WO2010146594A1 - Novel polymorphs of gemifloxacin mesylate - Google Patents

Novel polymorphs of gemifloxacin mesylate Download PDF

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Publication number
WO2010146594A1
WO2010146594A1 PCT/IN2009/000346 IN2009000346W WO2010146594A1 WO 2010146594 A1 WO2010146594 A1 WO 2010146594A1 IN 2009000346 W IN2009000346 W IN 2009000346W WO 2010146594 A1 WO2010146594 A1 WO 2010146594A1
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Prior art keywords
gemifloxacin mesylate
gemifloxacin
crystalline
solvent
mesylate
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PCT/IN2009/000346
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French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Musku Madhan Mohana Reddy
Donikena Sridhar
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Hetero Research Foundation
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Priority to PCT/IN2009/000346 priority Critical patent/WO2010146594A1/en
Publication of WO2010146594A1 publication Critical patent/WO2010146594A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention provides novel crystalline forms of gemifloxacin mesylate and its hydrates, processes for their preparation and pharmaceutical compositions comprising them.
  • the present invention also provides novel solvated forms of gemifloxacin mesylate and processes for their preparation.
  • U.S. Patent No. 5,633,262 disclosed a novel quinoline (naphthyridine) carboxylic acid derivatives and pharmaceutically acceptable salts thereof. These compounds are antibacterial agents. Among them gemifloxacin, chemically 7-[3-
  • 8-naphthyridine-3-carboxylic acid is a third generation fluorinated quinolone antibacterial agent.
  • Gemifloxacin is represented by the following structure:
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice.
  • polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules.
  • Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Gemifloxacin mesylate can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • WO Patent Publication No. 98/42705 disclosed various polymorphic forms, anhydrate, trihydrate (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at about 7.7 and 1 1.8 degrees), sesquihydrte (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at about 8.0, 12.2 and 14.7 degrees) and solvate (ethanol content 0.1 1 %, 1.9% and 0.12%) of gemifloxacin methanesulfonate.
  • WO Patent Publication No. 00/17199 disclosed a gemifloxacin methanesulfonate sesquihydrate was characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at 8.2, 12.2 and 14.6.
  • WO Patent Publication No. 2006/134431 disclosed a crystalline form of gemifloxacin formate hydrate.
  • WO Patent Publication No. 2006/134608 disclosed various polymorphic forms gemifloxacin, designated as gemifloxacin hemihydrate, gemifloxacin monohydrate, gemifloxacin sesquihydrate, crystalline gemifloxacin lactate (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at 7.4, 7.7, 8.2, 9.1 , 12.4, 18.5, 19.8, 23.6, 25.7 and 26.8 degrees) and crystalline gemifloxacin formate.
  • 2008/053324 disclosed an anhydrate form of gemifloxacin mesylate it is denoted by Form A (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at 4.23, 12.66, 13.92, 16.90, 17.90, 19.28, 24.78 and 26.22 degrees) and also disclosed a crystalline solid intermediate 6-fluoro-7-[3-( ⁇ [(1 Z)-3-ethoxy-1 -methyl-3-oxoprop-1 -en-1 - ylJaminoJmethyO ⁇ - ⁇ ethoxyiminoJ-pyrrolidin-i-yll-i-cyclopropyl ⁇ -oxo-i ⁇ - dihydro-i . ⁇ -naphthyridine-S-carboxylic acid (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at 3.42, 7.06, 7.56, 8.16, 9.38, 10.36, 12.06, 14.26, 14.94, 15.50, 16.08,
  • One object of the present invention is to provide a novel crystalline sesquihydrate forms of gemifloxacin mesylate, process for their preparation and pharmaceutical compositions comprising them.
  • Another object of the present invention is to provide a novel crystalline anhydrous forms of gemifloxacin mesylate, process for their preparation and pharmaceutical compositions comprising them.
  • Still another object of the present invention is to provide a gemifloxacin mesylate 1 ,4-dioxane solvate and process for their preparation.
  • the present invention provided a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 1 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.2, 9.9, 10.4, 15.0, 17.1 , 19.5, 25.7 and 26.2 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing gemifloxacin mesylate crystalline sesquihydrate from 1 , which comprises: a) dissolving gemifloxacin mesylate in an alcohol solvent or mixture thereof, optionally mixed with one or more other solvent or water; b) maintaining the contents in step (a) at elevated temperature at above 4O 0 C; c) a portion of solvent from the solution obtained in step (b) until at least separation of gemifloxacin mesylate as solid occurs; and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 1.
  • the present invention provided a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 10.7, 1 1.7, 18.7, 22.7 and 25.6 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing gemifloxacin mesylate crystalline sesquihydrate from 2, which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) adding an anti solvent or a mixture of anti solvents selected from ethyl acetate, ethyl formate, isopropyl acetate, methyl ethyl ketone and isobutyl methyl ketone to the solution obtained in step (a); c) slurring the reaction mass obtained in step (b); and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
  • the present invention provides a process for preparing gemifloxacin mesylate crystalline sesquihydrate from 2, which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) cooling the solution, optionally distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
  • the present invention provided a novel crystalline form of gemifloxacin mesylate designated as form 3 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 25.7, 26.2 and 27.0 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing gemifloxacin mesylate crystalline anhydrous from 3, which comprises: a) dissolving gemifloxacin mesylate in methanol and water in the ratio of about 8:2; b) distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline anhydrous form 3.
  • the present invention provided a novel crystalline form of gemifloxacin mesylate designated as form 4 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.3, 10.6, 10.8, 14.5, 18.5 and 24.9 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing gemifloxacin mesylate crystalline anhydrous from 4, which comprises heating gemifloxacin mesylate crystalline hydrate at above 80 deg C.
  • the present invention provides a process for preparing gemifloxacin mesylate crystalline anhydrous from 4, which comprises: a) suspending gemifloxacin mesylate crystalline hydrate in toluene; and b) subjecting the suspension obtained in step (a) to azeotropic distillation at 50 to 80 0 C to obtain gemifloxacin mesylate crystalline anhydrous form 4.
  • the present invention provided gemifloxacin mesylate acetic acid solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 4.9, 9.3, 15.3, 17.8, 21.3 and 25.4 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing gemifloxacin mesylate acetic acid solvate, which comprises dissolving gemifloxacin mesylate in acetic acid and adding methyl tert-butyl ether to the solution to obtain gemifloxacin mesylate acetic acid solvate.
  • the present invention provided gemifloxacin mesylate N-methylpyrrolidone solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 6.9, 7.1 , 13.9, 20.0, 21.0 and 25.6 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing gemifloxacin mesylate N-methylpyrrolidone solvate, which comprises dissolving gemifloxacin mesylate in N-methylpyrrolidone and adding an anti solvent to the solution to obtain gemifloxacin mesylate N-methylpyrrolidone solvate.
