Title of Invention

PROCESS FOR PREPARING NOVEL CRYSTALLINE FORM OF GATIFLOXACIN

Abstract

The present invention relates to a process for purification of novel polymorphic form of Gatifloxacin which comprises dissolving Gatifloxacin in about 15 -50 volumes of methanol at reflux temperature, removing insolubles if any, cooling and maintaining the resultant clear solution to a temperature of about 10°C to -10°C, for about 30 min to 4 hrs followed by isolating and drying at temperature of about 45 to 65°C.

Full Text

Field of the Invention: The present invention relates to a process for preparing a novel crystalline form of Gatifloxacin Form-Z. Background of the Invention: Gatifloxacin, chemically l-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl piperazin-1-yl)-4-oxo-l,4-dihydro-3-quinoline carboxylic acid, is represented by the following formula Gatifloxacin belongs to the class of fluoroquinolones, has potent antibacterial activity, has higher selectivity against bacteria from mammalian cells which results in excellent selective toxicity and is marketed under brand name "Tequin". Gatifloxacin is preferably administered orally or intravenously and the usual dose is 400 mg once daily. US Patent No. US 4,980,470 diescribes the method for preparation of Gatifloxacin hemihydrate by condensation of 1 -Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid with 2-methylpiperazine in anhydrous DMSO followed by column chromatographic purification and recrystallization from methanol. European Patent No EP 464,823 discloses a method for the preparation of Gatifloxacin by condensation of 2-methyl piperazine with (l-Cyclopropyl-6,7-difluoro-8-methoxy-4- 1 A oxo-l,4-dihydro-3-quinoline carboxylic acid-0 ,0 )bis (acetate-O)-borate in presence of triethyl amine, acetonitrile followed by hydrolysis of the resulting intermediate [1- Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-l-pipe^ quinoline carboxylic acid-03,04]bis (acetate-O)-borate with triethyl amine in mixture of ethanol, water and crystallization from ethanol. US patent No US 5,880,283 describes the process for Gatifloxacin sesquihydrate by heating the aqueous suspension of l-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl piperazin-l-yl)-4-oxo-l,4-dihydro-3-quinoline carboxylic acid to 80 - 90°C followed by hot filtration at that temperature and drying. US Patent No US 4,997,943 discloses the Gatifloxacin hydrochloride salts, describes the process for preparation of Gatifloxacin hydrochloride by reaction of l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylic acid boron difluride chelate with 2-methyl piperazine in DMSO, isolating the intermediate l-Cyclopropyl-7-(3-methylpiperazin-l-yl)-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylic acid boron difluoride chelate which on treatment with triethylamine in aqueous ethanol followed by isolation of the crystals and treating with hydrochloric acid in ethanol. US Patent No US 6,413,969 discloses the several polymorphs or hydrate forms of Gatifloxacin and their X-ray diffraction patterns. The Sesquihydrate, pentahydrate and hexahydrate are crystallized directly from aqueous solutions. Other crystalline forms are crystallized from molten phase or by solid-soild transformations. US Patent 6, 413,969 further describes Gatifloxacin pentahydrate as the most physically stable form and discloses the process for preparation of Gatifloxacin pentahydrate by water equilibration of any other crystal form of Gatifloxacin. PCT Publication No WO 03/086402 discloses two anhydrous crystalline forms, Form-I and Form-II of Gatifloxacin, their X-ray diffraction pattern, DSC and IR spectrums and describes the methods for preparation as by removal of water azeotropically from Gatifloxacin hydrate in aromatic or aliphatic hydrocarbon. It further describes the Gatifloxacin hydrate used is having the moisture content ranging from 2.5 to 50.0%. PCT Publication No. WO 03/ 94919 discloses the several crystalline forms of Gatifloxacin, Form- A, B, C. D, El, F, G, H, Form-J and their X-ray diffraction patterns, TGA, DSC and IR spectrums. This PCT publication further describes the process for the preparation methods for the crystalline forms Form-A to Form-J, Form-Q and Form-T2RP by slurrying / crystallization from iso-propanol (Form-A), n-butanol, ethanol (Form-B), n-butanol (Form-C), methanol (Form-D), aqueous methanol (Form-F, Form-G), toluene (Form-H), n-butanol (Form-I, without drying) and the solvated forms Form-J with isopropanol, methyl ethyl ketone, acetone, n-butanol and THF. The Form-El is prepared from the mixture of acetonitrile- water, preparation methods for Form- Q and Form -T2RP were also disclosed. PCT Publication No WO 03/ 105851 discloses Gatifloxacin crystalline forms Form-O, mixture of Form-0 -Sesquihydrate, Form-V and the methods for making them. The Form-0 contains the water content equivalent to trihydrate (11.8%), prepared by crystallization from mixed solvent of ethanol - acetonitrile and is the wet compound. The Form-V having the water content about 1% to 3% is prepared by crystallization and treating the isolated solid with moist gas. PCT Publication No WO 04/ 12739 discloses the several crystalline forms of Gatifloxacin, Form-L, Form-M, Form-P, Form-Q, Form-S and Form-Tl along with their preparation methods as follows. The Form-L by recrystallization from methanol: water (90: 10), Form-M by slurrying in absolute ethanol, Form-P