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WO2010001408A2 - Novel polymorphic forms of gemifloxacin mesylate - Google Patents

Novel polymorphic forms of gemifloxacin mesylate Download PDF

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Publication number
WO2010001408A2
WO2010001408A2 PCT/IN2009/000329 IN2009000329W WO2010001408A2 WO 2010001408 A2 WO2010001408 A2 WO 2010001408A2 IN 2009000329 W IN2009000329 W IN 2009000329W WO 2010001408 A2 WO2010001408 A2 WO 2010001408A2
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Prior art keywords
gemifloxacin mesylate
crystalline
gemifloxacin
mesylate form
powder
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PCT/IN2009/000329
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French (fr)
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WO2010001408A3 (en
Inventor
Ramakoteswara Rao Jetti
Ramireddy Bommareddy Aggi
Debashish Datta
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Mylan Laboratories Ltd
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Matrix Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel forms of Gemifloxacin mesylate hereafter designated as Gemifloxacin mesylate polymorphic Form H, I, J, K, L and M.
  • the invention further relates to process for the preparation of novel forms of Gemifloxacin mesylate.
  • Gemifloxacin mesylate is a synthetic broad-spectrum antibacterial agent for oral administration. It is related to the fluoroquinolone class of antibiotics and available as the mesylate salt in the sesquihydrate form. Chemically, Gemifloxacin is (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-l,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid and it's chemical structure is represented by Formula-I.
  • Gemifloxacin and its pharmaceutically acceptable salts are first disclosed in US patent 5,633,362. Further the patent discloses process for the preparation of Gemifloxacin comprising reacting l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro [l,8]naphtha- yridine-3-carboxylicacid is reacted with 4-aminomethylpyrrolidin-3-one-O-methyl oxime difluoroacetate in the presence of base in acetonitrile. After completion of the condensation reaction, the reaction mixture is diluted with water separated solid is filtered to give Gemifloxacin. The Gemifloxacin so produced is further converted into pharmaceutically acceptable salts by conventional methods.
  • US 5,776,944 patent discloses salts and hydrate forms of Gemifloxacin mesylate and processes thereof.
  • the process comprises suspending Gemifloxacin in a mixture of dichloromethane and ethanol, adding methanesulfonic acid dropwise, stirring the resulting solution and filtering the obtained solid to give anhydrous Gemifloxacin mesylate having the melting point 195° C.
  • Gemifloxacin mesylate anhydrous so obtained is dissolved in a mixture of water and acetone or water and ethanol followed by cooling and filtration to give Gemifloxacin mesylate 1.5 hydrate (Gemifloxacin sesquihydrate).
  • US '944 patent discloses process for the preparation of Gemifloxacin mesylate anhydrous, sesquihydrate and trihydrate. Gemifloxacin mesylate hydrated forms are characterized by powder X-Ray Diffraction.
  • US 6,723,734 B2 patent discloses hydrate forms of Gemifloxacin mesylate having the moisture quantity 1-4 moles with respect to Gemifloxacin mesylate.
  • the patent further discloses Gemifloxacin mesylate solvates selected from C M halo alkanes and Ci -8 alcohols such as dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, propanol and so forth.
  • US 6,818,771 patent discloses a process for the preparation of Gemifloxacin mesylate sesquihydrate directly from Gemifloxacin, wherein Gemifloxacin is suspended in a mixture of water and Ci-C 4 alcohol followed by adding methanesulfonic acid, cooling the resulting solution and filtering to give Gemifloxacin mesylate sesquihydrate.
  • the present invention discloses novel stable polymorphic forms of Gemifloxacin mesylate having good stability and purity. And these novel forms can also be prepared by an efficient, economic and reproducible process particularly in large scale preparation with free flowing nature.
  • the main object of the present invention is to provide novel Gemifloxacin mesylate polymorphic forms, Form H, I, J, K, L and M.
  • Another object of the present invention is to provide process for the preparation of crystalline Gemifloxacin mesylate polymorphic forms, Form H, I, J, K, L and M.
  • the main aspect of the present invention is to provide novel crystalline Gemifloxacin mesylate polymorphic Form H. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form H comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent; b) removing the solvent from the reaction mixture; c) and isolating Gemifloxacin mesylate Form H.
  • Another aspect of the present invention is to provide novel crystalline Gemifloxacin mesylate polymorphic Form I. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form I comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent; b) precipitating by adding an anti-solvent; and c) isolating the crystalline Gemifloxacin mesylate Form I.
  • Another aspect-of- the- present— invention is to provide crystalline Gemifloxacin mesylate polymorphic Form J. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form J comprising the steps of: a) preparing a solution of Gemifloxacin mesylate from a suitable solvent; b) followed by complete removal of solvent; and c) isolating the Gemifloxacin mesylate Form J.
  • Another aspect of the present invention is to provide crystalline Gemifloxacin mesylate polymorphic Form K. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form K comprising the steps of: a) suspending Gemifloxacin mesylate in a solvent; b) followed by azeotropic distillation; and c) isolating the Gemifloxacin mesylate Form K.
  • Another aspect of the present invention is to provide an alternate process for the preparation of Gemifloxacin mesylate Form K comprising the steps of a) heating Gemifloxacin mesylate Form I or Form J; b) isolating Gemifloxacin mesylate Form K.
  • Another aspect of the present invention is to provide crystalline Gemifloxacin mesylate polymorphic Form L. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form L comprising the steps of: a) suspending Gemifloxacin mesylate in a suitable solvent at room temperature; and b) heating to reflux temperature and isolating the Gemifloxacin mesylate Form L.
  • Another aspect of the present invention is to provide crystalline Gemifloxacin mesylate polymorphic Form M. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form M comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent mixture; b) precipitating by addition of an anti solvent; and c) isolating Gemifloxacin mesylate Form M on drying.
  • Figure 1 illustrates the powder XRD pattern of Gemifloxacin mesylate Form H.
  • FIG. 1 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form H.
  • FIG 3 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form H.
  • Figure 4 illustrates the powder XRD pattern of Gemifloxacin mesylate Form I.
