Indian Patents. 252762:MANUFACTURING PROCESS FOR HIGHLY PURE CRYSTALLINE GRANISETRON BASE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

Title of Invention	MANUFACTURING PROCESS FOR HIGHLY PURE CRYSTALLINE GRANISETRON BASE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
Abstract	The present invention discloses an improved, commercial process for the preparation of high purity (>99.9%) crystalline base of granisetron (1 -methyl-N- [(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-lH-indazole-3-carboxamide), having the formula (1), and its use in the process for the manufacture of pharmaceutically acceptable hydrochloride salt.

Full Text	INTRODUCTION The present invention relates to an improved process for the preparation of high purity crystalline base of Granisetron, and its pharmaceutically acceptable salts. More particularly the present invention provides an improved process for the preparation of high purity (>99.9%) crystalline base of Granisetron and its pharmaceutically acceptable hydrochloride salt. Granisetron base and its pharmaceutically acceptable salts are well known antiemetic drug. BACK GROUND OF THE INVENTION Granisetron is currently being used in the anticancer chemotherapy. It is 1 -methyl-TV-[(3-en It is shown to be a potent and selective 5-hydroxy tryptamine 5-HT3 receptor antagonist. It was also shown to be a highly effective inhibitor of cytotoxic drug and x-ray irradiation induced emesis. Granisetron was first developed and disclosed by Beecham group (GB), in their European Patent Application EP 200444; corresponding to US 4886808. According to Example (6) of EP 200444, Granisetron of the formula (1) can be prepared by reacting a solution of 1-methyl indazole-3-carboxylic acid chloride in dichloromethane with a solution of endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine and triethylamine in dichloromethane. After the normal workup and subsequent evaporation of the solvent, Granisetron base was obtained as an oil. This oil was purified by using column chromatography and reacted with hydrogen chloride to give the desired compound, Granisetron Hydrochloride (mp: 290-2°C). In this patent the preparation of the starting material, l-methyl-indazole-3-carbonyl chloride was not disclosed and also the reaction conditions for the condensation of acid chloride with endo-amine was not disclosed. Moreover this process is not suitable for industrial production of the drug as it involves the purification by column chromatography, which is not practicable and cumbersome process. Other processes for preparing Granisetron were later disclosed. International application WO 95/23799, discloses an alternative process for preparing Granisetron or a pharmaceutically acceptable salt thereof, which process comprises deprotecting a compound of structure (2), where R is a nitrogen- protecting group which does not significantly reduce the nucleophilicity of a secondary amino group and optionally forming a pharmaceutically acceptable salt. International application WO 97/30049, discloses an alternative process for preparing Granisetron, by cyclisation of a previously methylated compound of formula (3), Although the said international application discloses a process for preparing Granisetron, by methylation followed by cyclisation, it should be noted that the yield from the last steps might be very low. International Application WO 03/080606, discloses an alternative process for preparing Granisetron, or a pharmaceutical^ acceptable salt thereof, which comprises: (a) cyclisation of a compound of formula (4), in an inert solvent and at a temperature between 0-100°C in the presence of a strong acid in order to yield the compound of the formula (5). (b) methylation of the compound of the formula (5), with an alkylating agent, in the presence of a base, in an inert solvent and at a temperature between 0-160°C and optionally obtaining a pharmaceutically acceptable salt thereof. According to the process disclosed in examples (3) of the above said patent WO 03/080606, the Granisetron Base (residue) obtained, is having a purity of 77.7% and m.p: 121-122°C and when this base was converted to Granisetron Hydrochloride, its purity was enhanced to 92%. Similarly, according to the process disclosed in Example (4) of the above said patent the purity of Granisetron Base was 84.1% and that of Hydrochloride salt was 94% only. In the same way, the process disclosed in Example (5) of the above said patent, gives the Granisetron base purity as 84.7% and that of hydrochloride as 96%. The Example (6) gives the Granisetron base purity as 86% and that of hydrochloride salt as 97%. By any means, the Granisetron base obtained by the process disclosed in the above said patent WO 03/080606 was having a maximum purity of 86% and that of hydrochloride was 97% only, which is not acceptable for pharmaceutical use as an Active Pharmaceutical Ingredient (API). Thus, there is a need for a highly pure Granisetron base or its pharmaceutically acceptable hydrochloride salt, which can be produced industrially. OBJECTIVES OF THE PRESENT INVENTION Accordingly, the main objective of the present invention is to provide an improved process for the preparation of crystalline and highly pure (>99.9%) Granisetron base of the formula (1), Another objective of the present invention is to provide an improved process for the manufacture of salts of Granisetron, preferably the hydrochloride, in which the crystalline and highly pure (>99%) granisetron base is used. The crystalline base of Granisetron prepared according to the present invention has a melting point between 148 - 152°C, more preferably between 150 - 152°C. Whereas its purity is more than 99.6%, preferably more than 99.8%, most preferably more than 99.9% by HPLC (% area) and the following identified and pharmacoepial listed impurities are in the range of 0 to 0.05% (% area) (i) endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl)-2-methyl-2H-indazole-3-carboxamide (ii) endo-N- (9-methyl-9-azabicyclo [3.3.1]non-3-yl -lH-indazole-3-carboxamide (iii) endo-N- (9-azabicyclo [3.3.1] non-3-yl)-1 -methyl-1 H-indazole-3-carboxamide (iv) 1 -methyl-1 H-indazole-3 -carboxylic acid (v) exo-N-(9-methyl-9-azabicyclo[3.3.1 ]non-3-yl)-1 -methyl-1 H-indazole-3-carboxamide (vi) 2-methyl-2H-indazole-3-carboxylic acid (vii) 1 H-indazole-3 -carboxylic acid (viii) (1 -methylindazol-3-yl)carboxylic anhydride SUMMARY OF THE INVENTION Accordingly, the present invention provides a process for the preparation of high purity(>99.9% by HPLC) crystalline Granisetron base of the formula (1), which comprises, (i) suspending the crude base of granisetron in a protic solvent or a mixture of protic solvents, such as alcohols, at 25-35°C, cooling to a temperature in the range of 0 to 15°C, preferably 0 to 5°C and stirring for a period in the range of one to three hours. (ii) filtering the crystals so formed in the alcoholic solvent medium used in step (ii), by conventional techniques, washing the crystals with the same solvent and if necessary drying the crystalline Granisetron base formed under vacuum and if desired, (iii) converting the Granisetron base obtained in step (ii) above into its pharmaceutical^ acceptable salts thereof by conventional techniques. The alcoholic solvent used in step (i) may be selected from, isopropyl alcohol, ethyl alcohol, methyl alcohol, isobutyl alcohol, etc., preferably, isopropyl alcohol. Granisetron base prepared according to the present invention was found to be a stable crystalline solid with very high melting point (150 - 152°C) and high purity (> 99.9% by HPLC area %). The melting point observed by us is nearly 30°C higher than the prior art melting point. This process for preparation of high purity Granisetron crystals is novel and simple. It avoids the cumbersome column chromatography purification disclosed in prior art method. If desired the granisetron base (wet or dry) as obtained in step (ii) above, can be further converted into its pharmaceutically acceptable salts, such as hydrochloride in a commercially simple and viable process. Accordingly, the present invention also provides a process for the preparation of high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base of formula (1), which comprises, (a) suspending the crystalline Granisetron base (wet or dry) obtained in step (ii) of the process defined above in aqueous or non-aqueous alcoholic solvent or a mixture thereof (b) treating