by recrystallization from ethanol: water (99:1), Form-Q by recrystallization from acetonitrile: water (98:2), Form-S by recrystallization of wet Gatifloxacin from acetonitrile followed by slurrying in ethanol resulted the wet compound. After drying this Form-S becomes the Form- T2RP. The dry Gatifloxacin on recrystallization from acetonitrile, followed by slurrying in ethanol and drying under vacuum gives the Form-Tl. Our co-pending Indian patent application No. 603/CHE/2003 discloses the preparation of Gatifloxacin by reaction of ethyl l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylate with aq. hydrofluoroboricacid followed by Isolation of the intermediate, condensation with 2-methyl piperazine, hydrolysis of the resulted intermediate 1 -cyclopropyl-7-(3-methylpiperazin-1 -yl)-6-fluon>8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid boron difluoride chelate with triethyl amine in 20% aqueous ethanol and recrystallization from methanol as Gatifloxacin hemihydrate. The X-ray diffraction pattern, IR spectrum "of the obtained Gatifloxacin hemihydrate also disclosed, Surprisingly it has been observed by the inventors when recrystallization of Gatifloxacin is attempted in various solvents, new crystalline forms of Gatifloxacin having the water content about 2 to 5 %, characterized by their unique x-ray diffraction pattern. Summary of the invention: The main object of the present invention is to provide a process for preparation of novel crystalline form of Gatifloxacin Form-Z. Yet another object of the invention is to characterize the novel crystalline form of Gatifloxacin Form-Z. Gatifloxacin on dissolution in methanol by heating, removal of insolubles followed by gradual cooling and maintaining at temperature of about 0°C, isolation and drying affords the Gatifloxacin Form-Z. Gatifloxacin Form-Z exhibits the x-ray diffraction patterns at 7.3, 8.7, 9.5, 11.2, 12.1, 12.8, 14.0, 14.8, 15.3, 16.0, 19.2, 21.0, 21.6, 23.2, 24.0, 24.4, 25.9 and 26.6 ± 0.2° 29. A typical X-ray difractogram is shown in Fig-1. The IR absorptions are observed at 3422, 1727,1616,1585,1543, 1449,1395,1356,1320, 1279,1056, 998, 940, 886 and 822 cm'1 ± 2 cm"1 along with other absorption peaks. The DSC shows a small broad endotherm at 104°C and a sharp strong endotherm peak at 181°C. A typical DSC thermogram is shown in Fig-2. Brief description of the drawings: Fig. 1 shows the representative X-ray diffraction diagram of the Gatifloxacin Form-Z Fig.2 shows the representative DSC thermogram of the Gatifloxacin Form-Z Detailed description of the Invention: According to the present invention dissolving Gatifloxacin in about 15 to 50 volumes preferably about 20 to 35 volumes of methanol by heating to reflux temperature, removing insolubles if any, cooling and maintaining the resultant clear solution to a temperature of about 10°C to - 10°C, for about 30 min., to 4 hrs preferably for about 1 to 2 hrs followed by isolating and drying at temperature of about 45 to 65°C preferably about 50 - 55°C gives the Gatifloxacin Form-Z. The obtained Gatifloxacin Form-Z XRD and DSC are as per the enclosed Fig.l and Fig. 2 respectively. The starting material Gatifloxacin is prepared by the prior art methods. The novel crystalline form of Gatifloxacin Form-Z of the present invention is having the water content in the range of 2 to 5%. The invention can be further illustrated by the below non-limiting examples. Example: Preparation of crystalline Gatifloxacin Form-Z The Gatifloxacin (6.3 g) is suspended in methanol (190 ml, 30 volumes), the temperature is raised and maintained at reflux temperature for 30 min. to get a clear solution. The solution is filtered. The filtrate is gradually cooled and maintained at -2°C to 0°C for 1 hr. The product is filtered, washed with methanol (60 ml) and dried at 50°C - 55°C to constant weight. The dry weight of the Gatifloxacin is 5.6 g (Yield: 70.0%) Water content (by KF): 2.55% The XRD and DSC pattern are as indicated in Fig. 1 and Fig. 2. We claim: 1. A process for the preparation of novel crystalline Gatifloxacin Form-Z comprising the steps: - Dissolving Gatifloxacin in methanol - Removing insolubles if any - Cooling the reaction mixture to -10°C to 10°C - Maintaining the reaction mixture at -10°C to 10°C for 30 min. to 4hrs - Isolating and drying the product to get crystalline Gatifloxacin Form-Z Wherein Form-Z is characterized by x-ray reflections at about 7.3, 8.7, 9.5, 11.2, 12.1, 12.8, 14.0, 14.8, 15.3, 16.0, 19.2, 21.0, 21.6, 23.2, 24.0, 24.4, 25.9 and 26.6 ± 0.2° 20 2. The process as claimed in claim 1, wherein the volume of methanol used for dissolution of Gatifloxacin is 20 to 35 volumes with respect to Gatifloxacin. 3. The process as claimed in claim 1, wherein the Gatifloxacin is dissolved in methanol at a temperature of 30°C to 70°C. 4. The process as claimed in claim 1, wherein the drying temperature is 45°C to 65°C

Documents:

523-che-2004 form-1 12-04-2011.pdf

523-CHE-2004 FORM-13 30-11-2010.pdf

523-che-2004 correspondence others 12-04-2011.pdf

523-che-2004-abstract.pdf

523-che-2004-claims duplicate.pdf

523-che-2004-claims original.pdf

523-che-2004-correspondnece-others.pdf

523-che-2004-correspondnece-po.pdf

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

523-che-2004-description(complete) original.pdf

523-che-2004-drawings.pdf

523-che-2004-form 1.pdf

523-che-2004-form 19.pdf

523-che-2004-form 3.pdf

523-che-2004-pct.pdf