  • FIG. 5 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form I.
  • FIG. 6 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form I.
  • Figure 7 illustrates the powder XRD pattern of Gemifloxacin mesylate Form J.
  • FIG. 8 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form J.
  • FIG. 9 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form J.
  • Figure 10 illustrates the powder XRD pattern of Gemifloxacin mesylate Form K.
  • FIG 11 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form K.
  • Figure 12 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form K.
  • Figure 13 illustrates the powder XRD pattern of Gemifloxacin mesylate Form L.
  • FIG 14 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form L.
  • Figure 15 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form L.
  • Figure 16 illustrates the powder XRD pattern of Gemifloxacin mesylate Form M.
  • Figure 17 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form M.
  • Figure 18 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form M.
  • the present invention relates to novel forms of Gemifloxacin mesylate hereinafter designated as Gemifloxacin mesylate polymorphic Form H, I, J, K, L and M.
  • the invention further relates to process for the preparation of novel crystalline forms of Gemifloxacin mesylate.
  • the said forms differ from the other prior art polymorphs in their physical properties, spectral data and method of preparation and characterized by X-ray powder diffraction, Differential scanning calorimetry (DSC), Thermo gravimetric analysis (TGA/DTA) and/or by Karl-Fisher titrator.
  • the said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu- anode X-ray tube was operated at 4OkV and 30mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • the DSC measurements were carried out on Mettler Toledo 822 star 6 and TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used. Thermo gravimetric Analysis (TGA/SDTA)
  • TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 l e .
  • the experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.
  • Water content was determined on Metrohm Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.
  • Crystalline Gemifloxacin mesylate Form H is characterized by powder X-ray diffraction pattern with peaks at 9.15, 9.30, 11.68, 18.20, 26.28, 26.94, 27.17 ⁇ 0.2 2 ⁇ values.
  • Crystalline Gemifloxacin mesylate Form H is further characterized by powder X-ray diffraction pattern with peaks at 5.24, 9.15, 9.30, 11.68, 16.66, 17.31, 18.20, 21.04, 26.28, 26.94/27.17 ⁇ 0.2 2 ⁇ values as shown in Figure 1.
  • Crystalline Gemifloxacin mesylate Form H is further characterized by DSC with characteristic sharp exothermic peak at 214.57°C as shown in Figure 2. Crystalline Gemifloxacin mesylate Form H shows no substantial weight loss ( ⁇ 1%) in TGA/DTA as shown in Figure 3 and also Karl-Fisher method shows moisture content less than 1% .
  • Form H is anhydrate form.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form H comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent such as DMF; b) removing the solvent from the reaction mixture; and c) isolating Gemifloxacin mesylate Form H.
  • Gemifloxacin mesylate is dissolved in DMF at 60-90 0 C, preferably 8O 0 C.
  • the clear solution is concentrated using vacuum distillation at 60-80 0 C, preferably 70 0 C to obtain Gemifloxacin mesylate Form H as free powder.
  • the Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
  • the novel polymorphic Form H is physically and chemically stable (Table 1).
  • Crystalline Gemifloxacin mesylate Form I is characterized by powder X-ray diffraction pattern with peaks at 4.88, 9.30, 14.90, 19.97, 20.75, 25.14 ⁇ 0.2 2 ⁇ values.
  • Crystalline Gemifloxacin mesylate Form I is further characterized by powder X-ray diffraction pattern with peaks at 4.88, 9.31, 9.79, 14.90, 17.54, 19.97, 20.75, 21.38, 24.32, 24.70, 25.14, 26.35 ⁇ 0.2 2 ⁇ values as shown in Figure 4.
  • Crystalline Gemifloxacin mesylate Form I is further characterized by DSC with an endothermic peak at 135.50 0 C attributed to desolvation and followed by an exothermic peak at 234.71 0 C corresponding to the melting of the product as shown in Figure 5.
  • Crystalline Gemifloxacin mesylate form I is DMF solvate with DMF content of 13-14%, which is analyzed by TGA/DTA as shown in Figure 6 and moisture content of 2-3% supported by Karl-Fisher method.
  • Form I is mono-DMF solvate.
  • Another aspect of the present invention is to provide process for the preparation of crystalline Gemifloxacin mesylate Form I comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent such as DMF; b) precipitating by adding an anti-solvent selected from acetonitrile; and isolating c) the crystalline Gemifloxacin mesylate Form I.
  • Gemifloxacin mesylate is dissolved in DMF at 60-90 0 C, preferably 80 0 C.
  • the Clear solution is cooled to 20-35 0 C, preferably 25- 30 0 C.
  • acetonitrile is added at 25-30 0 C.
  • Crystalline Gemifloxacin mesylate Form I precipitates out as free solid.
  • the Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
  • Crystalline Gemifloxacin mesylate Form J is characterized by powder X-ray diffraction pattern with peaks at 11.07, 11.29 14.96, 15.83, 17.84, 20.25, 22.49 ⁇ 0.2 2 ⁇ values.
  • Crystalline Gemifloxacin mesylate Form J is further characterized by powder X-ray diffraction pattern with peaks at 5.53, 7.90, 11.07, 11.29, 14.96, 15.83, 17.84, 20.25, 22.49, 22.85, 24.24, 24.99 ⁇ 0.2 2 ⁇ values as shown in Figure 7.
  • Crystalline Gemifloxacin mesylate Form J is further characterized by DSC with two endothermic peaks; first at about 140 0 C, second at about 154 0 C attributed to desolvation followed by two exothermic peaks at 159.15°C and 186.65°C attributes to recrystallisation and finally an exothermic peak at 225.57 0 C corresponding to the melting of the product as shown in Figure 8.
  • Crystalline Gemifloxacin mesylate Form J is further characterized by DSC with two endothermic peaks; first at about 140 0 C, second at about 154 0 C attributed to desolvation followed by two exothermic peaks at 159.15°C and 186.65°C attributes to recrystallisation and finally an exothermic peak at 225.57 0 C corresponding to the melting of the product as shown in Figure 8.