the resultant suspension with molar quantity of aqueous or alcoholic hydrochloric acid (c) filtering off the resulting Granisetron hydrochloride salt formed and washing the wet cake with the same solvent and if necessary, drying it (d) dissolving the wet or dry Granisetron hydrochloride in a polar solvent such as water, alcohols, amides, nitriles, esters, and the like or a mixture thereof (e) treating the resultant solution with a decolorizing agent (f) filtering off the decolorizing agent from the solution containing the Granisetron hydrochloride (g) distilling off the solvent partially from the solution and cooling to a temperature in the range of 25-35°C (h) filtering the resulting crystalline salt of Granisetron hydrochloride by conventional methods and washing the wet cake with same solvent and drying it The starting compound namely endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l-methyl-1H-indazole-3-carboxamide may be prepared by any known conventional methods, for example, by the method described in Example 6 of EP 200444. The aqueous or non-aqueous alcoholic solvent used in step (a) is selected from the methanol, ethanol, isopropanol, n-butanol, preferably isopropanol. The polar solvent used in step (d) is selected from water; alcohols like methanol, ethanol, isopropanol, n-butanol, preferably isopropanol; amides like N,N-dimethylformamide; nitriles like acetonitrile; esters like ethyl acetate, isopropyl acetate or a mixture thereof. The decolorizing agent used in step (e) is for example activated charcoal. Accordingly, the process of the present invention for preparing hydrochloride salt of Granisetron is very high yielding (>90%), commercially feasible with pharmaceutical^ acceptable quality. The present invention is illustrated by the following examples, which are not intended to limit the effective scope of this invention in any way. EXAMPLE 1 Preparation of l-Methyl-indazole-3-carbonyl chloride Into an all glass reactor, charged chloroform (12L), followed by l-methyl-indazole-3-carboxylic acid (2Kg) and N,N-dimethylformamide (0.2L). Then slowly added thionyl chloride (4Kg) at room temperature. Raised the mass temperature to reach reflux condition and maintained at reflux condition for 4 hr. Checked the completion of the reaction by HPLC. Then distilled off chloroform and excess thionyl chloride completely under vaccum. Cooled the reaction to room temperature and added chloroform (5L) and again distilled off chloroform completely under vacuum. Repeated the operation one more time with fresh chloroform (5L). Cooled the reaction mass to room temperature. As the acid chloride is an unstable compound, dissolved the acid chloride in methylene chloride (40L) and kept the reaction mass under nitrogen atmosphere till proceed to next stage. A small sample was taken, triturated with n-hexane, quickly filtered under nitrogen atmosphere and dried under vacuum and checked IR and M.P. The IR spectrum showed a strong band at 1748 cm'1 and MP is 122°C. Example 2 Preparation of l-methyl-A^[(3-e/irf^)-9-methyl-9-azabicyclo[3JJ]non-3-yI]-l^-indazole-3-carboxamide [Granisetron base] The methylene chloride layer containing l-methyl-indazole-3-carbonylchloride (prepared from 2Kg of l-methyl-indazole-3-carboxylic acid, according to the Example-1) was transferred to an all glass reactor under nitrogen atmosphere and cooled to 15-20°C. Slowly added a mixture of endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (2Kg) and triethylamine (1.45Kg) in about 1!4 hr and maintained the reaction mass for lA hr at the same temperature and checked the completion of the reaction by HPLC. Then treated the organic layer with 8L of 10% sodium bicarbonate solution twice and finally washed the organic layer with 10L of DM water. The organic layer was dried with anhydrous sodium sulphate and distilled off methylene chloride completely under vacuum. To the residue remained in the reactor, isopropyl alcohol (5L) added and cooled to 0-5 °C and stirred for about 2 hr to make good slurry and centrifuged and washed the cake with chilled isopropyl alcohol. Dried the material under vacuum to get a very nice crystalline solid. Drywt = 3.2Kg M.P = 152°C HPLC purity = 99.9% Example 3 Preparation of l-methyl-A^[(3-ewrf0)-9-methyl^ carboxamide mono hydrochloride (Granisetron Hydrochloride) - Technical grade Into an all glass reactor, charged isopropyl alcohol (40L), followed by Granisetron base (3Kg) prepared by the process described in Example 2. Cooled the reaction mass to 20-25°C and isopropyl alcohol containing HC1 was slowly added (HC1 1.1 mole to 1 mole of Granisetron base) at 20-25°C and stirred for 45 min at the same temperature, so that Granisetron HC1 precipitated out. Then slowly raised the mass temperature to reflux condition and refluxed for about 2 hr and cooled to 30»35°C and maintained for about 1 hr at that temperature and centrifuged the mass and washed the cake with isopropyl alcohol and dry the material at 65-70°C till constant weight obtained. Drywt = 3.2Kg HPLC purity - 99.86% The pharmaceutical grade Granisetron HC1 was prepared by recrystallisation of technical grade material obtained, in aqueous isopropyl alcohol by adopting the following procedure. Example 4 Preparation of Granisetron HC1 (Pharma Grade) from aqueous Isopropyl alcohol Into a glass-lined reactor, charged isopropyl alcohol (28L), DM water (7L) and Granisetron hydrochloride (3Kg dry), prepared by the process described in Example 3 under stirring. Then slowly raised the mass temperature to 65-70°C and maintained for 45 minutes at the same temperature for complete dissolution. Then charged activated carbon slurry in isopropyl alcohol (0.5Kg in 4 L of isopropyl alcohol and 1L of water) into the reactor. Maintained for 45 min at the same temperature and filtered into another glass lined reactor, and washed the cake with aq. isopropyl alcohol (5L of isopropyl alcohol in 1L water) and collected the filtrate into the glass lined reactor. Charged fresh isopropyl alcohol (30L) into the reactor and distilled out about 30-35L of isopropyl alcohol and water mixture. Cooled the reaction mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 30-35L of isopropyl alcohol and water mixture. Cooled the mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 30-35L of isopropyl alcohol and water mixture. Repeated the process for 4 more times (Moisture content in distillate should be about 1.0%w/v.). Then cooled the reaction mass to 30-35°C and maintained for 90 minutes at the same temperature and centrifuged the material, washed the cake with isopropyl alcohol (10L). Dried the material in a vacuum tray drier at 70-75°C till LOD (Loss on drying) is not more than 0.5%. Dry wt = 2.8Kg Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1. Example 5 Preparation of l-methyl-A^[(3-^/i^)-9-methyl-9-azabicyclo[33.1]non-3-yl]-l/^-indazole-3-carboxamide [Granisetron Base] The methylene chloride layer containing l-methyl-indazole-3-carbonyl chloride [prepared from 2Kg of l-methyl-indazole-3-carboxylic acid, according to the process described in the Example-1] was transferred into an all glass reactor under nitrogen atmosphere and cooled to 15-20°C. To this a mixture of endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (2Kg) and triethylamine (1.45Kg) was slowly added in about VA hr and maintained the reaction mass for lA hr at the same temperature and checked the completion of the reaction by HPLC. Then treated the organic layer with 8L of 10% sodium bicarbonate solution twice and finally washed the organic layer with 10L of DM water. The organic layer was dried with anhydrous sodium sulphate and distilled off methylene chloride completely under vacuum. To the residue remained in the reactor, isopropyl alcohol (5L) added and cooled to 0-5°C and stirred for about 2 hr to make good slurry and centrifuged and washed the cake with chilled isopropyl alcohol. The wet Granisetron base obtained was directly used (without drying) to prepare Granisetron HC1 (Tech) as given in the example (6) below. Example 6 Preparation of l-methyl-Ar-[(3-^/irfo)-9-methyl-9-azabicyclo[3.3,l]non-3-yl]-l^-indazole-3-carboxamide mono hydrochloride [Granisetron Hydrochloride] - Technical grade Into another all glass reactor, charged isopropyl alcohol (40L) followed by Granisetron base wet material (equivalent to 3Kg dry), as obtained by the process described in Example 5. Cooled the reaction mass to 20-25°C and isopropyl alcohol containing