|Title of Invention||
PROCESS FOR PREPARING NOVEL CRYSTALLINE FORM OF GATIFLOXACIN
|Abstract||The present invention relates to a process for purification of novel polymorphi form of gatifloxacin which comprises dissolving gatifloxacin in about 15-50 volumes of methanol,removing insolubles if any,adding organic base to the solution,maintaining the solution at temperature of 30degeere C to 70 degeere C, for about 20 min to 4 hrs,followed by gradual cooling and maintaining the reaction mass to-10 to20degeere C for about 1-4 hrs,isolation and drying at temperature of about 45degeereC to 65degeere C.|
Field of the Invention:
The present invention relates to a process for preparing a novel crystalline form of Gatifloxacin Form-X.
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 hemihydrate by condensation of l-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylic acid with 2-methylpiperazine in anhydrous DMSO followed by column chromatographic purification and recrystallization from methanol.
European Patent No 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-oxo-l,4-dihydro-3-quinoline carboxylic acid-03,04) 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-piperazinyl)-4-oxo-l,4-dihydro-3-quinoline carboxylic acid-03,04] bis (acetate-O)-borate with triethyl amine in mixture of ethanol, water and crystallization from ethanol.
US patent No 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-1-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 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-1 -yl)-6-fluoro-8-methoxy-4-oxo-1,4-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 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-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, Forai-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, 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 preparaed from the mixture of acetonitrile- water, preparation methods for Form- 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-fluoro-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 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-X.
Yet another object of the invention is to characterize the novel crystalline form of Gatifloxacin Form-X.
Gatifloxacin on dissolution in methanol followed by removal of insolubles if any, mixing with organic base, maintaining further for a time period followed by cooling to -10°C to 20°C, isolating the product and drying to yield Gatifloxacin Form-X.
Gatifloxacin Form-X has the moisture content about 2.4 % to 5%. The X-ray diffraction pattern shows the characteristic peaks at 7.8, 11.8, 13.7, 17.7, 19.8, 20.6 and 26.0 ± 0.2 2-
theta values. The X-ray diffraction further exhibits the peaks at 8.8, 9.8, 10.3, 12.8, 14.2, 14.9, 17.3, 18.2, 19.2, 21.2, 23.9 and 28.6 ± 0.2° 29. A typical X-ray diffraction difractogram of Form-X is shown in Fig-1. The DSC shows a small broad endotherm at 107°C and a sharp strong endotherm peak at 191°C. A typical DSC thermogram of Form-X is shown in Fig-2. The IR absortion peaks are observed 3408, 1722, 1617, 1555, 1510, 1462, 1392, 1320, 1279, 1058, 939 and 822 cm"1 ± 2 cm"1 along with other absorption peaks.
Brief description of the drawings:
Fig. 1 shows the representative X-ray diffraction diagram of the Gatifloxacin Form-X Fig. 2 shows the representative DSC thermogram of the crystalline Gatifloxacin Form-X
Detailed description of the Invention:
According to the present invention dissolving Gatifloxacin in about 15-50 volumes preferably about 20-35 volumes of methanol, removing insolubles if any, adding organic base to the solution, the preferred organic base is triethylamine, diisopropyl ethylamine and mixture thereof. Maintaining the solution at temperature of 30°C to 70°C, preferably at reflux temperature of the solvent for about 20 min. to 4 hxs and more preferably for about 20 - 60 min, followed by gradual cooling and maintenance of the reaction mass to -10 to 20°C preferably 0°C to 10°C for about 1 - 4 hrs, isolation and drying at temperature of about 45°C to 65°C preferably about 50°C to 55°C resulting the Gatifloxacin Form-X.
Crystalline Gatifloxacin Form-X of the present invention is having the water content in the range of 2 to 5%.
The starting material Gatifloxacin is prepared by the prior art methods.
The invention can be further illustrated by the below non-limiting examples.
Example-1: Preparation of crystalline Gatifloxacin Form-X
Gatifloxacin (25.0 g) is suspended in methanol (625 ml) the temperature is raised and maintained at 60°C to 65°C for 20 min to get a clear solution. Activated carbon is added, mixed for 30 min and the solution is filtered. Triethyl amine (6.5 g) is added to the filtrate, maintained at reflux temperature for 45 min. The reaction mixture is gradually cooled and maintained at 8°C to 10°C for 2 hrs. The product is filtered, washed with methanol (50 ml) and dried at 45°C to 50°C to constant weight.
Dry weight of the pure Gatifloxacin is 18.0 g (Yield: 72.0 %)
The X-ray diffraction pattern and DSC is as indicated in Fig.l & Fig. 2.
Example-2: Preparation of crystalline Gatifloxacin Form-X
Gatifloxacin (25.0 g) is suspended in methanol (625 ml), temperature is raised and maintained at 60°C to 65°C for 20 min to get a clear solution. Activated carbon is added, mixed for 30 min and the solution is filtered. Diisopropyl ethylamine (8.6 g) is added to the filtrate, maintained at reflux temperature for 45 min. The reaction mass is gradually cooled and maintained at 5°C to 10°C for 2 hrs. The product is filtered, washed with methanol (50 ml) and dried at 45°C - 50°C to constant weight.
Dry weight of the pure Gatifloxacin is 17.8 g (Yield: 71.2 %)
The X-ray diffraction pattern and DSC is as indicated in Fig.l & Fig. 2.
1. A process for the preparation of novel crystalline Gatifloxacin Form-X comprising the
- Dissolving Gatifloxacin in methanol
- Removing insolubles if any
- Adding organic base to the reaction mixture
Maintaining the reaction mixture at an appropriate temperature
- Cooling the reaction mixture to -10°C to 20°C
- Maintaining the reaction mixture for 1 hr to 4hrs
- Isolating and drying the to get crystalline Gatifloxacin Form-X
wherein the obtained Form-X is characterized by x-ray reflections at about 7.8, 8.8, 9.8, 10.3, 11.8, 12.8, 13.7, 14.2, 14.9,17.3, 17.7,18.2, 19.2, 19.8, 20.6, 21.2, 23.9, 26.0 and 28.6 ±0.2° 28
2. A process as claimed in claim 1, wherein the volume of methanol for dissolution of
Gatifloxacin is 20 volumes to 35 volumes with respect to Gatifloxacin
3. A process as claimed in claims 1 and 2, wherein Gatifloxacin is dissolved in methanol at
45°C to reflux temperature
4. A process as claimed in claims 1, wherein the addition of organic base is at temperature
30°C to 70°C
5. A process as claimed in claim 1, wherein the organic base is triethyl amine, diisopropyl
ethylamine and more selectively triethyl amine
6. A process as claimed in claim 1, wherein the maintenance temperature of the reaction
mass is 30°C to 70°C, preferably at reflux temperature of the solvent
7. A process as claimed in claim 1, wherein the drying temperature is 45°C to 65°C
|Indian Patent Application Number||521/CHE/2004|
|PG Journal Number||26/2007|
|Date of Filing||04-Jun-2004|
|Name of Patentee||M/S. MATRIX LABORATORIES LTD|
|Applicant Address||1-1-151/1,IV FLOOR, SAIRAM TOWERS,ALEXANDER ROAD, SECUNDERABAD, A.P-500 003.|
|PCT International Classification Number||A61K 31/4725|
|PCT International Application Number||N/A|
|PCT International Filing date|