  • J is DMSO solvate with DMSO content of 13-14%, which is analyzed by TGA/DTA as shown in Figure 9 and moisture content of 2-3% supported by Karl-Fisher method.
  • Form J is mono-DMSO solvate.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form J, comprising the steps of: a) preparing a solution of Gemifloxacin mesylate from a suitable solvent such as DMSO; b) complete removal of solvent; and c) isolating the Gemifloxacin mesylate Form J.
  • Gemifloxacin mesylate is dissolved in DMSO at 70-90 0 C, preferably 70 0 C.
  • the clear solution is filtered over hyflo to remove undissolved particulate matter and subjected to distillation under vacuum at 70-90 0 C, preferably 80 0 C.
  • Crystalline Gemifloxacin Form J crystallizes out as free powder.
  • the Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
  • Crystalline Gemifloxacin mesylate Form K is characterized by powder X-ray diffraction pattern with peaks at 6.66, 7.84, 17.83, 20.06, 25.65 ⁇ 0.2 2 ⁇ values. Crystalline Gemifloxacin mesylate Form K is further characterized by powder X-ray diffraction pattern with peaks at 6.66, 7.84, 11.78, 17.83, 20.06, 25.65, 26.06 ⁇ 0.2 2 ⁇ values as shown in Figure 10.
  • Crystalline Gemifloxacin mesylate Form K is further characterized by DSC with characteristic sharp exothermic peak at 233.40 0 C as shown in Figure 1 1.
  • Crystalline Gemifloxacin mesylate Form K shows no substantial weight loss (-1%) in TGA/DTA as shown in Figure 12 and also Karl-Fisher method shows moisture content about 1%.
  • Form K is anhydrate form.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form K, comprising the steps of: a) suspending Gemifloxacin mesylate in toluene; b) carrying out azeotropic distillation; and c) isolating the Gemifloxacin mesylate Form K.
  • Gemifloxacin mesylate is suspended in toluene and subjected to azeotropic distillation for 4-6 hrs, preferably 5 hrs.
  • the resulting solution is cooled to 20-40 0 C, preferably 25-30 0 C and stirred for 30-90 min, preferably 60 min.
  • the solid is filtered to obtain Gemifloxacin mesylate Form K.
  • the Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
  • the another aspect of the present invention is to provide an alternate process for preparing Form K of Gemifloxacin mesylate, comprising the steps of: a) heating crystalline Gemifloxacin Mesylate Form I; and b) isolating Gemifloxacin mesylate Form K.
  • Gemifloxacin mesylate Form I is heated in a vacuum oven under pressure at 120-160 0 C, preferably 140 0 C, for about 1-5 hrs, preferably 2 hrs.
  • the another aspect of the present invention is to provide an alternate process for preparing Form K of Gemifloxacin mesylate comprising steps of: a) heating crystalline Gemifloxacin Mesylate Form J and b) isolating Gemifloxacin mesylate Form K.
  • Gemifloxacin mesylate Form J is heated in a vacuum oven under pressure at 120-160 0 C, preferably 14O 0 C for about 1-5 hrs, preferably 2 hrs.
  • the novel polymorphic Form K is physically and chemically stable (Table 1).
  • Crystalline Gemifloxacin mesylate Form L is characterized by powder X-ray diffraction pattern having peaks at about 10.80, 18.76, 22.77, 25.65 ⁇ 0.2 2 ⁇ values.
  • Crystalline Gemifloxacin mesylate Form L is further characterized by powder X-ray diffraction pattern with peaks at 10.80, 11.76, 17.37, 17.76, 18.76, 19.79, 20.68, 21.71, 22.77, 25.65 ⁇ 0.2 2 ⁇ values as shown in Figure 13.
  • Crystalline Gemifloxacin mesylate Form L is further characterized by DSC with characteristic sharp exothermic peak at 240.36 0 C as shown in Figure 14. Crystalline Gemifloxacin mesylate Form L shows no substantial weight loss (-1%) in TGA/DTA as shown in Figure 15 and also Karl-Fisher method shows moisture content ⁇ 1% .
  • Form L is anhydrate form.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form L comprising the step: a) suspending Gemifloxacin mesylate in a suitable solvent such as DMF; b) heating the contents to obtain a clear solution; and c) isolating the Gemifloxacin mesylate Form L.
  • Gemifloxacin mesylate is dissolved in DMF at 90-100 0 C, preferably at 100 0 C. Solid precipitates out immediately within 10 min from the clear solution at 100 0 C.
  • the reaction mass is cooled to 20-40 0 C, preferably at 25-
  • the solid is filtered to obtain crystalline Gemifloxacin mesylate Form L.
  • the Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
  • the novel polymorphic Form L is physically and chemically stable (Table 1).
  • Crystalline Gemifloxacin mesylate Form M is characterized by powder X-ray diffraction pattern with peaks at 5.40, 14.63, 24.93 ⁇ 0.2 2 ⁇ values.
  • Crystalline Gemifloxacin mesylate Form M is characterized by powder X-ray diffraction pattern with peaks at 5.40, 10.94, 14.63, 18.48, 24.93 ⁇ 0.2 2 ⁇ values as shown in Figure 16.
  • Crystalline Gemifloxacin mesylate Form M is further characterized by DSC with characteristic sharp exothermic peak at 213.46°C as shown in Figure 17. Crystalline Gemifloxacin mesylate Form M shows no substantial weight loss ( ⁇ 1%) in TGA/DTA as shown in Figure 18 and Karl-Fisher method shows moisture content less than 1% .
  • Form M is anhydrate form.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form M comprising the steps: a) dissolving Gemifloxacin mesylate in a suitable solvent mixture selected from the group of alcohols such as methanol, ethanol, propanol and water; b) precipitating by addition of an anti-solvent such as acetonitrile; and c) isolating Gemifloxacin mesylate Form M on drying.
  • a suitable solvent mixture selected from the group of alcohols such as methanol, ethanol, propanol and water
  • an anti-solvent such as acetonitrile
  • Gemifloxacin mesylate is suspended in solvent selected from methanol, ethanol, propanol, DM water or mixtures thereof preferably methanol and water solvent mixture.