HC1 (1.1 mole to 1 mole of Granisetron base) was slowly added maintaining mass temperature at 20-25°C. Maintained the reaction mixture for 45 minutes at the same temperature and then slowly raised to reflux condition. Then refluxed for about two hrs and then cooled to 30-35°C. Maintained at the same temperature for about 1 hour and centrifuged the material and washed the cake with about 8L of isopropyl alcohol. The wet cake obtained was directly used (without drying) for rectystallisation to get pharmaceutical grade granisetron hydrochloride as given in the following Example 7. Example 7 Preparation of Granisetron HCI (Pharma Grade) from Aqueous Isopropyl alcohol Into a glass-lined reactor, charged isopropyl alcohol (28L), DM water (7L) and Granisetron hydrochloride wet cake (equivalent to 3Kg dry), prepared by the process described in Example 6 under stirring. Then slowly raised the mass temperature to 65-70°C and maintained for 45 min at the same temperature for complete dissolution. Then charged activated carbon slurry (prepared by mixing of 0.5 Kg of activated carbon with 4L of isopropyl alcohol and 1L of water) into the reactor. Maintained for 45 min at the same temperature and filtered into another glass lined reactor, and washed the cake with aq. isopropyl alcohol (5L of isopropyl alcohol and 1L water) and collected the filtrate into the glass lined reactor. Charged fresh isopropyl alcohol (30L) into the reaction and distilled out about 30-35L of isopropyl alcohol and water mixture. Cooled the mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 3 0-3 5 L of isopropyl alcohol and water mixture. Cooled the mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 30-35L of isopropyl alcohol and water mixture. Repeated the process for 4 more times (Moisture content in distillate should be about 1.0%w/v). Then cooled the reaction mass to 30-35°C and maintained for 90 min at the same temperature and centrifuged the material, washed the cake with isopropyl alcohol (10L). Dried the resultant pharmaceutical grade Granisetron hydrochloride material in a vacuum tray drier at 70-75 °C till LOD is not more than 0.5%w/w. Dry wt - 2.75Kg Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1. Example 8 Preparation of Granisetron HCl(Pha) from Ethyl alcohol Into a 1L three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, condenser, etc. charged 650mL of ethyl alcohol, followed by lO.Og Granisetron HCI (Tech) prepared by the process described in Example 3 and slowly raised the temperature to 70±2°C, and stirred for 15 min to get clear solution. Then 2.0g of activated carbon added, stirred for lOmin and filtered. Washed the cake with 20 ml of ethyl alcohol. Distilled off around 175 ml of ethyl alcohol from the filtrate and cooled to 25-35°C and maintained for 90min and filtered. Washed the cake with 30 ml of ethyl alcohol and dried the material at 70-75°C till constant weight is obtained. Dry weight : 8.0g Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1. Example 9 Preparation of Granisetron HC1 (Pharma Grade) from Methyl alcohol Into a three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, condenser, etc. charged lOOmL of methanol, followed by lO.Og granisetron HC1 (Tech) prepared by the process described in Example 3 and raised the temperature to 60±2°C, and maintained for about 15 min to get clear solution. Then 2.0g activated carbon added, filtered and washed the carbon cake with 15mL of methanol. Then distilled off methanol around 50mL from the filtrate and cooled to the reaction mass to 25-35°C and maintained for 90min and filtered the mass. Washed the cake with 20 ml of methanol and dried the material at 70-75 °C till constant weight is obtained. Dry weight : 7.0g Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1. Example 10 Preparation of Granisetron HC1 (Pharma Grade) from N,N-Dimethylformamide Into a three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, condenser, etc charged 1250 ml of N,N-dimethylformamide, followed by lO.Og Granisetron HC1 (Tech) prepared by the process described in Example 3 and raised the temperature to 70±2°C, and maintained for about 15min to get clear solution. Then 2.0g activated carbon added, filtered and washed the carbon cake with 15mL of N,N-dimethylformamide. Then distilled off N,N-dimethylformamide around 625mL from the filtrate and cooled the reaction mass to 25-35°C and maintained for 90min and filtered the mass. Washed the cake with 20mL of N,N-dimethylformamide and dried the material at 70-75°C till constant weight is obtained. Dry weight : 7.6g Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1. Advantages of the present invention 1. Granisetron base prepared by the present process is of high purity (>99.9%). 2. The process does not require any chromatographic purification; therefore it is simple, commercially viable, and economical. 3. The high purity Granisetron base prepared according to the present invention can be converted to pharmaceutically acceptable salts such as hydrochloride salt with pharmaceutically acceptable grade. WE CLAIM: 1. An improved process for the preparation of high purity (>99.9% by HPLC) crystalline Granisetron base of formula (1), which comprises, (i) suspending the crude base of Granisetron in a protic solvent or a mixture of protic solvents, such as alcohols, at 25-35°C, cooling to a temperature in the range of 0 to 15°C, preferably 0 to 5°C and stirring for a period in the range of one to three hours (ii) filtering the crystals so formed in the alcoholic solvent medium used in step (ii), by conventional techniques, washing the crystals with the same solvent and if necessary drying the crystalline Granisetron base formed under vacuum and if desired, (iii) converting the Granisetron base obtained in step (ii) above into its pharmaceutically acceptable salts thereof by conventional techniques 2. An improved process for the preparation of high purity (>99.9% by HPLC) crystalline Granisetron base as claimed in claim 1 where in the alcoholic solvent used in step (i) is selected from isopropyl alcohol, ethyl alcohol, methyl alcohol, isobutyl alcohol, preferably, isopropyl alcohol. 3. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base, which comprises, (a) suspending the crystalline Granisetron base (wet or dry) obtained in step (ii) of the process defined in claim 1 above in aqueous or non-aqueous alcoholic solvent or a mixture thereof (b) treating the resultant suspension with molar quantity of aqueous or alcoholic hydrochloric acid (c) filtering off the resulting Granisetron hydrochloride salt formed and washing the wet cake with the same solvent and if necessary, drying it (d) dissolving the wet or dry Granisetron hydrochloride in a polar solvent such as water, alcohols, amides, nitriles, esters, and the like or a mixture thereof (e) treating the resultant solution with a decolorizing agent (f) filtering off the decolorizing agent from the solution containing the Granisetron hydrochloride (g) distilling off the solvent partially from the solution and cooling to a temperature in the range of25-35°C (h) filtering the resulting crystalline salt of Granisetron hydrochloride by conventional methods and washing the wet cake with same solvent and drying it 4. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base as claimed in claim 3 wherein the non-aqueous alcoholic solvent used in step (a) is selected from methyl alcohol, ethyl alcohol, isoproyl alcohol, preferably isopropyl alcohol. 5. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base as claimed in claims 3 & 4 where in the polar solvent used in step (d) is selected from a group consisting of alcohols like methyl alcohol, ethyl alcohol, isopropyl alcohol with or without water or amides like N,N-dimethylformamide or nitriles like acetonitrile or esters like ethyl acetate, isopropyl acetate or a mixture thereof. 6. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base as claimed in claims 3 to 5 wherein the decolorizing agent used in step (e) is selected as activated charcoal. 7. An improved process for the preparation of crystalline, high purity (>99.9% by HPLC) Granisetron base of formula (1) given in claim 1 as herein described with reference to the Examples 2 & 5. 8. An improved process for the preparation of hydrochloride salt from high purity (>99.9% by HPLC) Granisetron base of formula (1) given in claim 1 as herein described with reference to the Examples 3? 4, and 6 to 10.

