractogram for the sumatriptan succinate.

FIG. 6 is a DSC curve for the sumatriptan base isolated from water.

DETAILED DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The disclosed embodiment of the present invention provides a cost effective and industrial feasible process for preparing sumatriptan acid addition salts, a novel crystalline form of sumatriptan base and product thereof, wherein the process is improved upon prior arts in view of reducing process steps, avoiding repeated crystallizations and purification of the resultant.

According to the present invention the preparation of acid addition salts of sumatriptan is disclosed in Scheme I, wherein the process involves initial reaction of 4-hydrazino-N-methyl benzene methane sulfonamide hydrochloride with 4, 4- dimethoxy-N, N-dimethylbutanamine in an aqueous hydrochloric acid. After completion of the condensation reaction, the reaction mass pH is adjusted 8.0 to 11.0 with base. The preferred reaction mass pH is 9.0 to 9.5. The base is selected from sodium hydroxide, potassium hydroxide, ammonia or triethyl amine. The preferred base is aqueous sodium hydroxide.

Sumatriptan acid addition salt Sumatriptan acid addition salt Sumatriptan add addition salt

Sumatriptan Base Sumatriptan acid addition salt

Scheme I

The resulting solution is further extracted with solvent, preferably dichloromethane and the resultant combined organic layer is washed with water. Then the solvent is removed under reduced pressure to give residue, which is further diluted with organic solvents selected from dichloromethane, dichloroethane, chloroform, preferably in dichloromethane. and the process further involves cooling the obtained reaction mass between -10° C to 25° C, preferably 0° C to 5° C. Polyphosphoric acid ester which is diluted with dichloromethane, is added to the reaction mass and temperature is maintained between 20-60° C. After completion of the cyclization reaction, reaction mass is cooled to 0-5° C. Further the resultant reaction mass is diluted with water followed by separating the organic and aqueous layer obtained therein.

Further the obtained aqueous layer pH is adjusted to 9.0 to 12.0 with base wherein base is selected from sodium hydroxide, potassium hydroxide, ammonia .The resulting solution is extracted with water immiscible organic solvents, which are selected from dichloromethne, dichloroethane, chloroform, toluene, ethyl acetate. The preferred water immiscible organic solvent is ethyl acetate.

According to the present invention, silica gel is added to the resultant ethyl acetate layer obtained from above process steps at ambient temperature and stir for 1- 2 hours. The sumatriptan product is adsorbed on the silica gel and the impurities are not adsorbed on silica gel. Sumatriptan base is completely adsorbed on acidic silica gel due to sumatriptan base having the basic nature. The acidic impurities not adsorbed on silica gel are removed by simple filtration, without performing any purification steps such as column chromatography, or repeated crystallization methods in different solvents. The resultant silica gel containing sumatriptan is filtered and isolated as pure sumatriptan base. Further, the obtained sumatriptan base is treated with pharmaceutically acceptable acids to prepare corresponding pharmaceutically acceptable acid addition salts with improved yield.

In an alternate way, the above silica gel containing pure sumatriptan is filtered and suspended in a solvent selected from methanol, ethanol, isopropyl alcohol. Silica gel is suspended in alcoholic solvent and stirred for 1 to 2 hours, then filtered and washed with solvent. The sumatriptan base is soluble in alcohol and the filtrate is containing the sumatriptan base, which is concentrated under reduced pressure to give sumatriptan base. The preferred solvent is methanol. Further, according to the present invention, sumatriptan base is isolated, as a solid without performing purification techniques like column chromatography or crystallization process subjecting to apply external heating and cooling.

The resultant sumatriptan base is optionally dissolved in a solvent and treated with pharmaceutically acceptable acids to give corresponding pharmaceutically acceptable acid addition salts with improved yield.

The pharmaceutically acceptable acid used according to the present invention is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, methanesulfonic acid, oxalic acid, succinic acid or any other acid suitable to give corresponding pharmaceutically acceptable acid addition salts. Another embodiment of present invention is isolation of novel crystalline sumatriptan base, wherein the above isolated sumatriptan acid addition salt is dissolved in water or a mixture of water and water miscible organic solvents to give clear solution. The water miscible organic solvent is selected from methanol, ethanol, isopropyl alcohol; acetone. The preferred water miscible organic solvent is methanol.

Sumatriptan acid addition salt

Sumatriptan Base The resulting solution pH is adjusted to 8.0 to 11.0 with base in the presence of anti oxidant such as sodium dithionite, butylated hydroxy toluene or butylated hydroxyl anisole to precipitate the crystalline sumatriptan base. The base is like alkali/alkaline earth hydroxides carbonate sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.