  • solvent selected from methanol, ethanol, propanol, DM water or mixtures thereof preferably methanol and water solvent mixture.
  • the reaction is heated to 40-60 0 C, preferably 50- 55°C to obtain clear solution.
  • the clear solution is reheated to 40-60 0 C, preferably 50-55 0 C and an anti-solvent such as acetonitrile is added at 50-55 0 C over 10-50 min, preferably 30 min.
  • Reaction mass is further cooled to 25-3O 0 C.
  • the solid is filtered and dried at 50-55 0 C to get crystalline Gemifloxacin mesylate Form M.
  • the Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
  • Example 1 Preparation of Gemifloxacin mesylate Form H 1Og of Gemifloxacin mesylate was dissolved in DMF (50ml) at 80 0 C. The hot solution was filtered through hyflo bed to remove undissolved solid particulate. The resulting solution was distilled completely under vacuum at 70 0 C for 2h to get free powder. The resulting solid was identified as Gemifloxacin mesylate Form H.
  • Example 9 Solid state stability of Gemifloxacin mesylate polymorphs in slurry, relative Humidity (RH) and drying conditions

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Abstract

The present invention relates to novel crystalline forms of 1-cyclopropyl-y-chloro-ό- fluoro-4-oxo-1,4-dihydro[1,8]-naphthyridine-3-carboxylic acid mesylate salt (Gemifloxacin mesylate) hereafter designated as Gemifloxacin mesylate polymorphic Forms-H, I, J, K, L and M and process for the preparation thereof.

Description

NOVEL POLYMORPHIC FORMS OF GEMIFLOXACIN MESYLATE
FIELD OF INVENTION:
The present invention relates to novel forms of Gemifloxacin mesylate hereafter designated as Gemifloxacin mesylate polymorphic Form H, I, J, K, L and M. The invention further relates to process for the preparation of novel forms of Gemifloxacin mesylate.
BACKGROUND OF THE INVENTION:
Gemifloxacin mesylate is a synthetic broad-spectrum antibacterial agent for oral administration. It is related to the fluoroquinolone class of antibiotics and available as the mesylate salt in the sesquihydrate form. Chemically, Gemifloxacin is (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-l,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid and it's chemical structure is represented by Formula-I.
Figure imgf000002_0001
Gemifloxacin and its pharmaceutically acceptable salts are first disclosed in US patent 5,633,362. Further the patent discloses process for the preparation of Gemifloxacin comprising reacting l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro [l,8]naphtha- yridine-3-carboxylicacid is reacted with 4-aminomethylpyrrolidin-3-one-O-methyl oxime difluoroacetate in the presence of base in acetonitrile. After completion of the condensation reaction, the reaction mixture is diluted with water separated solid is filtered to give Gemifloxacin. The Gemifloxacin so produced is further converted into pharmaceutically acceptable salts by conventional methods. US 5,776,944 patent discloses salts and hydrate forms of Gemifloxacin mesylate and processes thereof. The process comprises suspending Gemifloxacin in a mixture of dichloromethane and ethanol, adding methanesulfonic acid dropwise, stirring the resulting solution and filtering the obtained solid to give anhydrous Gemifloxacin mesylate having the melting point 195° C.
Gemifloxacin mesylate anhydrous so obtained is dissolved in a mixture of water and acetone or water and ethanol followed by cooling and filtration to give Gemifloxacin mesylate 1.5 hydrate (Gemifloxacin sesquihydrate). US '944 patent discloses process for the preparation of Gemifloxacin mesylate anhydrous, sesquihydrate and trihydrate. Gemifloxacin mesylate hydrated forms are characterized by powder X-Ray Diffraction.
US 6,723,734 B2 patent discloses hydrate forms of Gemifloxacin mesylate having the moisture quantity 1-4 moles with respect to Gemifloxacin mesylate. The patent further discloses Gemifloxacin mesylate solvates selected from CM halo alkanes and Ci-8 alcohols such as dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, propanol and so forth.
US 6,818,771 patent discloses a process for the preparation of Gemifloxacin mesylate sesquihydrate directly from Gemifloxacin, wherein Gemifloxacin is suspended in a mixture of water and Ci-C4 alcohol followed by adding methanesulfonic acid, cooling the resulting solution and filtering to give Gemifloxacin mesylate sesquihydrate.
In our co-pending Indian patent application (139/CHE/2008), amorphous form, crystalline forms A, B, C, D, E, F and G of Gemifloxacin mesylate are disclosed.
In literature only solvated and hydrated polymorphs are known and there remains a need for alternative stable polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale
The present invention discloses novel stable polymorphic forms of Gemifloxacin mesylate having good stability and purity. And these novel forms can also be prepared by an efficient, economic and reproducible process particularly in large scale preparation with free flowing nature.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide novel Gemifloxacin mesylate polymorphic forms, Form H, I, J, K, L and M.
Another object of the present invention is to provide process for the preparation of crystalline Gemifloxacin mesylate polymorphic forms, Form H, I, J, K, L and M.
SUMMARY OF THE INVENTION:
The main aspect of the present invention is to provide novel crystalline Gemifloxacin mesylate polymorphic Form H. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form H comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent; b) removing the solvent from the reaction mixture; c) and isolating Gemifloxacin mesylate Form H.
Another aspect of the present invention is to provide novel crystalline Gemifloxacin mesylate polymorphic Form I. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form I comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent; b) precipitating by adding an anti-solvent; and c) isolating the crystalline Gemifloxacin mesylate Form I.
Another aspect-of- the- present— invention is to provide crystalline Gemifloxacin mesylate polymorphic Form J. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form J comprising the steps of: a) preparing a solution of Gemifloxacin mesylate from a suitable solvent; b) followed by complete removal of solvent; and c) isolating the Gemifloxacin mesylate Form J.