Full Text

INTRODUCTION
The present invention relates to an improved process for the preparation of high purity crystalline base of Granisetron, and its pharmaceutically acceptable salts. More particularly the present invention provides an improved process for the preparation of high purity (>99.9%) crystalline base of Granisetron and its pharmaceutically acceptable hydrochloride salt. Granisetron base and its pharmaceutically acceptable salts are well known antiemetic drug.
BACK GROUND OF THE INVENTION
Granisetron is currently being used in the anticancer chemotherapy. It is 1 -methyl-TV-[(3-en It is shown to be a potent and selective 5-hydroxy tryptamine 5-HT3 receptor antagonist. It was also shown to be a highly effective inhibitor of cytotoxic drug and x-ray irradiation induced emesis.
Granisetron was first developed and disclosed by Beecham group (GB), in their European Patent Application EP 200444; corresponding to US 4886808. According to Example (6) of EP 200444, Granisetron of the formula (1) can be prepared by reacting a solution of 1-methyl indazole-3-carboxylic acid chloride in dichloromethane with a solution of endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine and triethylamine in dichloromethane. After the normal workup and subsequent evaporation of the solvent, Granisetron base was obtained as an oil. This oil was purified by using column chromatography and reacted with hydrogen chloride to give the desired compound, Granisetron Hydrochloride (mp: 290-2°C).