The precipitated crystalline solid is filtered and washed and dried to give crystalline sumatriptan base, which is having powder diffraction pattern having peaks at about 9.97 (±) 0.2, 17.29 (±) 0.2, 21.68 (±) 0.2, two-theta.

The precipitated crystalline solid is filtered and washed and dried to give crystalline sumatriptan base, which is having powder diffraction pattern having peaks at about 9.97 (±) 0.2, 13.3 (±) 0.2, 15.88 (±) 0.2, 21.09 (±) 0.2, 21.64 (±) 0.2, 22.76 (±) 0.2, two-theta

Differential scanning calorimetry thermogram (DSC) of this novel crystalline sumatriptan base having a peak at about 67 ° C, about 106 ° C and 174° C (±) 0.1% at 10° C/ minute.

According to the prior art processes sumatriptan base is crystallized from isopropyl alcohol, acetone, acetonitrile etc. The sumatriptan crystallized from isopropyl alcohol and acetone are having the similar PXRD pattern, where as sumatriptan base isolated from the water or mixture of water and water miscible organic solvent is having the different PXRD pattern, which is not known in the prior art.

According to the present invention, crystalline sumatriptan base isolated from water or a mixture of water and water miscible organic solvents, having different

PXRD pattern with improved quality and yield. Isolation of sumatriptan base from the water or a mixture of water and water miscible organic solvent does not involve the solvent distillation and crystallization.

According to the present invention, the isolated pure crystalline sumatriptan base is converted to pharmaceutically acceptable salt by conventional method without subjecting extra purification steps. The following examples will further illustrate certain specific aspects and embodiments of the invention in greater detail and are not to be construe as limiting the scope of the invention. Example 1

A) 3 -(2-DimethylaminoVN-methyl- 1 H-indole-5 -methane sulphonamide benzoate A mixture of 100 gm of 4-hydrazino-N-methyl benzene methane sulphonamide hydrochloride, 1000 ml water, 82.5 gm 4-dimethylamino butyraldehyde diethyl acetal and 100 ml 2N HCl was taken and stirred for 2 hours at 25-30°C. After reaction completion, reaction mass was basified with liquid ammonia and extracted with dichloromethane 750X2 ml. The dichloromethane layer and 700 gm polyphosphoric ester in 1500 ml dichloromethane was stirred at 35-40⁰C for 2 hours and then 2 litres of water was added. The organic layer was separated and aqueous layer was basified with saturated sodium carbonate solution and the product was extracted with ethyl acetate. The organic layer was distilled off completely under vacuum and 500 ml acetone was added. Reaction mass was heated to reflux and 20.6 gm (0.169mol) of benzoic acid was added. After 2 hours of cooling at 0-5°C,the crystal were filtered and dried to give 60-65 gm of 3 -(2-Dimethylamino)-N-methyl-l H-indole-5 -methane sulphonamide benzoate.

B) Preparation of pure 3-(2-DimethylaminoVN-methyl-lH-indole-5-methane sulphonamide

100 gm (0.239mol) of the above 3-(2-dimethylamino)-N-methyl-lH-indole-5- methane sulphonamide benzoate was taken in 500 ml methanol and stirred under reflux for 30 minutes. The methanol solution was treated with 10 gm charcoal and filtered and further cooled to 0-5⁰C and filtered to give pure sumatriptan benzoate, of which the weight was 60-65 gm.

100 gm of the pure benzoate salt was taken in water (1000 ml) and stirred. Simultaneously liquid was added slowly to obtain a pH of 9.0-9.5. The mixture was stirred for 1 hour and cooled to 0-5⁰C. The cooled solution is further filtered, washed with water and sumatriptan base was collected and dried under vacuum at 40-45⁰C. C) Preparation of pure 3-(^"2-pimethylamino)-N-methyl-lH-indole-5-methane sulphonamide succinate

100 gm (0.339 mol) of the pure 3-(2-Dimethylamino)-N-methyl-lH-indole-5- methane sulphonamide was taken in 2000 ml 95% ethanol and 42 gm (0.356 mol) succinic acid was added at reflux temperature. The mass was stirred under reflux for 30 min., later cooled to 0-5°C and finally precipitated salt was filtered. The crystals thus obtained were dried at 45-5O⁰C under vacuum. The product weight was 120 gm.

Example 2 A) 3 -f 2-Dimethylamino)-N-methyl- 1 H-indole-5 -methane sulphonamide

A mixture of 100 gm (0.398mol) of 4-Hydrazino-N-methyl benzene methane sulphonamide hydrochloride, 1000 ml water, 82.5 gm (0.436mol) 4 -dimethylamino butyraldehyde diethyl acetal and 100 ml 2N HCl was taken and stirred for 2 hrs at 25- 3O⁰C. After reaction completion basified with Hq. ammonia and extracted with dichloromethane 750X2 ml.