Another aspect of the present invention is to provide crystalline Gemifloxacin mesylate polymorphic Form K. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form K comprising the steps of: a) suspending Gemifloxacin mesylate in a solvent; b) followed by azeotropic distillation; and c) isolating the Gemifloxacin mesylate Form K.
Another aspect of the present invention is to provide an alternate process for the preparation of Gemifloxacin mesylate Form K comprising the steps of a) heating Gemifloxacin mesylate Form I or Form J; b) isolating Gemifloxacin mesylate Form K.
Another aspect of the present invention is to provide crystalline Gemifloxacin mesylate polymorphic Form L. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form L comprising the steps of: a) suspending Gemifloxacin mesylate in a suitable solvent at room temperature; and b) heating to reflux temperature and isolating the Gemifloxacin mesylate Form L.
Another aspect of the present invention is to provide crystalline Gemifloxacin mesylate polymorphic Form M. Accordingly, the present invention provides process for the preparation of crystalline Gemifloxacin mesylate Form M comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent mixture; b) precipitating by addition of an anti solvent; and c) isolating Gemifloxacin mesylate Form M on drying.
BRIEF DESCRIPTION OF THE DRAWINGS
Further description of preferred embodiments of the invention which are shown in the accompanying figures, wherein:
Figure 1 illustrates the powder XRD pattern of Gemifloxacin mesylate Form H.
Figure 2 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form H.
Figure 3 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form H. Figure 4 illustrates the powder XRD pattern of Gemifloxacin mesylate Form I.
Figure 5 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form I.
Figure 6 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form I.
Figure 7 illustrates the powder XRD pattern of Gemifloxacin mesylate Form J.
Figure 8 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form J.
Figure 9 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form J.
Figure 10 illustrates the powder XRD pattern of Gemifloxacin mesylate Form K.
Figure 11 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form K.
Figure 12 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form K. Figure 13 illustrates the powder XRD pattern of Gemifloxacin mesylate Form L.
Figure 14 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form L. Figure 15 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form L.
Figure 16 illustrates the powder XRD pattern of Gemifloxacin mesylate Form M. Figure 17 illustrates Differential scanning calorimetric (DSC) curve of Gemifloxacin mesylate Form M.
Figure 18 illustrates Thermo gravimetric Analysis (TGA/DTA) of Gemifloxacin mesylate Form M.
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to novel forms of Gemifloxacin mesylate hereinafter designated as Gemifloxacin mesylate polymorphic Form H, I, J, K, L and M. The invention further relates to process for the preparation of novel crystalline forms of Gemifloxacin mesylate. The said forms differ from the other prior art polymorphs in their physical properties, spectral data and method of preparation and characterized by X-ray powder diffraction, Differential scanning calorimetry (DSC), Thermo gravimetric analysis (TGA/DTA) and/or by Karl-Fisher titrator.
Powder X-ray Diffraction (PXRD)
The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu- anode X-ray tube was operated at 4OkV and 30mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Differential Scanning Calorimetry (DSC)
The DSC measurements were carried out on Mettler Toledo 822 star6 and TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used. Thermo gravimetric Analysis (TGA/SDTA)
TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 le. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.
Karl-Fisher
Water content was determined on Metrohm Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.
Crystalline Gemifloxacin mesylate Form H is characterized by powder X-ray diffraction pattern with peaks at 9.15, 9.30, 11.68, 18.20, 26.28, 26.94, 27.17 ± 0.2 2Θ values.
Crystalline Gemifloxacin mesylate Form H is further characterized by powder X-ray diffraction pattern with peaks at 5.24, 9.15, 9.30, 11.68, 16.66, 17.31, 18.20, 21.04, 26.28, 26.94/27.17 ± 0.2 2Θ values as shown in Figure 1.
Crystalline Gemifloxacin mesylate Form H is further characterized by DSC with characteristic sharp exothermic peak at 214.57°C as shown in Figure 2. Crystalline Gemifloxacin mesylate Form H shows no substantial weight loss (<1%) in TGA/DTA as shown in Figure 3 and also Karl-Fisher method shows moisture content less than 1% . Preferably, Form H is anhydrate form.
Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form H comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent such as DMF; b) removing the solvent from the reaction mixture; and c) isolating Gemifloxacin mesylate Form H.
According to the present invention, Gemifloxacin mesylate is dissolved in DMF at 60-900C, preferably 8O0C. The clear solution is concentrated using vacuum distillation at 60-800C, preferably 700C to obtain Gemifloxacin mesylate Form H as free powder. The Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
According to present invention, the novel polymorphic Form H is physically and chemically stable (Table 1).
Crystalline Gemifloxacin mesylate Form I is characterized by powder X-ray diffraction pattern with peaks at 4.88, 9.30, 14.90, 19.97, 20.75, 25.14 ± 0.2 2Θ values.
Crystalline Gemifloxacin mesylate Form I is further characterized by powder X-ray diffraction pattern with peaks at 4.88, 9.31, 9.79, 14.90, 17.54, 19.97, 20.75, 21.38, 24.32, 24.70, 25.14, 26.35 ± 0.2 2Θ values as shown in Figure 4.
Crystalline Gemifloxacin mesylate Form I is further characterized by DSC with an endothermic peak at 135.500C attributed to desolvation and followed by an exothermic peak at 234.710C corresponding to the melting of the product as shown in Figure 5. Crystalline Gemifloxacin mesylate form I is DMF solvate with DMF content of 13-14%, which is analyzed by TGA/DTA as shown in Figure 6 and moisture content of 2-3% supported by Karl-Fisher method. Preferably, Form I is mono-DMF solvate.
Another aspect of the present invention is to provide process for the preparation of crystalline Gemifloxacin mesylate Form I comprising the steps of: a) dissolving Gemifloxacin mesylate in a suitable solvent such as DMF; b) precipitating by adding an anti-solvent selected from acetonitrile; and isolating c) the crystalline Gemifloxacin mesylate Form I.