In this patent the preparation of the starting material, l-methyl-indazole-3-carbonyl chloride was not disclosed and also the reaction conditions for the condensation of acid chloride with endo-amine was not disclosed. Moreover this process is not suitable for industrial production of the drug as it involves the purification by column chromatography, which is not practicable and cumbersome process.
Other processes for preparing Granisetron were later disclosed. International application WO 95/23799, discloses an alternative process for preparing Granisetron or a pharmaceutically acceptable salt thereof, which process comprises deprotecting a compound of structure (2),

where R is a nitrogen- protecting group which does not significantly reduce the nucleophilicity of a secondary amino group and optionally forming a pharmaceutically acceptable salt.
International application WO 97/30049, discloses an alternative process for preparing Granisetron, by cyclisation of a previously methylated compound of formula (3),

Although the said international application discloses a process for preparing Granisetron, by methylation followed by cyclisation, it should be noted that the yield from the last steps might be very low.

International Application WO 03/080606, discloses an alternative process for preparing Granisetron, or a pharmaceutical^ acceptable salt thereof, which comprises: (a) cyclisation of a compound of formula (4), in an inert solvent and at a temperature between 0-100°C in the presence of a strong acid in order to yield the compound of the formula (5).

(b) methylation of the compound of the formula (5), with an alkylating agent, in the presence of a base, in an inert solvent and at a temperature between 0-160°C and optionally obtaining a pharmaceutically acceptable salt thereof.
According to the process disclosed in examples (3) of the above said patent WO 03/080606, the Granisetron Base (residue) obtained, is having a purity of 77.7% and m.p: 121-122°C and when this base was converted to Granisetron Hydrochloride, its purity was enhanced to 92%.
Similarly, according to the process disclosed in Example (4) of the above said patent the purity of Granisetron Base was 84.1% and that of Hydrochloride salt was 94% only.
In the same way, the process disclosed in Example (5) of the above said patent, gives the Granisetron base purity as 84.7% and that of hydrochloride as 96%. The Example (6) gives the Granisetron base purity as 86% and that of hydrochloride salt as 97%.

By any means, the Granisetron base obtained by the process disclosed in the above said patent WO 03/080606 was having a maximum purity of 86% and that of hydrochloride was 97% only, which is not acceptable for pharmaceutical use as an Active Pharmaceutical Ingredient (API).
Thus, there is a need for a highly pure Granisetron base or its pharmaceutically acceptable hydrochloride salt, which can be produced industrially.
OBJECTIVES OF THE PRESENT INVENTION
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of crystalline and highly pure (>99.9%) Granisetron base of the formula (1),

Another objective of the present invention is to provide an improved process for the manufacture of salts of Granisetron, preferably the hydrochloride, in which the crystalline and highly pure (>99%) granisetron base is used.
The crystalline base of Granisetron prepared according to the present invention has a melting
point between 148 - 152°C, more preferably between 150 - 152°C. Whereas its purity is more
than 99.6%, preferably more than 99.8%, most preferably more than 99.9% by HPLC (% area)
and the following identified and pharmacoepial listed impurities are in the range of 0 to 0.05%
(% area)
(i) endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl)-2-methyl-2H-indazole-3-carboxamide
(ii) endo-N- (9-methyl-9-azabicyclo [3.3.1]non-3-yl -lH-indazole-3-carboxamide
(iii) endo-N- (9-azabicyclo [3.3.1] non-3-yl)-1 -methyl-1 H-indazole-3-carboxamide
(iv) 1 -methyl-1 H-indazole-3 -carboxylic acid
(v) exo-N-(9-methyl-9-azabicyclo[3.3.1 ]non-3-yl)-1 -methyl-1 H-indazole-3-carboxamide
(vi) 2-methyl-2H-indazole-3-carboxylic acid

(vii) 1 H-indazole-3 -carboxylic acid
(viii) (1 -methylindazol-3-yl)carboxylic anhydride
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of high purity(>99.9% by HPLC) crystalline Granisetron base of the formula (1),

which comprises,
(i) suspending the crude base of granisetron in a protic solvent or a mixture of protic solvents, such as alcohols, at 25-35°C, cooling to a temperature in the range of 0 to 15°C, preferably 0 to 5°C and stirring for a period in the range of one to three hours.
(ii) filtering the crystals so formed in the alcoholic solvent medium used in step (ii), by conventional techniques, washing the crystals with the same solvent and if necessary drying the crystalline Granisetron base formed under vacuum and if desired,
(iii) converting the Granisetron base obtained in step (ii) above into its pharmaceutical^ acceptable salts thereof by conventional techniques.
The alcoholic solvent used in step (i) may be selected from, isopropyl alcohol, ethyl alcohol, methyl alcohol, isobutyl alcohol, etc., preferably, isopropyl alcohol.
Granisetron base prepared according to the present invention was found to be a stable crystalline solid with very high melting point (150 - 152°C) and high purity (> 99.9% by HPLC area %). The melting point observed by us is nearly 30°C higher than the prior art melting point. This process for preparation of high purity Granisetron crystals is novel and simple. It avoids the cumbersome column chromatography purification disclosed in prior art method.