The dichloromethane layer and 700 gm polyphosphoric ester in 1500ml dichloromethane was stirred at 35-4O⁰C for 2 hours and then 2 litres of water was added. The organic layer was separated and aqueous layer was basified with saturated sodium carbonate solution and the product was extracted with ethyl acetate. The organic layer was distilled off completely under vacuum and 200 ml methyl isobutylketone was added. After 2 hours of cooling at 10-15°C, the crystal were filtered and dried to give 40-45 gm of 3-(2-Dimethylamino)-N-methyl-lH-indole-5~ methane sulphonamide. B) Preparation of 3 -(2-Dimethylamino)-N-methyl- 1 H-indole-5-methane sulphonamide hydrochloride

100 gm of the above (Example-2A) 3-(2-Dimethylamino)-N-methyl-lH- indole-5-methane sulphonamide was taken in 300 ml methanol. 38.65 ml of concentrated. HCl was added slowly at 25-30°C. The solution was cooled to 10-15⁰C and filtered. The product weight was 80-85 gm.

C) Preparation of pure 3-(2-Dimethylamino)-N-methyl-lH-indole-5-methane sulphonamide

100 gm (0.302 mol) of the 3-(2-Dimethylamino)-N-methyl-lH-indole-5- methane sulphonamide hydrochloride salt was taken in water (1000 ml). The aqueous solution was treated with 10 gm charcoal and filtered. Under stirring sodium carbonate solution was added slowly to obtain a pH of 9.0-9.5. The mixture was stirred for 2 hours, filtered, washed with water and dried under vacuum at 40-45°C. Cl Preparation of pure 3-(2-pimethylamino)-N-methyl-lH-indole-5-methane sulphonamide succinate

100 gm (0.339 mol) of the pure 3-(2-Pimethylamino)-N-methyl-lH-indole-5- methane sulphonamide was taken in 2000 ml 95% ethanol and 42 gm (0.356 mol) succinic acid was added at reflux temperature. The mass was stirred under reflux for 30 minutes, later cooled to 0-5⁰C and finally precipitated salt was filtered. The crystals thus obtained were dried at 45-50°C under vacuum. The product weight was 120 gm. Example 3

Preparation of pure 3-(2-DimethylaminoVN-methyl- 1 H-indole-5 -methane sulphonamide

100 gm (0.239mol) of the 3-(2-Dimethylamino)-N-methyl-lH-indole-5- methane sulphonamide benzoate salt was taken in mixture of water (500 ml) and methanol (500 ml). The solution was treated with 10 gm charcoal, 5 gm sodium dithionite and filtered. Under stirring liquid Ammonia solution was added slowly to obtain a pH of 9.0-9.5. The mixture was stirred for 2 hours. The resultant solution was cooled to 0-5°C, filtered, washed with water and dried under vacuum at 40-45°C.

Example 4

A) 3-(^"2-DimethylaminoVN-methyl-lH-indole-5-methane sulphonamide benzoate A mixture of 100 gm (0.398mol) of 4-Hydrazino-N-methyl benzene methane sulphonamide hydrochloride, 1000 ml water, 82.5 gm (0.436mol) 4 -dimethylamino butyraldehyde diethyl acetal and 100 ml 2N HCl was taken and stirred for 2 hours at 25-30°C. After reaction completion, the solution was basified with liquid ammonia and extracted with dichloromethane 500X2 ml. The dichloromethane layer and 1000 gm polyphosphoric ester in 600ml dichloromethane was stirred at 35-40°C for 2 hours and then 2 litres water was added. The organic layer was separated and aqueous layer was basified with sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was treated with silica gel 60-100 mesh and then filtered. Silica gel washed with ethyl acetate 1000X3 ml. The absorbed product on silica gel was eluted with methanol 1000X2 ml. Filtrate methanol was distilled off completely under vacuum and 500 ml acetone was added. It was further heated to reflux and 20.6 gm (0.169mol) of benzoic acid was added. After 2 hours of cooling at 0-5⁰C, the crystal were filtered and dried to give 60-65 gm of 3-(2-Dimethylamino)-N-methyl-lH-indole-5-methane sulphonamide benzoate. The purity of the product was 92-95% ( HPLC). B) Preparation of pure S-G-pimethylaminoVN-methyl-lH-indole-S-methane sulphonamide

100 gm (0.239mol) of the above impure 3~(2-Dimethylamino)-N-methyl-lH- indole-5 -methane sulphonamide benzoate was taken in 500 ml methanol and stirred under reflux for 30 minutes. The methanol solution was treated with 10 gm charcoal and filtered. The solution was cooled to 0-5°C and filtered. Purified benzoate (60-65 gm) has purity of 97% (HPLC).

100 gm of the pure benzoate salt was taken in water (1000 ml) and under stirring liquid ammonia was added slowly to obtain a pH of 9.0-9.5. The mixture was stirred for 1 hour and then cooled to 0-5°C, filtered, washed with water and dried under vacuum at 40-45°C. The product has the purity 98-99 %( HPLC).

C) Preparation of pure 3-(2-Dimethylamino^')-N-methyl-lH-indole-5-methane sulphonamide succinate

100 gm(0.339 mol) of the pure 3-(2-Dimethylamino)-N-methyl-lH-indole-5- methane sulphonamide was taken in 2000 ml 95% ethanol and 42 gm(0.356 mol) succinic acid was added at reflux temperature. The mass was stirred under reflux for 30 minutes. Later it was cooled to 0-5°C and finally precipitated salt was filtered. The crystals thus obtained were dried at 45-50°C under vacuum. The product 120 gm has the purity of 99.5 % (HPLC).

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description and examples given above are intended to illustrate and not to limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof that do not depart from the spirit and scope of the invention.

Claims

We Claim:

1. An improved process for preparing crystalline form of Sumatriptan base comprising the steps of:

(a) suspending the Sumatriptan acid addition salt in a water or mixture of water and water miscible organic solvents;

(b) adjusting pH of step b) to basic with base; and

(c) isolating the Sumatriptan base.

2. The process according to claim 1, wherein the acid addition salts are selected from a group comprising hydrochloride, hydrobromide, phosphate, benzoate, methane sulphonate, oxalate, or succinate.

3. The process according to claim 1, wherein the water miscible organic solvent is selected from a group comprising methanol, ethanol, isopropyl alcohol.

4. The process according to claim 1, wherein the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, ammonia, triethyl amine.

5. The process according to claim 1, wherein the process further comprising using anti-oxidant.

6. The process according to claim 5, wherein the anti-oxidant is selected from sodium dithionite, butylated hydroxyl toluene or butylated hydroxyl anisole.

7. A novel pure crystalline Sumatriptan base, wherein said base is characterized by having new pattern peaks employing analytical tools selected from X-ray powder diffractometer, differential scanning calorimetry thermogram or Infrared spectrophotometer.

8. The novel pure crystalline Sumatriptan base according to claim 7, wherein said base is characterized by having X-ray powder diffraction pattern peaks at about 9.97 (±) 0.2, 17.29 (±) 0.2, 21.68 (±) 0.2, two-theta.

9. The novel crystalline Sumatriptan base according to claim 7, wherein said base is characterized by having an X-ray powder diffraction pattern peaks at about 9.97 (±) 0.2, 13.3 (±) 0.2, 15.88 (±) 0.2, 21.09 (±) 0.2, 21.64 (±) 0.2, 22.76 (±) 0.2, two-theta.

10. The novel crystalline Sumatriptan base according to claim 7, wherein said base is characterized by having an differential scanning calorimetry thermogram having a peak at about 67 ° C, about 106 ° C and 174° C (±) 0.1%.

11. An improved process for preparing sumatriptan acid addition salt, wherein the process comprising the steps of: a) adsorbing Sumatriptan base solution on stationary phase; b) leaching/ treating the resultant stationary phase with an acid; and c) isolating acid addition salt of sumatriptan .

12. The process according to claim 11, wherein the sumatriptan base solution is prepared employing a solvent selected from ethyl acetate, acetone or methyl ethyl ketone.

13. The process according to the claim 11, wherein the stationary phase is silica gel.

14. The process according to the claim 11, wherein the acid is selected from a group comprising hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, methane sulphonic acid, oxalic acid and succinic acid.

15. An improved process for preparing Sumatriptan acid addition salt, wherein the process comprising the steps of: a) adsorbing Sumatriptan base solution on stationary phase; b) leaching/ treating the resultant stationary phase with a solvent; c) adding acid to the resultant of step (b); and d) isolating acid addition salt of Sumatriptan .

16. The process according to claim 15, wherein the sumatriptan base solution is prepared employing a solvent selected from ethyl acetate, acetone or methyl ethyl ketone.

17. The process according to the claim 15, wherein the stationary phase is silica gel.

18. The process according to claim 15, wherein the solvent is selected from a group comprising methanol, ethanol, isopropyl alcohol.

19. The process according to the claim 15, wherein the acid is selected from a group comprising hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, methane sulphonic acid, oxalic acid and succinic acid.