According to the present invention, Gemifloxacin mesylate is dissolved in DMF at 60-900C, preferably 800C. The Clear solution is cooled to 20-350C, preferably 25- 300C. To the solution, acetonitrile is added at 25-300C. Crystalline Gemifloxacin mesylate Form I precipitates out as free solid. The Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate. Crystalline Gemifloxacin mesylate Form J is characterized by powder X-ray diffraction pattern with peaks at 11.07, 11.29 14.96, 15.83, 17.84, 20.25, 22.49 ± 0.2 2Θ values.
Crystalline Gemifloxacin mesylate Form J is further characterized by powder X-ray diffraction pattern with peaks at 5.53, 7.90, 11.07, 11.29, 14.96, 15.83, 17.84, 20.25, 22.49, 22.85, 24.24, 24.99 ± 0.2 2Θ values as shown in Figure 7.
Crystalline Gemifloxacin mesylate Form J is further characterized by DSC with two endothermic peaks; first at about 1400C, second at about 1540C attributed to desolvation followed by two exothermic peaks at 159.15°C and 186.65°C attributes to recrystallisation and finally an exothermic peak at 225.570C corresponding to the melting of the product as shown in Figure 8. Crystalline Gemifloxacin mesylate Form
J is DMSO solvate with DMSO content of 13-14%, which is analyzed by TGA/DTA as shown in Figure 9 and moisture content of 2-3% supported by Karl-Fisher method.
Preferably, Form J is mono-DMSO solvate.
Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form J, comprising the steps of: a) preparing a solution of Gemifloxacin mesylate from a suitable solvent such as DMSO; b) complete removal of solvent; and c) isolating the Gemifloxacin mesylate Form J.
According to the present invention, Gemifloxacin mesylate is dissolved in DMSO at 70-900C, preferably 700C. The clear solution is filtered over hyflo to remove undissolved particulate matter and subjected to distillation under vacuum at 70-900C, preferably 800C. Crystalline Gemifloxacin Form J crystallizes out as free powder. The Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
Crystalline Gemifloxacin mesylate Form K is characterized by powder X-ray diffraction pattern with peaks at 6.66, 7.84, 17.83, 20.06, 25.65 ± 0.2 2Θ values. Crystalline Gemifloxacin mesylate Form K is further characterized by powder X-ray diffraction pattern with peaks at 6.66, 7.84, 11.78, 17.83, 20.06, 25.65, 26.06 ± 0.2 2Θ values as shown in Figure 10.
Crystalline Gemifloxacin mesylate Form K is further characterized by DSC with characteristic sharp exothermic peak at 233.400C as shown in Figure 1 1. Crystalline Gemifloxacin mesylate Form K shows no substantial weight loss (-1%) in TGA/DTA as shown in Figure 12 and also Karl-Fisher method shows moisture content about 1%. Preferably, Form K is anhydrate form.
Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form K, comprising the steps of: a) suspending Gemifloxacin mesylate in toluene; b) carrying out azeotropic distillation; and c) isolating the Gemifloxacin mesylate Form K.
According to the present invention, Gemifloxacin mesylate is suspended in toluene and subjected to azeotropic distillation for 4-6 hrs, preferably 5 hrs. The resulting solution is cooled to 20-400C, preferably 25-300C and stirred for 30-90 min, preferably 60 min. The solid is filtered to obtain Gemifloxacin mesylate Form K. The Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
The another aspect of the present invention is to provide an alternate process for preparing Form K of Gemifloxacin mesylate, comprising the steps of: a) heating crystalline Gemifloxacin Mesylate Form I; and b) isolating Gemifloxacin mesylate Form K.
According to one embodiment of the present invention, Gemifloxacin mesylate Form I is heated in a vacuum oven under pressure at 120-1600C, preferably 1400C, for about 1-5 hrs, preferably 2 hrs.
The another aspect of the present invention is to provide an alternate process for preparing Form K of Gemifloxacin mesylate comprising steps of: a) heating crystalline Gemifloxacin Mesylate Form J and b) isolating Gemifloxacin mesylate Form K.
According to one embodiment of the present invention, Gemifloxacin mesylate Form J is heated in a vacuum oven under pressure at 120-1600C, preferably 14O0C for about 1-5 hrs, preferably 2 hrs.
According to present invention, the novel polymorphic Form K is physically and chemically stable (Table 1).
Crystalline Gemifloxacin mesylate Form L is characterized by powder X-ray diffraction pattern having peaks at about 10.80, 18.76, 22.77, 25.65 ± 0.2 2Θ values.
Crystalline Gemifloxacin mesylate Form L is further characterized by powder X-ray diffraction pattern with peaks at 10.80, 11.76, 17.37, 17.76, 18.76, 19.79, 20.68, 21.71, 22.77, 25.65 ± 0.2 2Θ values as shown in Figure 13.
Crystalline Gemifloxacin mesylate Form L is further characterized by DSC with characteristic sharp exothermic peak at 240.360C as shown in Figure 14. Crystalline Gemifloxacin mesylate Form L shows no substantial weight loss (-1%) in TGA/DTA as shown in Figure 15 and also Karl-Fisher method shows moisture content <1% . Preferably, Form L is anhydrate form.
Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form L comprising the step: a) suspending Gemifloxacin mesylate in a suitable solvent such as DMF; b) heating the contents to obtain a clear solution; and c) isolating the Gemifloxacin mesylate Form L.
According to the present invention, Gemifloxacin mesylate is dissolved in DMF at 90-1000C, preferably at 1000C. Solid precipitates out immediately within 10 min from the clear solution at 1000C. The reaction mass is cooled to 20-400C, preferably at 25-
300C. The solid is filtered to obtain crystalline Gemifloxacin mesylate Form L. The Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
According to present invention, the novel polymorphic Form L is physically and chemically stable (Table 1).
Crystalline Gemifloxacin mesylate Form M is characterized by powder X-ray diffraction pattern with peaks at 5.40, 14.63, 24.93 ± 0.2 2Θ values.
Crystalline Gemifloxacin mesylate Form M is characterized by powder X-ray diffraction pattern with peaks at 5.40, 10.94, 14.63, 18.48, 24.93 ± 0.2 2Θ values as shown in Figure 16.