If desired the granisetron base (wet or dry) as obtained in step (ii) above, can be further converted into its pharmaceutically acceptable salts, such as hydrochloride in a commercially simple and viable process.
Accordingly, the present invention also provides a process for the preparation of high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base of formula (1),
which comprises,
(a) suspending the crystalline Granisetron base (wet or dry) obtained in step (ii) of the process defined above in aqueous or non-aqueous alcoholic solvent or a mixture thereof
(b) treating the resultant suspension with molar quantity of aqueous or alcoholic hydrochloric acid
(c) filtering off the resulting Granisetron hydrochloride salt formed and washing the wet cake with the same solvent and if necessary, drying it
(d) dissolving the wet or dry Granisetron hydrochloride in a polar solvent such as water, alcohols, amides, nitriles, esters, and the like or a mixture thereof
(e) treating the resultant solution with a decolorizing agent
(f) filtering off the decolorizing agent from the solution containing the Granisetron hydrochloride
(g) distilling off the solvent partially from the solution and cooling to a temperature in the range of 25-35°C
(h) filtering the resulting crystalline salt of Granisetron hydrochloride by conventional methods and washing the wet cake with same solvent and drying it

The starting compound namely endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l-methyl-1H-indazole-3-carboxamide may be prepared by any known conventional methods, for example, by the method described in Example 6 of EP 200444.
The aqueous or non-aqueous alcoholic solvent used in step (a) is selected from the methanol, ethanol, isopropanol, n-butanol, preferably isopropanol. The polar solvent used in step (d) is selected from water; alcohols like methanol, ethanol, isopropanol, n-butanol, preferably isopropanol; amides like N,N-dimethylformamide; nitriles like acetonitrile; esters like ethyl acetate, isopropyl acetate or a mixture thereof. The decolorizing agent used in step (e) is for example activated charcoal.
Accordingly, the process of the present invention for preparing hydrochloride salt of Granisetron is very high yielding (>90%), commercially feasible with pharmaceutical^ acceptable quality.
The present invention is illustrated by the following examples, which are not intended to limit the effective scope of this invention in any way.
EXAMPLE 1 Preparation of l-Methyl-indazole-3-carbonyl chloride
Into an all glass reactor, charged chloroform (12L), followed by l-methyl-indazole-3-carboxylic acid (2Kg) and N,N-dimethylformamide (0.2L). Then slowly added thionyl chloride (4Kg) at room temperature. Raised the mass temperature to reach reflux condition and maintained at reflux condition for 4 hr. Checked the completion of the reaction by HPLC. Then distilled off chloroform and excess thionyl chloride completely under vaccum. Cooled the reaction to room temperature and added chloroform (5L) and again distilled off chloroform completely under vacuum. Repeated the operation one more time with fresh chloroform (5L). Cooled the reaction mass to room temperature. As the acid chloride is an unstable compound, dissolved the acid chloride in methylene chloride (40L) and kept the reaction mass under nitrogen atmosphere till proceed to next stage. A small sample was taken, triturated with n-hexane, quickly filtered under nitrogen atmosphere and dried under vacuum and checked IR and M.P. The IR spectrum showed a strong band at 1748 cm'1 and MP is 122°C.

Example 2 Preparation of l-methyl-A^[(3-e/irf^)-9-methyl-9-azabicyclo[3JJ]non-3-yI]-l^-indazole-3-carboxamide [Granisetron base]
The methylene chloride layer containing l-methyl-indazole-3-carbonylchloride (prepared from
2Kg of l-methyl-indazole-3-carboxylic acid, according to the Example-1) was transferred to an
all glass reactor under nitrogen atmosphere and cooled to 15-20°C. Slowly added a mixture of
endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (2Kg) and triethylamine (1.45Kg) in about
1!4 hr and maintained the reaction mass for lA hr at the same temperature and checked the
completion of the reaction by HPLC. Then treated the organic layer with 8L of 10% sodium
bicarbonate solution twice and finally washed the organic layer with 10L of DM water. The
organic layer was dried with anhydrous sodium sulphate and distilled off methylene chloride
completely under vacuum. To the residue remained in the reactor, isopropyl alcohol (5L) added
and cooled to 0-5 °C and stirred for about 2 hr to make good slurry and centrifuged and washed
the cake with chilled isopropyl alcohol. Dried the material under vacuum to get a very nice
crystalline solid.
Drywt = 3.2Kg
M.P = 152°C
HPLC purity = 99.9%
Example 3 Preparation of l-methyl-A^[(3-ewrf0)-9-methyl^ carboxamide mono hydrochloride (Granisetron Hydrochloride) - Technical grade
Into an all glass reactor, charged isopropyl alcohol (40L), followed by Granisetron base (3Kg)
prepared by the process described in Example 2. Cooled the reaction mass to 20-25°C and
isopropyl alcohol containing HC1 was slowly added (HC1 1.1 mole to 1 mole of Granisetron
base) at 20-25°C and stirred for 45 min at the same temperature, so that Granisetron HC1
precipitated out. Then slowly raised the mass temperature to reflux condition and refluxed for
about 2 hr and cooled to 30»35°C and maintained for about 1 hr at that temperature and
centrifuged the mass and washed the cake with isopropyl alcohol and dry the material at 65-70°C
till constant weight obtained.
Drywt = 3.2Kg

HPLC purity - 99.86%
The pharmaceutical grade Granisetron HC1 was prepared by recrystallisation of technical grade
material obtained, in aqueous isopropyl alcohol by adopting the following procedure.
Example 4 Preparation of Granisetron HC1 (Pharma Grade) from aqueous Isopropyl alcohol
Into a glass-lined reactor, charged isopropyl alcohol (28L), DM water (7L) and Granisetron hydrochloride (3Kg dry), prepared by the process described in Example 3 under stirring. Then slowly raised the mass temperature to 65-70°C and maintained for 45 minutes at the same temperature for complete dissolution. Then charged activated carbon slurry in isopropyl alcohol (0.5Kg in 4 L of isopropyl alcohol and 1L of water) into the reactor. Maintained for 45 min at the same temperature and filtered into another glass lined reactor, and washed the cake with aq. isopropyl alcohol (5L of isopropyl alcohol in 1L water) and collected the filtrate into the glass lined reactor.
Charged fresh isopropyl alcohol (30L) into the reactor and distilled out about 30-35L of isopropyl alcohol and water mixture. Cooled the reaction mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 30-35L of isopropyl alcohol and water mixture. Cooled the mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 30-35L of isopropyl alcohol and water mixture. Repeated the process for 4 more times (Moisture content in distillate should be about 1.0%w/v.).
Then cooled the reaction mass to 30-35°C and maintained for 90 minutes at the same
temperature and centrifuged the material, washed the cake with isopropyl alcohol (10L). Dried
the material in a vacuum tray drier at 70-75°C till LOD (Loss on drying) is not more than 0.5%.
Dry wt = 2.8Kg
Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.