  • the present invention provided gemifloxacin mesylate 1 ,4-dioxane solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 7.2, 15.8, 18.2 and 24.7 ⁇ 0.2 degrees.
  • the present invention provides a process for preparing gemifloxacin mesylate 1 ,4-dioxane solvate, which comprises crystallizing gemifloxacin mesylate 1 ,4-dioxane solvate from a solution of gemifloxacin mesylate in 1 ,4-dioxane solvent.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline forms of gemifloxacin mesylate selected from sesquihydrate form 1 , sesquihydrate form 2, anhydrous form 3 and anhydrous form 4 or a mixture thereof; and a pharmaceutically acceptable excipient.
  • Figure 1 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline sesquihydrate form 1.
  • Figure 2 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline sesquihydrate form 2.
  • Figure 3 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline anhydrous form 3.
  • Figure 4 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline anhydrous form 4.
  • Figure 5 is X-ray powder diffraction spectrum of gemifloxacin mesylate acetic acid solvate.
  • Figure 6 is X-ray powder diffraction spectrum of gemifloxacin mesylate N-methylpyrrolidone.
  • Figure 7 is X-ray powder diffraction spectrum of gemifloxacin mesylate 1 ,4-dioxane solvate.
  • Figure 8 is Differential scanning calorimetry (DSC) thermogram of gemifloxacin mesylate crystalline sesquihydrate form 1.
  • Figure 9 is Differential scanning calorimetry (DSC) thermogram of gemifloxacin mesylate crystalline sesquihydrate form 2.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-K ⁇ radiation. Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 10.4 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 1 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.2, 9.9, 10.4, 15.0, 17.1 , 19.5, 25.7 and 26.2 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline sequihydrate form 1 is shown in figure 1.
  • Gemifloxacin mesylate crystalline sesquihydrate form 1 of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 8.
  • DSC Differential Scanning Calorimetry
  • a process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 1 which comprises: a) dissolving gemifloxacin mesylate in an alcohol solvent or mixture thereof, optionally mixed with one or more other solvent or water; b) maintaining the contents in step (a) at elevated temperature at above 40 0 C; c) a portion of solvent from the solution obtained in step (b) until at least separation of gemifloxacin mesylate as solid occurs; and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 1.
  • the alcohol solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of a methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
  • Preferable alcohol solvent is selected from methanol and ethanol.
  • the other solvent used in step (a) is a solvent or a mixture of solvents and may be selected from the group consisting of a dichloromethane, acetonitrile, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, 1 ,4-dioxane, n-heptane, cyclohexane and hexane.
  • Preferable other solvent is selected from dichloromethane, acetonitrile, diisopropyl ether, methyl tert-butyl ether, ethyl acetate and 1 ,4-dioxane.
  • the contents are maintained at 40 to 110 0 C and more preferably the contents are maintained at reflux.
  • the solvent may be removed from the solution in step (c) by known methods, for example, distillation or spray drying.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is 50 percent distilled off.
  • the isolation of gemifloxacin mesylate crystalline sesquihydrate form 1 if required may be performed by conventional techniques such as centrifugation and filtration.
  • a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 10.7, 11.7, 18.7, 22.7 and 25.6 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline sesquihydrate form 2 is shown in figure 2.
  • Gemifloxacin mesylate crystalline sesquihydrate form 2 of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 9.
  • DSC Differential Scanning Calorimetry
  • a process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 2 which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) adding an anti solvent or a mixture of anti solvents selected from ethyl acetate, ethyl formate, isopropyl acetate, methyl ethyl ketone and isobutyl methyl ketone to the solution obtained in step (a); c) slurring the reaction mass obtained in step (b); and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
  • Preferable anti solvent is ethyl acetate or ethyl formate.
  • the temperature at which slurrying is carried out is not critical and the slurrying may conveniently be carried out at room temperature.
  • a process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 2 which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) cooling the solution, optionally distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
  • the solution is cooled to a temperature of between 0 to 15 0 C.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
  • the isolation of gemifloxacin mesylate crystalline sesquihydrate form 2, if required may be performed by conventional techniques such as centrifugation and filtration.
  • a novel crystalline form of gemifloxacin mesylate designated as form 3 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 25.7, 26.2 and 27.0 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline anhydrous form 3 is shown in figure 3.
  • a process for the preparation of gemifloxacin mesylate crystalline anhydrous form 3 which comprises: a) dissolving gemifloxacin mesylate in methanol and water in the ratio of about 8:2; b) distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline anhydrous form 3.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure.
  • the distillation may preferably be carried out until the solvent is almost completely distilled off.
  • the isolation of gemifloxacin mesylate crystalline anhydrous form 3, if required may be performed by conventional techniques such as centrifugation and filtration.
  • a novel crystalline form of gemifloxacin mesylate designated as form 4 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.3, 10.6, 10.8, 14.5, 18.5 and 24.9 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline anhydrous form 4 is shown in figure 4.
  • a process for the preparation of gemifloxacin mesylate crystalline anhydrous form 4 which comprises heating gemifloxacin mesylate crystalline hydrate at above 80 0 C.
  • heating may be performed at 80 to 120 0 C.
  • the heating may be carried out until gemifloxacin mesylate crystalline hydrate is completely converted into gemifloxacin mesylate crystalline anhydrous form 4.
  • a process for the preparation of gemifloxacin mesylate crystalline anhydrous form 4 which comprises: a) suspending gemifloxacin mesylate crystalline hydrate in toluene; and b) subjecting the suspension obtained in step (a) to azeotropic distillation at 50 to 80 0 C to obtain gemifloxacin mesylate crystalline anhydrous form 4.
  • the hydrates are monohydrate, sesquihydrate, sesquihydrate form 1 , sesquihydrate form 2, dihydrate and trihydrate.
  • gemifloxacin mesylate acetic acid solvate characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 4.9, 9.3, 15.3, 17.8, 21.3 and 25.4 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate acetic acid solvate is shown in figure 5.
  • a process for the preparation of gemifloxacin mesylate acetic acid solvate which comprises dissolving gemifloxacin mesylate in acetic acid and adding methyl tert-butyl ether to the solution to obtain gemifloxacin mesylate acetic acid solvate.
  • gemifloxacin mesylate N-methylpyrrolidone solvate characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 6.9, 7.1 , 13.9, 20.0, 21.0 and 25.6 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate N-methylpyrrolidone solvate is shown in figure 6.
  • a process for the preparation of gemifloxacin mesylate N-methylpyrrolidone solvate which comprises dissolving gemifloxacin mesylate in N- methylpyrrolidone and adding an anti solvent to the solution to obtain gemifloxacin mesylate N-methylpyrrolidone solvate.
  • the anti solvent used may be a solvent or mixture of solvents selected from the group consisting of a acetonitrile, 1 ,4-dioxane, acetone, cyclohexane and n-heptane.
  • Preferable anti solvent is selected from acetonitrile and 1 ,4- dioxane.
