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 by heating to reflux temperature, removing insolubles if any, reducing the volume of the solution to about half of the original volume to one third volume under reduced pressure at temperature below 60°C, gradual cooling and maintaining at temperature of about 10°C to -20°C for about 30 min to about 4 hrs, followed by isolating and drying at temperature of about 45°C 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-Y. 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. 4,980,470 describes the method for preparation of Gatifloxacin hemi hydrate by condensation of 1 -Cyc!opropyl-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 recrystallizations from methanol. European Patent No 464,823 discloses a method for the preparation of Gatifloxacin by condensation of 2-methyl pauperizing with (l-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3-qmnoline carboxylic acid-0\0"") bis (acetate-0)-borate in presence of triethyl amine, acetonitrile followed by hydrolysis of the resulting intermediate [1- Cyclopropyl-6-fluoro-8-raethoxy-7-(3-methyl-l-pipeTazmyl)-4-oxo-V,4-dihydro-3-quinoline carboxylic acid-03,0"4] bis (acetate-O)-borate with triethyl amine in mixture of ethanol, water and crystallization iron ethanol. US patent No 5,880,283 describes the process for Gatifloxacin sesquihydrale by heating the aqueous suspension of l-Cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl piperazin-1-yl)-4-oxo-l,4-dihydro-3-quinoiine carboxylic acid to 80 - 90°C followed by hot filtration at that temperature and drying. US Patent No 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-1,4-dihydro-3-quinoline carboxylic acid boron difluride chelae 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 footedly isolation of the crystals and treating with hydrochloric acid in ethanol. US Patent No 6,413,969 discloses the several polymorphs or hydrate forms of Gatifloxacin and their X-ray diffraction patters. The Sesquihydrate, pentahydrate and hexahydrate are crystallized directly from aqueous solutions. Other crystalline forms are crystallized from molten phase or by solid-solid 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 Fonn-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-i2 and Form-T2RP by slurring / crystallization from iso-propanol (Form-A), n-butane, ethanol (Form-B), n-butanes (Form-C), methanol (Form-D), aqueous methanol (Form-F, Form-G), toluene (Form-H), n-butane (Form-I, without drying) and the solvated forms Form-J with isopropanol, methyl ethyl ketene, acetone, n-butanes and THF. The Form-EI is prepared from the mixture of acetonitrile- water, preparation methods for Form- i3 and Form -T2RP were also disclosed. PCT Publication No WO 03/ 105851 discloses Gatifloxacin crystalline forms Form-0, mixture of Form-0 -Sesquihydrate, Form-V and the methods for making them. The Form-0 contains the water content equivalent to cryohydrate (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 recrystallizations from methanol: water (90: 10), Form-M by slurring in absolute ethanol, Form-P by recrystallizations from ethanol: water (99:1), Form-Q by recrystallizations from acetonitrile: water (98:2), Form-S by recrystallizations of wet Gatifloxacin from acetonifrile followed by slurring in ethanol resulted the wet compound. After drying this Form-S becomes the Form- T2RP. The dry Gatifloxacin on recrystallization from acetonitrile, followed by scurrying in ethanol and drying under vacuum gives the Form-Tl. Our co-pending Indian patent application No. 6Q3/CHE/2QQ3 discloses the preparation of Gatifloxacin by reaction of ethyl l-cyclopropyI-6, 7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxyl ate with a. hydrofluoroboricacid followed by Isolation of the intermediate, condensation with 2-methyl piperazine, hydrolysis of the resulted intermediate l-cyclopropyl-7-{3-methylpiperazin-l-yl)-6-fluoro-8-methoxy"4-oxo-l,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 that when recrystallization of Gatifloxacin is attempted in various solvents, new crystalline forms of Gatifloxacin having the water content about 2-5 %, 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-Y. Yet another object of the invention is to characterize the novel crystalline form of Gatifloxacin Form-Y. Gatifloxacin on dissolution in methanol by heating, removal of insoluble, concentrating the solution to about half of the original volume to one third volume under vacuum followed by gradual cooling and maintenance at about - lO°C, isolation and drying gives the Gatifloxacin Form-Y. Gatifloxacin Form-Y exhibits the characteristic x-ray diffraction pattern, peaks at 5.1, 6.2, 7.8, 9.1, 9.8,10.4.12.9,13.6, 14.3, 17.3, 17.7,18.3.18.8,19.6,20.7, 21.1, 23.4, 23.9, 24.4, 25.4, 25.9 and 26.6 ± 0.2 2-theta values. The IR absorption peaks are observed at 3425, 1725, 1618, 1542, 1511, 1461, 1393, 1356, 1320, 1279, 1058, 939 and 822 cm""±2 cm"" along with other absorption peaks. The DSC shows broad endotherm at 112""C and a strong endotherm peak at 186°C Brief description of the drawings: Fig. 1: X-ray diffraction pattern of the crystalline Gatifloxacin Form-Y Fig. 2: DSC of the crystalline Gatifloxacin Form-Y 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 insoluble if any, reducing the volume of the solution to about half of the original volume to one third volume under reduced pressure at temperature below 60°C preferably below SCC, gradual cooling and maintaining at temperature of about lO°C to -20°C preferably -5°C to -15°C, for about 30 min. to about 4 hrs, preferably for 30 min., to 2 hrs followed by isolating and drying at temperature of about 45°"C to 65°C preferably about sec - 55°C yields the Gatifloxacin Form-Y. The XRD and DSC of the obtained Gatifloxacin Form-Y are as per the enclosed Fig. 1 and Fig.2 respectively. The starting material Gatifloxacin is prepared by the prior art methods. The novel crystalline form of Gatifloxacin Form-Y 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-V Gatifloxacin (79.0 g) Is suspended in methanol (2765 ml, 35 volumes), the temperature is raised to reflux temperature to get a clear solution, and the solution is filtered in hot. The filtrate is concentrated to about 1200 ml volume under reduced pressure at temperature below 50°C. The reaction mass is gradually cooled and maintained at -lO°C to -8°C for 45 min. The product is filtered, washed with methanol (40 ml) and dried at 50°C - 55°C to constant weight. The dry weight of the Gatifloxacin Form-Y is 60.4 g (yield: 76.5%), Water content (by KF): 3.11% The XRD and DSC pattern are as indicated in Fig. 1, and Fig. 2. We claim: 1. The process for the preparation of novel crystalline Gatifloxacin Form-Y comprising the steps: - Dissolving Gatifloxacin in methanol - Removing insolubles if any - Concentrating the reaction mass to half - one third of its original volume under reduced pressure. - Cooling the reaction mass to -20°C to 10°C - Maintaining the reaction mixture at -20°C to 10°C for 30 min to 4hrs - Isolating and drying the product to get crystalline Gatifloxacin Form - Y Wherein Form-Y is characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 5.1, 6.2, 7.8, 9.1, 9.8, 10.4, 12.9, 13.6, 14.3, 17.3, 17.7, 18.3, 18.8,19.6,20.7,21.1,23.4,23.9, 24.4, 25.4, 25.9 and 26.6 ±0.2 degrees 2. The process as claimed in claim 1, wherein the volume of methanol for dissolution of Gatifloxacin is 15 to 50 volumes, preferably 20 volumes to 35 volumes with respect to Gatifloxacin 3. The process as claimed in claims 1 and 2, wherein Gatifloxacin is dissolved in methanol at 45°C to reflux temperature 4. The process as claimed in claim 1, wherein the drying temperature is 45°C to 65°C

Documents:

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

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

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

522-che-2004 abstract-duplicate.pdf

522-che-2004 abstract.pdf

522-che-2004 claims-duplicate.pdf

522-che-2004 claims.pdf

522-che-2004 correspondence-others.pdf

522-che-2004 correspondence-po.pdf

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

522-che-2004 description (complete).pdf

522-che-2004 drawings-duplicate.pdf

522-che-2004 drawings.pdf

522-che-2004 form-1.pdf

522-che-2004 form-19.pdf

522-che-2004 form-3.pdf

522-che-2004 others.pdf

522-che-2004 pct search report.pdf

522-che-2004 pct.pdf