Example 5 Preparation of l-methyl-A^[(3-^/i^)-9-methyl-9-azabicyclo[33.1]non-3-yl]-l/^-indazole-3-carboxamide [Granisetron Base]
The methylene chloride layer containing l-methyl-indazole-3-carbonyl chloride [prepared from 2Kg of l-methyl-indazole-3-carboxylic acid, according to the process described in the Example-1] was transferred into an all glass reactor under nitrogen atmosphere and cooled to 15-20°C. To this a mixture of endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (2Kg) and triethylamine (1.45Kg) was slowly added in about VA hr and maintained the reaction mass for lA hr at the same temperature and checked the completion of the reaction by HPLC. Then treated the organic layer with 8L of 10% sodium bicarbonate solution twice and finally washed the organic layer with 10L of DM water. The organic layer was dried with anhydrous sodium sulphate and distilled off methylene chloride completely under vacuum. To the residue remained in the reactor, isopropyl alcohol (5L) added and cooled to 0-5°C and stirred for about 2 hr to make good slurry and centrifuged and washed the cake with chilled isopropyl alcohol. The wet Granisetron base obtained was directly used (without drying) to prepare Granisetron HC1 (Tech) as given in the example (6) below.
Example 6 Preparation of l-methyl-Ar-[(3-^/irfo)-9-methyl-9-azabicyclo[3.3,l]non-3-yl]-l^-indazole-3-carboxamide mono hydrochloride [Granisetron Hydrochloride] - Technical grade
Into another all glass reactor, charged isopropyl alcohol (40L) followed by Granisetron base wet material (equivalent to 3Kg dry), as obtained by the process described in Example 5. Cooled the reaction mass to 20-25°C and isopropyl alcohol containing HC1 (1.1 mole to 1 mole of Granisetron base) was slowly added maintaining mass temperature at 20-25°C. Maintained the reaction mixture for 45 minutes at the same temperature and then slowly raised to reflux condition. Then refluxed for about two hrs and then cooled to 30-35°C. Maintained at the same temperature for about 1 hour and centrifuged the material and washed the cake with about 8L of isopropyl alcohol. The wet cake obtained was directly used (without drying) for rectystallisation to get pharmaceutical grade granisetron hydrochloride as given in the following Example 7.

Example 7 Preparation of Granisetron HCI (Pharma Grade) from Aqueous Isopropyl alcohol
Into a glass-lined reactor, charged isopropyl alcohol (28L), DM water (7L) and Granisetron hydrochloride wet cake (equivalent to 3Kg dry), prepared by the process described in Example 6 under stirring. Then slowly raised the mass temperature to 65-70°C and maintained for 45 min at the same temperature for complete dissolution. Then charged activated carbon slurry (prepared by mixing of 0.5 Kg of activated carbon with 4L of isopropyl alcohol and 1L of water) into the reactor. Maintained for 45 min at the same temperature and filtered into another glass lined reactor, and washed the cake with aq. isopropyl alcohol (5L of isopropyl alcohol and 1L water) and collected the filtrate into the glass lined reactor.
Charged fresh isopropyl alcohol (30L) into the reaction and distilled out about 30-35L of isopropyl alcohol and water mixture. Cooled the mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 3 0-3 5 L of isopropyl alcohol and water mixture. Cooled the mass to 35-40°C and again charged 30L of fresh isopropyl alcohol and distilled out about 30-35L of isopropyl alcohol and water mixture. Repeated the process for 4 more times (Moisture content in distillate should be about 1.0%w/v).
Then cooled the reaction mass to 30-35°C and maintained for 90 min at the same temperature
and centrifuged the material, washed the cake with isopropyl alcohol (10L). Dried the resultant
pharmaceutical grade Granisetron hydrochloride material in a vacuum tray drier at 70-75 °C till
LOD is not more than 0.5%w/w.
Dry wt - 2.75Kg
Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.
Example 8 Preparation of Granisetron HCl(Pha) from Ethyl alcohol
Into a 1L three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, condenser, etc. charged 650mL of ethyl alcohol, followed by lO.Og Granisetron HCI (Tech) prepared by the process described in Example 3 and slowly raised the temperature to 70±2°C, and stirred for 15 min to get clear solution. Then 2.0g of activated carbon added, stirred

for lOmin and filtered. Washed the cake with 20 ml of ethyl alcohol. Distilled off around 175
ml of ethyl alcohol from the filtrate and cooled to 25-35°C and maintained for 90min and
filtered. Washed the cake with 30 ml of ethyl alcohol and dried the material at 70-75°C till
constant weight is obtained.
Dry weight : 8.0g
Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.
Example 9 Preparation of Granisetron HC1 (Pharma Grade) from Methyl alcohol
Into a three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer
pocket, condenser, etc. charged lOOmL of methanol, followed by lO.Og granisetron HC1 (Tech)
prepared by the process described in Example 3 and raised the temperature to 60±2°C, and
maintained for about 15 min to get clear solution. Then 2.0g activated carbon added, filtered and
washed the carbon cake with 15mL of methanol. Then distilled off methanol around 50mL from
the filtrate and cooled to the reaction mass to 25-35°C and maintained for 90min and filtered the
mass. Washed the cake with 20 ml of methanol and dried the material at 70-75 °C till constant
weight is obtained.
Dry weight : 7.0g
Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.
Example 10 Preparation of Granisetron HC1 (Pharma Grade) from N,N-Dimethylformamide
Into a three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, condenser, etc charged 1250 ml of N,N-dimethylformamide, followed by lO.Og Granisetron HC1 (Tech) prepared by the process described in Example 3 and raised the temperature to 70±2°C, and maintained for about 15min to get clear solution. Then 2.0g activated carbon added, filtered and washed the carbon cake with 15mL of N,N-dimethylformamide. Then distilled off N,N-dimethylformamide around 625mL from the filtrate and cooled the reaction mass to 25-35°C and maintained for 90min and filtered the mass.