  • gemifloxacin mesylate 1 ,4-dioxane solvate characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 7.2, 15.8,
  • a process for preparing gemifloxacin mesylate 1 ,4-dioxane solvate which comprises crystallizing gemifloxacin mesylate 1 ,4-dioxane solvate from a solution of gemifloxacin mesylate in 1 ,4-dioxane solvent.
  • 1 ,4-dioxane may alone be present as solvent in the solution or 1 ,4-dioxane in combination with water or any other solvent or solvents may be present.
  • 1 ,4-dioxane in combination with methanol, ethanol or isopropyl alcohol may be present in the solution.
  • a pharmaceutical composition comprising a polymorphic form of gemifloxacin mesylate selected from sesquihydrate form 1 , sesquihydrate form 2, anhydrous form 3 and anhydrous form 4 or a mixture thereof; and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable inert carrier which can be used may be a solid or liquid.
  • the solid or semi-solid pharmaceutical preparation in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments.
  • the liquid pharmaceutical preparation includes solutions, suspensions and emulsions.
  • Gemifloxacin mesylate (6 gm) was dissolved in water (15 ml) and methanol (45 ml) at room temperature, filtered. 50 percent of the solvent volume was distilled from the reaction mass under vacuum. After completion of the distillation, the reaction mass was cooled to 10 0 C and maintained at 10 0 C for 30 minutes. The separated solid was filtered, washed with methanol, and then dried at 20 to 25 0 C for 30 minutes to obtain 5.5 gm of gemifloxacin mesylate crystalline sesquihydrate form 1.
  • Gemifloxacin mesylate (5 gm) was dissolved in water (50 ml) and ethanol (100 ml) at room temperature, filtered. 50 percent of the solvent volume was distilled from the reaction mass under vacuum. After completion of the distillation, the reaction mass was cooled to 5 0 C and maintained at 5 0 C for 30 minutes. The separated solid was filtered, washed with ethanol, and then dried at 20 to 25 0 C for 30 minutes to obtain 4.0 gm of gemifloxacin mesylate crystalline sesquihydrate form 1.
  • Example 8 Gemifloxacin mesylate (5 gm) was dissolved in methanol (300 ml) and heated to reflux for 20 minutes. To the solution was added ethyl acetate (200 ml), cooled to 5 0 C and maintained at 5 0 C for 1 hour. The solid obtained was collected by filtration and the solid was washed with ethyl acetate, and then dried at 45 0 C for 30 minutes to obtain 4.5 gm of gemifloxacin mesylate crystalline sesquihydrate form 1.
  • Example 9
  • Gemifloxacin mesylate (6 gm) was dissolved in water (15 ml), methanol (15 ml) and 1 ,4-dioxane (15 ml) and stirred for 30 minutes to obtain clear solution. The solution obtained was filtered and the filtrate was cooled to 10 0 C and maintained at 10 0 C for 3 hours. The solid collected by filtration, washed with methyl tert-butyl ether (30 ml) and then dried at 35 0 C for 30 minutes to obtain 5.2 gm of gemifloxacin mesylate crystalline sesquihydrate form 1.
  • Gemifloxacin mesylate (5 gm) was dissolved in dimethylformamide (50 ml) and stirred for 20 minutes at 20 to 25 deg C. To the solution was added ethyl acetate (350 ml) and stirred for 12 hours, filtered. The solid obtained was washed with ethyl acetate and dried at 35 0 C for 2 hours to obtain 4.9 gm of gemifloxacin mesylate crystalline sesquihydrate form 2.
  • Gemifloxacin mesylate (10 gm) was dissolved in dimethylformamide (100 ml) at 70 to 75 0 C to obtain clear solution and filtered. The filtrate was cooled to
  • Example 12 Gemifloxacin mesylate (10 gm) was dissolved in dimethylformamide (100 ml) at 80 to 90 0 C to obtain clear solution and filtered. The filtrate was distilled off the solvent under reduced pressure at 60 to 70 0 C to obtain 9.3 gm of gemifloxacin mesylate crystalline sesquihydrate form 2.
  • Example 13 Gemifloxacin mesylate (5 gm) was dissolved in dimethylformamide (50 ml) at 80 to 90 0 C to obtain clear solution. The solution was cooled to 5 0 C and ethyl formate (100 ml) was added. The reaction mass was stirred for 2 hours and filtered. The solid obtained was washed with ethyl formate and dried at 35 0 C for 2 hours to obtain 4.9 gm of gemifloxacin mesylate crystalline sesquihydrate form 2.
  • Gemifloxacin mesylate (6 gm) was dissolved in methanol and water (30 ml, 8:2) and stirred for 1 hour, filtered. The filtrate was distilled off the solvent under reduced pressure to obtain 5.5 gm of gemifloxacin mesylate crystalline anhydrous form 3.
  • Gemifloxacin mesylate crystalline sesquihydrate form 1 (5 gm) obtained as in example 1 was added to toluene (80 ml) at room temperature. The reaction mass was subjected to azeotropic distillation at 55 to 65 0 C under reduced pressure to obtain 4.7 gm of gemifloxacin mesylate crystalline anhydrous form 4.
  • Gemifloxacin mesylate crystalline sesquihydrate form 1 (5 gm) obtained as in example 1 was heated at 100 deg C for 12 hours to obtain 4.6 gm of gemifloxacin mesylate crystalline anhydrous form 4.
  • Gemifloxacin mesylate (5 gm) was dissolved in N-methylpyrrolidone (75 ml) and heated to 45 to 50 0 C to obtain clear solution. To the solution was added acetonitrile (100 ml). The reaction mass was cooled to 10 0 C and maintained at 10 0 C for 30 minutes. The solid obtained was collected by filtration and washed with acetonitrile, and then dried at 35 0 C for 2 hours to obtain 4.8 gm of gemifloxacin mesylate N-methylpyrrolidone solvate.
  • Gemifloxacin mesylate (5 gm) was dissolved in N-methylpyrrolidone (75 ml) and heated to 45 to 50 0 C to obtain clear solution, filtered. To the filtrate was added 1 ,4-dioxane (100 ml). The reaction mass was cooled to 5 0 C and maintained at 5 0 C for 1 hour, filtered. The solid obtained was washed with 1 ,4- dioxane and dried at 40 0 C for 2 hours to obtain 4.9 gm of gemifloxacin mesylate N-methylpyrrolidone solvate.
  • Gemifloxacin mesylate (6 gm) was dissolved in water (15 ml), methanol (15 ml) and 1 ,4-dioxane (15 ml) and stirred for 30 minutes to obtain clear solution. The solution obtained was filtered and the filtrate was cooled to 0 to 5 0 C for 3 hours. The solid collected by filtration and the solid washed with 1 ,4- dioxane, and then dried at 35 0 C for 30 minutes to obtain 5 gm of gemifloxacin mesylate 1 ,4-dioxane solvate.

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Abstract

The present invention provides novel crystalline sesquihydrate form 1, sesquihydrate form 2, anhydrous form 3 and anhydrous form 4 of gemifloxacin mesylate, processes for their preparation and pharmaceutical compositions containing them. The present invention also provides gemifloxacin mesylate acetic acid solvate, gemifloxacin mesylate N-methylpyrrolidone solvate and gemifloxacin mesylate 1,4-dioxane solvate; and processes for their preparation.

Description

NOVEL POLYMORPHS OF G E M I F LOXAC I N MESYLATE
FIELD OF THE INVENTION
The present invention provides novel crystalline forms of gemifloxacin mesylate and its hydrates, processes for their preparation and pharmaceutical compositions comprising them. The present invention also provides novel solvated forms of gemifloxacin mesylate and processes for their preparation.
BACKGROUND OF THE INVENTION
U.S. Patent No. 5,633,262 disclosed a novel quinoline (naphthyridine) carboxylic acid derivatives and pharmaceutically acceptable salts thereof. These compounds are antibacterial agents. Among them gemifloxacin, chemically 7-[3-
(aminomethyl)-4-(methoxyimino)-1 -prrolidinyl]-1 -cyclopropyl-6-fluoro-1 ,4-dihydro
-4-0X0-1 , 8-naphthyridine-3-carboxylic acid is a third generation fluorinated quinolone antibacterial agent. Gemifloxacin is represented by the following structure:
Figure imgf000002_0001
Processes for the preparations of gemifloxacin and related compounds were disclosed in US Patent No. 5,633,262.
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other. Gemifloxacin mesylate can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
WO Patent Publication No. 98/42705 disclosed various polymorphic forms, anhydrate, trihydrate (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at about 7.7 and 1 1.8 degrees), sesquihydrte (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at about 8.0, 12.2 and 14.7 degrees) and solvate (ethanol content 0.1 1 %, 1.9% and 0.12%) of gemifloxacin methanesulfonate.
WO Patent Publication No. 00/17199 disclosed a gemifloxacin methanesulfonate sesquihydrate was characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at 8.2, 12.2 and 14.6.
WO Patent Publication No. 2006/134431 disclosed a crystalline form of gemifloxacin formate hydrate.
WO Patent Publication No. 2006/134608 disclosed various polymorphic forms gemifloxacin, designated as gemifloxacin hemihydrate, gemifloxacin monohydrate, gemifloxacin sesquihydrate, crystalline gemifloxacin lactate (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at 7.4, 7.7, 8.2, 9.1 , 12.4, 18.5, 19.8, 23.6, 25.7 and 26.8 degrees) and crystalline gemifloxacin formate. WO Patent Publication No. 2008/053324 disclosed an anhydrate form of gemifloxacin mesylate it is denoted by Form A (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at 4.23, 12.66, 13.92, 16.90, 17.90, 19.28, 24.78 and 26.22 degrees) and also disclosed a crystalline solid intermediate 6-fluoro-7-[3-({[(1 Z)-3-ethoxy-1 -methyl-3-oxoprop-1 -en-1 - ylJaminoJmethyO^-^ethoxyiminoJ-pyrrolidin-i-yll-i-cyclopropyl^-oxo-i ^- dihydro-i .δ-naphthyridine-S-carboxylic acid (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at 3.42, 7.06, 7.56, 8.16, 9.38, 10.36, 12.06, 14.26, 14.94, 15.50, 16.08, 18.54, 19.15, 20.05, 21.68, 22.90, 24.76, 26.42, 27.04, 28.33, 31.78, 37.84 and 43.98 degrees).
Thus there is a need for stable and reproducible crystalline forms of gemifloxacin mesylate and its hydrates.
We have discovered two novel crystalline sesquihydrate forms and two novel crystalline anhydrous forms of gemifloxacin mesylate. The novel forms have been found to be stable over the time and reproducible and so, suitable for pharmaceutical preparations.
One object of the present invention is to provide a novel crystalline sesquihydrate forms of gemifloxacin mesylate, process for their preparation and pharmaceutical compositions comprising them. Another object of the present invention is to provide a novel crystalline anhydrous forms of gemifloxacin mesylate, process for their preparation and pharmaceutical compositions comprising them.
Another object of the present invention is to provide a gemifloxacin mesylate acetic acid solvate and process for their preparation. Another object of the present invention is to provide a gemifloxacin mesylate N-methylpyrrolidone solvate and process for their preparation.
Still another object of the present invention is to provide a gemifloxacin mesylate 1 ,4-dioxane solvate and process for their preparation.
SUMMARY OF THE INVENTION
In one aspect, the present invention provided a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 1 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.2, 9.9, 10.4, 15.0, 17.1 , 19.5, 25.7 and 26.2 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing gemifloxacin mesylate crystalline sesquihydrate from 1 , which comprises: a) dissolving gemifloxacin mesylate in an alcohol solvent or mixture thereof, optionally mixed with one or more other solvent or water; b) maintaining the contents in step (a) at elevated temperature at above 4O0C; c) a portion of solvent from the solution obtained in step (b) until at least separation of gemifloxacin mesylate as solid occurs; and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 1.
In another aspect, the present invention provided a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 10.7, 1 1.7, 18.7, 22.7 and 25.6 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing gemifloxacin mesylate crystalline sesquihydrate from 2, which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) adding an anti solvent or a mixture of anti solvents selected from ethyl acetate, ethyl formate, isopropyl acetate, methyl ethyl ketone and isobutyl methyl ketone to the solution obtained in step (a); c) slurring the reaction mass obtained in step (b); and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
In another aspect, the present invention provides a process for preparing gemifloxacin mesylate crystalline sesquihydrate from 2, which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) cooling the solution, optionally distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
In another aspect, the present invention provided a novel crystalline form of gemifloxacin mesylate designated as form 3 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 25.7, 26.2 and 27.0 ± 0.2 degrees.
In another aspect, the present invention provides a process for preparing gemifloxacin mesylate crystalline anhydrous from 3, which comprises: a) dissolving gemifloxacin mesylate in methanol and water in the ratio of about 8:2; b) distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline anhydrous form 3. In another aspect, the present invention provided a novel crystalline form of gemifloxacin mesylate designated as form 4 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.3, 10.6, 10.8, 14.5, 18.5 and 24.9 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing gemifloxacin mesylate crystalline anhydrous from 4, which comprises heating gemifloxacin mesylate crystalline hydrate at above 80 deg C.
In another aspect, the present invention provides a process for preparing gemifloxacin mesylate crystalline anhydrous from 4, which comprises: a) suspending gemifloxacin mesylate crystalline hydrate in toluene; and b) subjecting the suspension obtained in step (a) to azeotropic distillation at 50 to 800C to obtain gemifloxacin mesylate crystalline anhydrous form 4. In another aspect, the present invention provided gemifloxacin mesylate acetic acid solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 4.9, 9.3, 15.3, 17.8, 21.3 and 25.4 ± 0.2 degrees.
In another aspect, the present invention provides a process for preparing gemifloxacin mesylate acetic acid solvate, which comprises dissolving gemifloxacin mesylate in acetic acid and adding methyl tert-butyl ether to the solution to obtain gemifloxacin mesylate acetic acid solvate.
In another aspect, the present invention provided gemifloxacin mesylate N-methylpyrrolidone solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 6.9, 7.1 , 13.9, 20.0, 21.0 and 25.6 ± 0.2 degrees. In another aspect, the present invention provides a process for preparing gemifloxacin mesylate N-methylpyrrolidone solvate, which comprises dissolving gemifloxacin mesylate in N-methylpyrrolidone and adding an anti solvent to the solution to obtain gemifloxacin mesylate N-methylpyrrolidone solvate.
In another aspect, the present invention provided gemifloxacin mesylate 1 ,4-dioxane solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 7.2, 15.8, 18.2 and 24.7 ± 0.2 degrees.
In another aspect, the present invention provides a process for preparing gemifloxacin mesylate 1 ,4-dioxane solvate, which comprises crystallizing gemifloxacin mesylate 1 ,4-dioxane solvate from a solution of gemifloxacin mesylate in 1 ,4-dioxane solvent.
In yet another aspect, the present invention provides a pharmaceutical composition comprising crystalline forms of gemifloxacin mesylate selected from sesquihydrate form 1 , sesquihydrate form 2, anhydrous form 3 and anhydrous form 4 or a mixture thereof; and a pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline sesquihydrate form 1.
Figure 2 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline sesquihydrate form 2.
Figure 3 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline anhydrous form 3. Figure 4 is X-ray powder diffraction spectrum of gemifloxacin mesylate crystalline anhydrous form 4.
Figure 5 is X-ray powder diffraction spectrum of gemifloxacin mesylate acetic acid solvate.
Figure 6 is X-ray powder diffraction spectrum of gemifloxacin mesylate N-methylpyrrolidone.
Figure 7 is X-ray powder diffraction spectrum of gemifloxacin mesylate 1 ,4-dioxane solvate.
Figure 8 is Differential scanning calorimetry (DSC) thermogram of gemifloxacin mesylate crystalline sesquihydrate form 1. Figure 9 is Differential scanning calorimetry (DSC) thermogram of gemifloxacin mesylate crystalline sesquihydrate form 2.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-Kα radiation. Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 10.4 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
DSC (Differential Scanning Calorimetry) measurements were performed with a DSC Q10 (TA Instruments, Inc.). About 2.3 mg of the powder was placed in an open aluminum pan and it was crimped with an aluminum Nd. The crimped sample was then placed in the DSC cell opposite to empty aluminum pan (as reference) and the sample was scanned at 10 deg C/min from 50 deg C to 300 deg C.
DETAILED DESCRIPTION OF THE INVENTION According to one aspect of the present invention, there is provided a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 1 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.2, 9.9, 10.4, 15.0, 17.1 , 19.5, 25.7 and 26.2 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline sequihydrate form 1 is shown in figure 1.
Gemifloxacin mesylate crystalline sesquihydrate form 1 of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 8.
According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 1 , which comprises: a) dissolving gemifloxacin mesylate in an alcohol solvent or mixture thereof, optionally mixed with one or more other solvent or water; b) maintaining the contents in step (a) at elevated temperature at above 400C; c) a portion of solvent from the solution obtained in step (b) until at least separation of gemifloxacin mesylate as solid occurs; and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 1.
The alcohol solvent used in step (a) may be a solvent or mixture of solvents selected from the group consisting of a methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. Preferable alcohol solvent is selected from methanol and ethanol. The other solvent used in step (a) is a solvent or a mixture of solvents and may be selected from the group consisting of a dichloromethane, acetonitrile, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, 1 ,4-dioxane, n-heptane, cyclohexane and hexane. Preferable other solvent is selected from dichloromethane, acetonitrile, diisopropyl ether, methyl tert-butyl ether, ethyl acetate and 1 ,4-dioxane.
Preferably, the contents are maintained at 40 to 1100C and more preferably the contents are maintained at reflux. The solvent may be removed from the solution in step (c) by known methods, for example, distillation or spray drying.
The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is 50 percent distilled off. The isolation of gemifloxacin mesylate crystalline sesquihydrate form 1 , if required may be performed by conventional techniques such as centrifugation and filtration.
According to another aspect of the present invention, there is provided a novel crystalline form of gemifloxacin mesylate sesquihydrate designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 10.7, 11.7, 18.7, 22.7 and 25.6 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline sesquihydrate form 2 is shown in figure 2.
Gemifloxacin mesylate crystalline sesquihydrate form 2 of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 9.
According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 2, which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) adding an anti solvent or a mixture of anti solvents selected from ethyl acetate, ethyl formate, isopropyl acetate, methyl ethyl ketone and isobutyl methyl ketone to the solution obtained in step (a); c) slurring the reaction mass obtained in step (b); and d) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
Preferable anti solvent is ethyl acetate or ethyl formate. The temperature at which slurrying is carried out is not critical and the slurrying may conveniently be carried out at room temperature. According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 2, which comprises: a) dissolving gemifloxacin mesylate in dimethylformamide; b) cooling the solution, optionally distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
Preferably, the solution is cooled to a temperature of between 0 to 150C. The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
The isolation of gemifloxacin mesylate crystalline sesquihydrate form 2, if required may be performed by conventional techniques such as centrifugation and filtration. According to another aspect of the present invention, there is provided a novel crystalline form of gemifloxacin mesylate designated as form 3 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 25.7, 26.2 and 27.0 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline anhydrous form 3 is shown in figure 3.
According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate crystalline anhydrous form 3, which comprises: a) dissolving gemifloxacin mesylate in methanol and water in the ratio of about 8:2; b) distilling off the solvent from a solution obtained in step (a); and c) isolating gemifloxacin mesylate crystalline anhydrous form 3.
The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
The isolation of gemifloxacin mesylate crystalline anhydrous form 3, if required may be performed by conventional techniques such as centrifugation and filtration. According to another aspect of the present invention, there is provided a novel crystalline form of gemifloxacin mesylate designated as form 4 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.3, 10.6, 10.8, 14.5, 18.5 and 24.9 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate crystalline anhydrous form 4 is shown in figure 4.
According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate crystalline anhydrous form 4, which comprises heating gemifloxacin mesylate crystalline hydrate at above 800C.
Preferably heating may be performed at 80 to 1200C. The heating may be carried out until gemifloxacin mesylate crystalline hydrate is completely converted into gemifloxacin mesylate crystalline anhydrous form 4.
According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate crystalline anhydrous form 4, which comprises: a) suspending gemifloxacin mesylate crystalline hydrate in toluene; and b) subjecting the suspension obtained in step (a) to azeotropic distillation at 50 to 800C to obtain gemifloxacin mesylate crystalline anhydrous form 4. Prefrabley, the hydrates are monohydrate, sesquihydrate, sesquihydrate form 1 , sesquihydrate form 2, dihydrate and trihydrate.
According to another aspect of the present invention there is provided gemifloxacin mesylate acetic acid solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 4.9, 9.3, 15.3, 17.8, 21.3 and 25.4 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate acetic acid solvate is shown in figure 5.
According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate acetic acid solvate, which comprises dissolving gemifloxacin mesylate in acetic acid and adding methyl tert-butyl ether to the solution to obtain gemifloxacin mesylate acetic acid solvate.
According to another aspect of the present invention there is provided gemifloxacin mesylate N-methylpyrrolidone solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 6.9, 7.1 , 13.9, 20.0, 21.0 and 25.6 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate N-methylpyrrolidone solvate is shown in figure 6.
According to another aspect of the present invention, there is provided a process for the preparation of gemifloxacin mesylate N-methylpyrrolidone solvate, which comprises dissolving gemifloxacin mesylate in N- methylpyrrolidone and adding an anti solvent to the solution to obtain gemifloxacin mesylate N-methylpyrrolidone solvate.
The anti solvent used may be a solvent or mixture of solvents selected from the group consisting of a acetonitrile, 1 ,4-dioxane, acetone, cyclohexane and n-heptane. Preferable anti solvent is selected from acetonitrile and 1 ,4- dioxane.
According to another aspect of the present invention there is provided gemifloxacin mesylate 1 ,4-dioxane solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 7.2, 15.8,
18.2 and 24.7 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of gemifloxacin mesylate 1 ,4-dioxane solvate is shown in figure 7.
According to another aspect of the present invention there is provided a process for preparing gemifloxacin mesylate 1 ,4-dioxane solvate, which comprises crystallizing gemifloxacin mesylate 1 ,4-dioxane solvate from a solution of gemifloxacin mesylate in 1 ,4-dioxane solvent.
According to the invention, 1 ,4-dioxane may alone be present as solvent in the solution or 1 ,4-dioxane in combination with water or any other solvent or solvents may be present. For example, 1 ,4-dioxane in combination with methanol, ethanol or isopropyl alcohol may be present in the solution.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a polymorphic form of gemifloxacin mesylate selected from sesquihydrate form 1 , sesquihydrate form 2, anhydrous form 3 and anhydrous form 4 or a mixture thereof; and a pharmaceutically acceptable excipient.
The pharmaceutically acceptable inert carrier which can be used may be a solid or liquid. The solid or semi-solid pharmaceutical preparation in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments.
The liquid pharmaceutical preparation includes solutions, suspensions and emulsions.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
EXAMPLES
Preparation of gemifloxacin mesylate crystalline sesquihvdrate form 1 Example 1
Gemifloxacin mesylate (5 gm) and methanol (300 ml) was mixed and heated to reflux, the resulting solution was filtered and distilled out half of the solvent. The reaction mass was cooled to 50C and maintained at 50C for 30 minutes. The solid obtained was collected by filtration and the solid was washed with methanol, and then dried at 20 to 250C for 30 minutes to obtain 4.5 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 2
Gemifloxacin mesylate (6 gm) was dissolved in water (15 ml) and methanol (45 ml) at room temperature, filtered. 50 percent of the solvent volume was distilled from the reaction mass under vacuum. After completion of the distillation, the reaction mass was cooled to 100C and maintained at 100C for 30 minutes. The separated solid was filtered, washed with methanol, and then dried at 20 to 250C for 30 minutes to obtain 5.5 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 3
The mixture of Gemifloxacin mesylate (5 gm), methanol (300 ml) and dichloromethane (300 ml) was heated to reflux. The resulting solution was filtered and distilled out maximum of the solvent. The reaction mass was cooled to 50C and maintained at 50C for 30 minutes, filtered. The solid obtained was washed with dichloromethane and dried at 20 to 250C to obtain 4.3 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 4
Gemifloxacin mesylate (5 gm) was dissolved in water (50 ml) and ethanol (100 ml) at room temperature, filtered. 50 percent of the solvent volume was distilled from the reaction mass under vacuum. After completion of the distillation, the reaction mass was cooled to 50C and maintained at 50C for 30 minutes. The separated solid was filtered, washed with ethanol, and then dried at 20 to 250C for 30 minutes to obtain 4.0 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 5
The mixture of gemifloxacin mesylate (6 gm), methanol (60 ml) and acetonitrile (60 ml) was heated to reflux to obtain a clear solution. The resulting solution was filtered and distilled out half of the solvent. The reaction mass was cooled to 150C and maintained at 150C for 30 minutes, filtered. The solid obtained was washed with acetonitrile and dried at 20 to 250C for 30 minutes to obtain 5.0 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 6
Gemifloxacin mesylate (5 gm), methanol (50 ml) and diisopropyl ether (50 ml) was mixed and heated to reflux, the resulting solution was filtered. 50 percent of the solvent volume was distilled from the reaction mass under vacuum. After completion of the distillation, the reaction mass was cooled to 100C and maintained at 100C for 30 minutes. The separated solid was filtered, washed with diisopropyl ether, and then dried at 20 to 250C for 30 minutes to obtain 4.5 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 7
The mixture of gemifloxacin mesylate (6 gm), methanol (60 ml) and methyl tert-butyl ether (60 ml) was heated to reflux to obtain a clear solution. The resulting solution was filtered and distilled out half of the solvent. The reaction mass was cooled to 50C and maintained at 50C for 30 minutes. The solid obtained was collected by filtration and the solid was washed with methyl tert-butyl ether, and then dried at 20 to 250C for 30 minutes to obtain 5.4 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 8 Gemifloxacin mesylate (5 gm) was dissolved in methanol (300 ml) and heated to reflux for 20 minutes. To the solution was added ethyl acetate (200 ml), cooled to 50C and maintained at 50C for 1 hour. The solid obtained was collected by filtration and the solid was washed with ethyl acetate, and then dried at 450C for 30 minutes to obtain 4.5 gm of gemifloxacin mesylate crystalline sesquihydrate form 1. Example 9
Gemifloxacin mesylate (6 gm) was dissolved in water (15 ml), methanol (15 ml) and 1 ,4-dioxane (15 ml) and stirred for 30 minutes to obtain clear solution. The solution obtained was filtered and the filtrate was cooled to 100C and maintained at 100C for 3 hours. The solid collected by filtration, washed with methyl tert-butyl ether (30 ml) and then dried at 350C for 30 minutes to obtain 5.2 gm of gemifloxacin mesylate crystalline sesquihydrate form 1.
Preparation of qemifloxacin mesylate crystalline sesquihydrate form 2
Example 10
Gemifloxacin mesylate (5 gm) was dissolved in dimethylformamide (50 ml) and stirred for 20 minutes at 20 to 25 deg C. To the solution was added ethyl acetate (350 ml) and stirred for 12 hours, filtered. The solid obtained was washed with ethyl acetate and dried at 350C for 2 hours to obtain 4.9 gm of gemifloxacin mesylate crystalline sesquihydrate form 2.
Example 1 1
Gemifloxacin mesylate (10 gm) was dissolved in dimethylformamide (100 ml) at 70 to 750C to obtain clear solution and filtered. The filtrate was cooled to
50C and maintained for 50C for 30 minutes. The solid obtained was collected by filtration, washed with dimethylformamide and dried at 450C for 2 hours to obtain
9.5 gm of gemifloxacin mesylate crystalline sesquihydrate form 2.
Example 12 Gemifloxacin mesylate (10 gm) was dissolved in dimethylformamide (100 ml) at 80 to 900C to obtain clear solution and filtered. The filtrate was distilled off the solvent under reduced pressure at 60 to 700C to obtain 9.3 gm of gemifloxacin mesylate crystalline sesquihydrate form 2.
Example 13 Gemifloxacin mesylate (5 gm) was dissolved in dimethylformamide (50 ml) at 80 to 900C to obtain clear solution. The solution was cooled to 50C and ethyl formate (100 ml) was added. The reaction mass was stirred for 2 hours and filtered. The solid obtained was washed with ethyl formate and dried at 350C for 2 hours to obtain 4.9 gm of gemifloxacin mesylate crystalline sesquihydrate form 2.
Preparation of gemifloxacin mesylate crystalline anhydrous form 3 Example 14
Gemifloxacin mesylate (6 gm) was dissolved in methanol and water (30 ml, 8:2) and stirred for 1 hour, filtered. The filtrate was distilled off the solvent under reduced pressure to obtain 5.5 gm of gemifloxacin mesylate crystalline anhydrous form 3.
Preparation of gemifloxacin mesylate crystalline anhydrous form 4 Example 15
Gemifloxacin mesylate crystalline sesquihydrate form 1 (5 gm) obtained as in example 1 was added to toluene (80 ml) at room temperature. The reaction mass was subjected to azeotropic distillation at 55 to 650C under reduced pressure to obtain 4.7 gm of gemifloxacin mesylate crystalline anhydrous form 4.
Example 16
Gemifloxacin mesylate crystalline sesquihydrate form 1 (5 gm) obtained as in example 1 was heated at 100 deg C for 12 hours to obtain 4.6 gm of gemifloxacin mesylate crystalline anhydrous form 4.
Preparation of gemifloxacin mesylate acetic acid solvate
Example 17
To the gemifloxacin mesylate (5 gm) was added acetic acid (50 ml) and stirred for 30 minutes. The reaction mass was heated to 450C for 30 minutes to obtain clear solution. The solution was cooled to 50C and methyl tert-butyl ether
(20 ml) was added to the solution. The solution was stirred for 1 hour, filtered and washed with methyl tert-butyl ether. The solid was dried at 350C to obtain
3.5 gm of gemifloxacin mesylate acetic acid solvate.
Preparation of gemifloxacin mesylate N-methylpyrrolidone solvate
Example 18
Gemifloxacin mesylate (5 gm) was dissolved in N-methylpyrrolidone (75 ml) and heated to 45 to 500C to obtain clear solution. To the solution was added acetonitrile (100 ml). The reaction mass was cooled to 100C and maintained at 100C for 30 minutes. The solid obtained was collected by filtration and washed with acetonitrile, and then dried at 350C for 2 hours to obtain 4.8 gm of gemifloxacin mesylate N-methylpyrrolidone solvate. Example 19
Gemifloxacin mesylate (5 gm) was dissolved in N-methylpyrrolidone (75 ml) and heated to 45 to 500C to obtain clear solution, filtered. To the filtrate was added 1 ,4-dioxane (100 ml). The reaction mass was cooled to 50C and maintained at 50C for 1 hour, filtered. The solid obtained was washed with 1 ,4- dioxane and dried at 400C for 2 hours to obtain 4.9 gm of gemifloxacin mesylate N-methylpyrrolidone solvate.
Preparation of gemifloxacin mesylate 1,4-dioxane solvate Example 20 Gemifloxacin mesylate (10 gm) was dissolved in water (25 ml) and 1 ,4- dioxane (25 ml) and stirred for 30 minutes, filtered. The filtrate was cooled to 0 to 50C and maintained at 0 to 50C for 3 hours, and then filtered. The solid obtained was washed with 1 ,4-dioxane and dried at 450C for 30 minutes to obtain 9.5 gm of gemifloxacin mesylate 1 ,4-dioxane solvate. Example 21
Gemifloxacin mesylate (6 gm) was dissolved in water (15 ml), methanol (15 ml) and 1 ,4-dioxane (15 ml) and stirred for 30 minutes to obtain clear solution. The solution obtained was filtered and the filtrate was cooled to 0 to 50C for 3 hours. The solid collected by filtration and the solid washed with 1 ,4- dioxane, and then dried at 350C for 30 minutes to obtain 5 gm of gemifloxacin mesylate 1 ,4-dioxane solvate.

Claims

We claim:
1. A gemifloxacin mesylate crystalline sesquihydrate form 1 , characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.2, 9.9, 10.4, 15.0, 17.1 , 19.5, 25.7 and 26.2 ± 0.2 degrees.
2. A gemifloxacin mesylate crystalline sesquihydrate form 1 , characterized by an x-ray powder diffractogram as shown in figure 1.
3. The gemifloxacin mesylate crystalline sesquihydrate form 1 as claimed in claim 1 , wherein the gemifloxacin mesylate crystalline sesquihydrate form 1 is further characterized by a differential scanning calorimetry thermogram as shown in figure 8.
4. A process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 1 as defined in claim 1 , which comprises: a. dissolving gemifloxacin mesylate in an alcohol solvent or mixture thereof, optionally mixed with one or more other solvent or water; b. maintaining the contents in step (a) at elevated temperature at above 400C; c. a portion of solvent from the solution obtained in step (b) until at least separation of gemifloxacin mesylate as solid occurs; and d. isolating gemifloxacin mesylate crystalline sesquihydrate form 1.
5. The process as claimed in claim 4, wherein the alcohol solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
6. The process as claimed in claim 5, wherein the alcohol solvent used in step (a) is selected from methanol and ethanol.
7. The process as claimed in claim 4, wherein the other solvent used in step (a) is a solvent or mixture of solvents selected from dichloromethane, acetonitrile, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, 1 ,4- dioxane, n-heptane, cyclohexane and hexane.
8. The process as claimed in claim 7, wherein the other solvent used in step (a) is selected from dichloromethane, acetonitrile, diisopropyl ether, methyl tert- butyl ether, ethyl acetate and 1 ,4-dioxane.
9. The process as claimed in claim 4, wherein the contents are maintained at 40 to 100°C.
10. The process as claimed in claim 9, wherein the contents are maintained at reflux.
11. A gemifloxacin mesylate crystalline sesquihydrate form 2, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 10.7, 11.7, 18.7, 22.7 and 25.6 ± 0.2 degrees.
12. A gemifloxacin mesylate crystalline sesquihydrate form 2, characterized by an x-ray powder diffractogram as shown in figure 2.
13. The gemifloxacin mesylate crystalline sesquihydrate form 2 as claimed in claim 11 , wherein the gemifloxacin mesylate crystalline sesquihydrate form 2 is further characterized by a differential scanning calorimetry thermogram as shown in figure 9.
14. A process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 2 as defined in claim 11 , which comprises: a. dissolving gemifloxacin mesylate in dimethylformamide; b. adding an anti solvent or a mixture of anti solvents selected from ethyl acetate, ethyl formate, isopropyl acetate, methyl ethyl ketone and isobutyl methyl ketone to the solution obtained in step (a); c. slurring the reaction mass obtained in step (b); and d. isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
15. The process as claimed in claim 14, wherein the anti solvent used in step (b) is selected from ethyl acetate or ethyl formate.
16. A process for the preparation of gemifloxacin mesylate crystalline sesquihydrate form 2 as defined in claim 11 , which comprises: a. dissolving gemifloxacin mesylate in dimethylformamide; b. cooling the solution, optionally distilling off the solvent from a solution obtained in step (a); and c. isolating gemifloxacin mesylate crystalline sesquihydrate form 2.
17. The process as claimed in claim 16, wherein the solution in step (b) is cooled to O to 150C.
18. A gemifloxacin mesylate crystalline anhydrous form 3, characterized by an x- ray powder diffractogram having peaks expressed as 2Θ angle positions at about 25.7, 26.2 and 27.0 ± 0.2 degrees.
19. A gemifloxacin mesylate crystalline anhydrous form 3, characterized by an x- ray powder diffractogram as shown in figure 3.
20. A process for the preparation of gemifloxacin mesylate crystalline anhydrous form 3 as defined in claim 18, which comprises: a. dissolving gemifloxacin mesylate in methanol and water in the ratio of about 8:2; b. distilling off the solvent from a solution obtained in step (a); and c. isolating gemifloxacin mesylate crystalline anhydrous form 3.
21. A gemifloxacin mesylate crystalline anhydrous form 4, characterized by an x- ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.3, 10.6, 10.8, 14.5, 18.5 and 24.9 ± 0.2 degrees.
22. A gemifloxacin mesylate crystalline anhydrous form 4, characterized by an x- ray powder diffractogram as shown in figure 4.
23. A process for the preparation of gemifloxacin mesylate crystalline anhydrous form 4 as defined in claim 21 , which comprises heating gemifloxacin mesylate crystalline hydrate at above 800C.
24. The process as claimed in claim 23, wherein the heating is carried out at about 80 to 1200C.
25. A process for the preparation of gemifloxacin mesylate crystalline anhydrous form 4 as defined in claim 21 , which comprises: a. suspending gemifloxacin mesylate crystalline hydrate in toluene; and b. subjecting the suspension obtained in step (a) to azeotropic distillation at 50 to 800C to obtain gemifloxacin mesylate crystalline anhydrous form 4.
26. The process as claimed in claim 23 and 25, where in the hydrates is monohydrate, sesquihydrate, sesquihydrate form 1 , sesquihydrate form 2, dihydrate and trihydrate.
27. A gemifloxacin mesylate acetic acid solvate, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 4.9, 9.3, 15.3, 17.8, 21.3 and 25.4 ± 0.2 degrees.
28. A gemifloxacin mesylate acetic acid solvate, characterized by an x-ray powder diffractogram as shown in figure 5.
29. A process for the preparation of gemifloxacin mesylate acetic acid solvate as defined in claim 27, which comprises dissolving gemifloxacin mesylate in acetic acid and adding methyl tert-butyl ether to the solution to obtain gemifloxacin mesylate acetic acid solvate.
30. .A gemifloxacin mesylate N-methylpyrrolidone solvate, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 6.9, 7.1 , 13.9, 20.0, 21.0 and 25.6 ± 0.2 degrees.
31. A gemifloxacin mesylate acetic N-methylpyrrolidone solvate, characterized by an x-ray powder diffractogram as shown in figure 6.
32. A process for the preparation of gemifloxacin mesylate N-methylpyrrolidone solvate as defined in claim 30, which comprises dissolving gemifloxacin mesylate in N-methylpyrrolidone and adding an anti solvent to the solution to obtain gemifloxacin mesylate N-methylpyrrolidone solvate.
33. The process as claimed in claim 32, wherein the anti solvent used in step (a) is a solvent or mixture of solvents selected from acetonitrile, 1 ,4-dioxane, acetone, cyclohexane and n-heptane.
34. The process as claimed in claim 33, wherein the alcohol solvent used in step
(a) is selected from acetonitrile and 1 ,4-dioxane.
35. A gemifloxacin mesylate 1 ,4-dioxane solvate, characterized by an x-ray powder diffractogram having peaks expressed as 2Θ angle positions at about
7.2, 15.8, 18.2 and 24.7 ± 0.2 degrees.
36. A gemifloxacin mesylate acetic 1 ,4-dioxane solvate, characterized by an x- ray powder diffractogram as shown in figure 7.
37. A process for the preparation of gemifloxacin mesylate 1 ,4-dioxane solvate as defined in claim 35, which comprises crystallizing gemifloxacin mesylate 1 ,4-dioxane solvate from a solution of gemifloxacin mesylate in 1 ,4-dioxane solvent.
38. The process as claimed in claim 37, wherein the 1 ,4-dioxane in combination with water or any other solvent or solvents.
39. The process as claimed in claim 38, wherein the solvent used in the process is methanol, ethanol or isopropyl alcohol.
40. A pharmaceutical composition comprising a polymorphic form of gemifloxacin mesylate selected from sesquihydrate form 1 , sesquihydrate form 2, anhydrous form 3 and anhydrous form 4 or a mixture thereof and a pharmaceutically acceptable excipient.
41. The pharmaceutical composition as claimed in claim 40, wherein the pharmaceutical composition is used in a solid or liquid.
42. The pharmaceutical composition as claimed in claim 41 , wherein the solid or semi-solid pharmaceutical preparation in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments.
43. The pharmaceutical composition as claimed in claim 41 , wherein the liquid pharmaceutical preparation includes solutions, suspensions and emulsions.
PCT/IN2009/000346 2009-06-16 2009-06-16 Novel polymorphs of gemifloxacin mesylate WO2010146594A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042705A1 (en) * 1997-03-21 1998-10-01 Lg Chemical Ltd. Salt of naphthyridine carboxylic acid derivative
WO2010001408A2 (en) * 2008-06-06 2010-01-07 Matrix Laboratories Ltd. Novel polymorphic forms of gemifloxacin mesylate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042705A1 (en) * 1997-03-21 1998-10-01 Lg Chemical Ltd. Salt of naphthyridine carboxylic acid derivative
WO2010001408A2 (en) * 2008-06-06 2010-01-07 Matrix Laboratories Ltd. Novel polymorphic forms of gemifloxacin mesylate

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