Crystalline Gemifloxacin mesylate Form M is further characterized by DSC with characteristic sharp exothermic peak at 213.46°C as shown in Figure 17. Crystalline Gemifloxacin mesylate Form M shows no substantial weight loss (<1%) in TGA/DTA as shown in Figure 18 and Karl-Fisher method shows moisture content less than 1% . Preferably, Form M is anhydrate form.
Another aspect of the present invention is to provide a process for the preparation of crystalline Gemifloxacin mesylate Form M comprising the steps: a) dissolving Gemifloxacin mesylate in a suitable solvent mixture selected from the group of alcohols such as methanol, ethanol, propanol and water; b) precipitating by addition of an anti-solvent such as acetonitrile; and c) isolating Gemifloxacin mesylate Form M on drying.
According to the present invention, Gemifloxacin mesylate is suspended in solvent selected from methanol, ethanol, propanol, DM water or mixtures thereof preferably methanol and water solvent mixture. The reaction is heated to 40-600C, preferably 50- 55°C to obtain clear solution. The clear solution is reheated to 40-600C, preferably 50-550C and an anti-solvent such as acetonitrile is added at 50-550C over 10-50 min, preferably 30 min. Reaction mass is further cooled to 25-3O0C. The solid is filtered and dried at 50-550C to get crystalline Gemifloxacin mesylate Form M. The Gemifloxacin mesylate used herein is selected from the group consisting of but not limited to amorphous or crystalline Gemifloxacin mesylate.
Solid State Stability
The solid state stability of the three novel anhydrous polymorphic forms Form H, K and L of Gemifloxacin mesylate was tested by storing approximately 2Og of the sample at accelerated stress conditions (40°C/75% relative humidity) for 6 months. The samples were checked by PXRD, Karl-Fisher titrator and HPLC. The results are given in the following Table 1.
Table 1 m/c Purity
Conditions PXRD (%) (%)
Initial Form H 0.83 99.7 After 6 months Same as initial 1.11 99.7
Initial Form K 1.37 99.7 After 6 months Same as initial 1.65 99.6
Initial Form L 0.18 99.8 After 6 months Same as initial 0.29 99.8
There is no substantial increase in moisture content was observed. The PXRD pattern remains same as initial and there is no degradation observed in HPLC and the final purity is more than 99.5%. The three novel anhydrous polymorphic forms Form H, K and L of Gemifloxacin mesylate were found to be chemically and physically very stable.
In the foregoing section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention and several variants of these examples would be evident to person ordinary skilled in the art.
EXAMPLES:
Example 1: Preparation of Gemifloxacin mesylate Form H 1Og of Gemifloxacin mesylate was dissolved in DMF (50ml) at 800C. The hot solution was filtered through hyflo bed to remove undissolved solid particulate. The resulting solution was distilled completely under vacuum at 700C for 2h to get free powder. The resulting solid was identified as Gemifloxacin mesylate Form H.
Example 2: Preparation of Gemifloxacin mesylate Form I
5g of Gemifloxacin mesylate was dissolved in DMF (20ml) at 800C. The hot solution was filtered through hyflo bed to remove undissolved solid particulate. The resulting solution was cooled to room temperature and then acetonitrile (100ml) was added for lOmin under agitation. A product was precipitated immediately which was further maintained under stirring for Ih. The resulting solid was identified as Gemifloxacin mesylate Form I.
Example 3: Preparation of Gemifloxacin mesylate Form J
5g of Gemifloxacin mesylate was dissolved in DMSO (10ml) at 800C. The hot solution was filtered through hyflo bed to remove undissolved solid particulate. The resulting solution was distilled completely under vacuum at 800C for 2h to get free powder. The resulting product was identified as Gemifloxacin mesylate Form J.
Example 4: Preparation of Gemifloxacin Form K
25g of Gemifloxacin mesylate was suspended in toluene (500ml) and azeotropically refluxed for 5h. The resulting solution was then cooled to room temperature and stirred for Ih. The solid product obtained was isolated and identified as Gemifloxacin mesylate Form K.
Example 5: Preparation of Gemifloxacin mesylate Form K by heating
2g of Gemifloxacin mesylate Form I was heated in a vacuum oven dryer at 1400C for 2h. The solid product obtained was identified as Gemifloxacin mesylate Form K. Example 6: Preparation of Gemifloxacin mesylate Form K by heating
2g of Gemifloxacin mesylate Form J was heated in a vacuum oven dryer at 14O0C for 2h. The solid product obtained was identified as Gemifloxacin mesylate Form K.
Example 7: Preparation of Gemifloxacin mesylate Form L
1Og of Gemifloxacin mesylate was dissolved in 50ml of DMF at temperature 1000C to obtain a clear solution. Immediately in lOmin the material was precipitated out at 1000C. Further cool the solution to room temperature and maintained for 2h under agitation. The solid product obtained was isolated and identified as Gemifloxacin mesylate Form L.
Example 8: Preparation of Gemifloxacin mesylate Form M
5g of Gemifloxacin mesylate was suspended in mixture of 20ml of methanol and 5ml of water at room temperature. The reaction mass was then heated at a temperature of about 50-550C to obtain a clear solution. Filter the hot solution through hyflo bed to remove the undissolved particulate. The solution was then re-heated to 50-550C and added 100ml of acetonitrile slowly for 30min under stirring. A white powdery material was precipitated out. The reaction mass is then further cooled to room temperature and maintained for 5h. The solid obtained was filtered and dried at 500C under vacuum. The product obtained was identified as Gemifloxacin mesylate Form M.
Example 9: Solid state stability of Gemifloxacin mesylate polymorphs in slurry, relative Humidity (RH) and drying conditions
Crystalline form A, B, C, D, E, F and G of Gemifloxacin mesylate are disclosed in the copending Indian application 139/CHE/2008 filed by Matrix laboratories Limited. And the said forms are prepared by the methods as disclosed in the co-pending application 139/CHE/2008. ' 5g of Gemifloxacin mesylate was suspended in indicated solvents of 10 volumes at 25-300C and stirred for 24 hrs.
5g of Gemifloxacin mesylate was stored under relative Humidity (RH) more than 90% for several days
5g of Gemifloxacin mesylate was heated in a vacuum oven dryer at different temperatures for several days
The results obtained in the above experiments are shown in below table.
Table 2
Figure imgf000017_0001

Claims

We Claim:
1. Crystalline Gemifloxacin mesylate Form H.
2. Crystalline Gemifloxacin mesylate Form H, characterized by powder X-ray diffraction pattern having diffraction angles at 9.15, 9.30, 1 1.68, 18.20, 26.28,
26.94, 27.17 ± 0.2 2Θ values.
3. The crystalline Gemifloxacin mesylate Form H according to claim 1, further characterized by powder X-ray diffraction pattern as shown in Figure 1.
4. The crystalline Gemifloxacin mesylate Form H according to claim 1, characterized by DSC as shown in Figure 2.
5. A process for the preparation of crystalline Gemifloxacin mesylate Form H comprising the steps of : a) dissolving Gemifloxacin mesylate in DMF; b) removing the solvent from reaction mixture; and c) isolating crystalline Gemifloxacin mesylate Form H.
6. Crystalline Gemifloxacin mesylate Form I.
7. Crystalline Gemifloxacin mesylate Form I characterized by powder X-ray diffraction pattern having diffraction angles at 4.88, 9.30, 14.90, 19.97, 20.75, 25.14 ± 0.2 2Θ values.
8. The crystalline Gemifloxacin mesylate Form I according to claim 6, further characterized by powder X-ray diffraction pattern as shown in Figure 4.
9. The crystalline Gemifloxacin mesylate Form I according to claim 6, characterized by DSC as shown in Figure 5.
10. A process for the preparation of Crystalline Gemifloxacin mesylate Form I comprising the steps of: a) dissolving Gemifloxacin mesylate in DMF; b) adding acetonitrile as an anti-solvent to the clear solution; and c) isolating crystalline Gemifloxacin mesylate Form I.
11. Crystalline Gemifloxacin mesylate Form J.
12. Crystalline Gemifloxacin mesylate Form J characterized by powder X-ray diffraction pattern having diffraction angles at about 1 1.07, 11.29 14.96, 15.83, 17.84, 20.25, 22.49 ± 0.2 2Θ values.
13. The crystalline Gemifloxacin mesylate Form J according to claim 11, further characterized by powder X-ray diffraction pattern as shown in Figure 7.
14. The crystalline Gemifloxacin mesylate Form J according to claim 1 1, characterized by DSC as shown in Figure 8.
15. A process for the preparation of crystalline Gemifloxacin mesylate Form J comprising the steps of: a) dissolving Gemifloxacin mesylate in DMSO; b) removing the solvent completely from the reaction mixture; and c) isolating crystalline Gemifloxacin mesylate Form J.
16. Crystalline Gemifloxacin mesylate Form K.
17. Crystalline Gemifloxacin mesylate Form K characterized by powder X-ray diffraction pattern having diffraction angles at 6.66, 7.84, 17.83, 20.06, 25.65 ± 0.2 20 values.
18. The crystalline Gemifloxacin mesylate Form K according to claim 16, further characterized by powder X-ray diffraction pattern as shown in Figure 10.
19. The crystalline Gemifloxacin mesylate Form K according to claim 16, characterized by DSC as shown in Figure 1 1.
20. A process for the preparation of crystalline Gemifloxacin mesylate Form K comprising the steps of: a) suspending Gemifloxacin mesylate in toluene; b) carrying out azeotropic distillation; and c) isolating crystalline Gemifloxacin mesylate Form K.
21. A process for the preparation of crystalline Gemifloxacin mesylate Form K comprising the steps of: a) heating crystalline Gemifloxacin mesylate Form I; and b) obtaining crystalline Gemifloxacin mesylate Form K.
22. A process for the preparation of crystalline Gemifloxacin mesylate Form K comprising the steps of: a) heating crystalline Gemifloxacin mesylate Form J; and b) obtaining crystalline Gemifloxacin mesylate Form K.
23. Crystalline Gemifloxacin mesylate Form L.
24. Crystalline Gemifloxacin mesylate Form L characterized by powder X-ray diffraction pattern having diffraction angles at 10.80, 18.76, 22.77, 25.65 ± 0.2 20 values.
25. The crystalline Gemifloxacin mesylate Form L according to claim 23, further characterized by powder X-ray diffraction pattern as shown in Figure 13.
26. The crystalline Gemifloxacin mesylate Form L according to claim 23, characterized by DSC as shown in Figure 14.
27. A process for the preparation of crystalline Gemifloxacin mesylate Form L comprising the steps of: a) suspending Gemifloxacin mesylate in DMF; b) heating the suspension to obtain a clear solution; and c) isolating crystalline Gemifloxacin mesylate Form L.
28. Crystalline Gemifloxacin mesylate Form M.
29. Crystalline Gemifloxacin mesylate Form M characterized by powder X-ray diffraction pattern having diffraction angles at 5.40, 14.63, 24.93 ± 0.2 2Θ values.
30. The crystalline Gemifloxacin mesylate Form M according to claim 28, further characterized by powder X-ray diffraction pattern as shown in Figure 16.
31. The crystalline Gemifloxacin mesylate Form M according to claim 28, characterized by DSC as shown in Figure 17.
32. A process for the preparation of crystalline Gemifloxacin mesylate Form M comprising the steps of: a) dissolving Gemifloxacin mesylate in a solvent; b) adding acetonitrile as an anti-solvent; and c) drying to obtain crystalline Gemifloxacin mesylate Form M.
33. The process for the preparation of Gemifloxacin mesylate Form M according to claim 32, wherein the solvent used for dissolution is selected from methanol, ethanol, propanol, water or mixtures thereof.
34. The Gemifloxacin mesylate used for the preparation of Form H, I, J, K, L and M according to claims 5, 10, 15, 20, 27 and 32 is either amorphous or crystalline Gemifloxacin mesylate.
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