Washed the cake with 20mL of N,N-dimethylformamide and dried the material at 70-75°C till
constant weight is obtained.
Dry weight : 7.6g
Granisetron hydrochloride is passing in all aspects as per the specifications of EP 5.1.
Advantages of the present invention
1. Granisetron base prepared by the present process is of high purity (>99.9%).
2. The process does not require any chromatographic purification; therefore it is simple, commercially viable, and economical.
3. The high purity Granisetron base prepared according to the present invention can be converted to pharmaceutically acceptable salts such as hydrochloride salt with pharmaceutically acceptable grade.

WE CLAIM:
1. An improved process for the preparation of high purity (>99.9% by HPLC) crystalline
Granisetron base of formula (1),
which comprises,
(i) suspending the crude base of Granisetron in a protic solvent or a mixture of protic solvents,
such as alcohols, at 25-35°C, cooling to a temperature in the range of 0 to 15°C, preferably 0
to 5°C and stirring for a period in the range of one to three hours (ii) filtering the crystals so formed in the alcoholic solvent medium used in step (ii), by
conventional techniques, washing the crystals with the same solvent and if necessary drying
the crystalline Granisetron base formed under vacuum and if desired, (iii) converting the Granisetron base obtained in step (ii) above into its pharmaceutically
acceptable salts thereof by conventional techniques
2. An improved process for the preparation of high purity (>99.9% by HPLC) crystalline Granisetron base as claimed in claim 1 where in the alcoholic solvent used in step (i) is selected from isopropyl alcohol, ethyl alcohol, methyl alcohol, isobutyl alcohol, preferably, isopropyl alcohol.
3. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base,
which comprises,
(a) suspending the crystalline Granisetron base (wet or dry) obtained in step (ii) of the process defined in claim 1 above in aqueous or non-aqueous alcoholic solvent or a mixture thereof
(b) treating the resultant suspension with molar quantity of aqueous or alcoholic hydrochloric acid

(c) filtering off the resulting Granisetron hydrochloride salt formed and washing the wet cake with the same solvent and if necessary, drying it
(d) dissolving the wet or dry Granisetron hydrochloride in a polar solvent such as water, alcohols, amides, nitriles, esters, and the like or a mixture thereof
(e) treating the resultant solution with a decolorizing agent
(f) filtering off the decolorizing agent from the solution containing the Granisetron hydrochloride
(g) distilling off the solvent partially from the solution and cooling to a temperature in the range of25-35°C
(h) filtering the resulting crystalline salt of Granisetron hydrochloride by conventional methods and washing the wet cake with same solvent and drying it
4. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base as claimed in claim 3 wherein the non-aqueous alcoholic solvent used in step (a) is selected from methyl alcohol, ethyl alcohol, isoproyl alcohol, preferably isopropyl alcohol.
5. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base as claimed in claims 3 & 4 where in the polar solvent used in step (d) is selected from a group consisting of alcohols like methyl alcohol, ethyl alcohol, isopropyl alcohol with or without water or amides like N,N-dimethylformamide or nitriles like acetonitrile or esters like ethyl acetate, isopropyl acetate or a mixture thereof.
6. An improved process for the preparation of a high purity (>99.8%) hydrochloride salt of Granisetron from the crystalline Granisetron base as claimed in claims 3 to 5 wherein the decolorizing agent used in step (e) is selected as activated charcoal.
7. An improved process for the preparation of crystalline, high purity (>99.9% by HPLC) Granisetron base of formula (1) given in claim 1 as herein described with reference to the Examples 2 & 5.

8. An improved process for the preparation of hydrochloride salt from high purity (>99.9% by HPLC) Granisetron base of formula (1) given in claim 1 as herein described with reference to the Examples 3? 4, and 6 to 10.

Documents:

0166-che-2006-abstract.pdf

0166-che-2006-claims.pdf

0166-che-2006-correspondnece-others.pdf

0166-che-2006-description(complete).pdf

0166-che-2006-form 1.pdf

0166-che-2006-form 3.pdf

0166-che-2006-form 5.pdf

166-CHE-2006 AMENDED CLAIMS 14-11-2011.pdf

166-CHE-2006 CORRESPONDENCE OTHERS 14-11-2011.pdf

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Patent Number

252762

Indian Patent Application Number

166/CHE/2006

PG Journal Number

22/2012

Publication Date

01-Jun-2012

Grant Date

30-May-2012

Date of Filing

01-Feb-2006

Name of Patentee

NATCO PHARAMA LIMITED

Applicant Address

NATCO PHARMA LIMITED NARCO HOUSE, ROAD NO.2, BANJARA HILLS HYDERABAD 500 033, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	NAGESHWAR RAO BOLLEPALLI	NATCO PHARMA LIMITED NARCO HOUSE, ROAD NO.2, BANJARA HILLS HYDERABAD 500 033, INDIA
2	JYOTHI PRASAD RAMANADHAM	NATCO PHARMA LIMITED NARCO HOUSE, ROAD NO.2, BANJARA HILLS HYDERABAD 500 033, INDIA
3	VENKAIAH CHOWDARY NANNAPANENI	NATCO PHARMA LIMITED NARCO HOUSE, ROAD NO.2, BANJARA HILLS HYDERABAD 500 033, INDIA

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA