Field of Invention

This invention, in general relates to an improved process for producing (R,S)-7- [(4Z)-
3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid (Gemifloxacin) and its
pharmaceutically acceptable salts. The present invention also provides novel
polymorphic forms of (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 mesylate and process for producing the same thereof.

Background of the Invention Gemifloxacin mesylate is a synthetic broad-spectrum antibacterial agent for oral administration. It belongs to the fluoroquinolone class of antibiotics and is available as a mesylate salt in the sesquihydrate form. Chemically, Gemifloxacin is (R,S)-7-[(42)-3 -(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid and it's chemical structure is represented by Formula-I.

Formula-I
Gemifloxacin and its pharmaceutically acceptable salts are first disclosed in US patent
5,633,362. Further, the patent discloses process for preparation of gemifloxacin
comprising reacting l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-
dihydro[l,8]naphthyri-dine-3-carboxylic acid with 4-aminomethylpyrrolidin-3-one-O-methyloxime difluoroacetate salt in presence of base in acetonitrile. After completion of the condensation reaction, the reaction mass is diluted with water and separated solid filtered to give gemifloxacin. The gemifloxacin so produced is further converted into pharmaceutically acceptable salts by conventional methods.

According to prior art processes, condensation reaction is carried out in the presence of base in an organic solvent medium. As a result, impurities are formed in the final condensation stage requiring repeated crystallizations to get desired quality of final product.

US 5,776,944 discloses salts and hydrate forms of gemifloxacin mesylate and processes thereof. The gemifloxacin is suspended in a mixture of dichloromethane and ethanol followed by adding methanesulphonic acid drop wise, stirring the resulting solution and filtering the obtained solid to give anhydrous gemifloxacin mesylate having the melting point 195° C.

The anhydrous gemifloxacin mesylate 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 mesylate 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 C1-4 haloalkanes and C1-8 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 gemifloxacin mesylate sesquihydrate from gemifloxacin, wherein the gemifloxacin is suspended in a mixture of water and C1-C4 alcohol followed by adding methanesulphonic acid, cooling the resulting solution and filtration to give gemifloxacin mesylate sesquihydrate.

Alternatively, there still exists a need to develop a process for producing gemifloxacin in pure form, whereby the process requires minimal purification steps. In addition, there is a need to develop novel stable polymorphic forms of gemifloxacin and its pharmaceutically acceptable salts.

Objects and Summary of the Invention It is a principal object of the present invention to provide an improved process for producing (R,S)-7- [(4Z)-3-(aminomemyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-l,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid and its pharmaceutically acceptable salts with improved yield and quality.

It is another object of the present invention to provide novel polymorphic forms of (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate and process for producing the same.

The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.

In accordance with an embodiment of the present invention, there is provided an
improved process for producing (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-
1 -pyrrolidinyl]-l -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[ 1,8]naphthyridine-3-
carboxylic acid (Gemifloxacin) comprising condensing l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid with 4-amino-methylpyrrolidin-3-one-O-methyloxime oxalate salt in presence of a base in a mixture of water and water miscible organic solvent.

In accordance with another embodiment of the present invention, the (R,S)-7- [(4Z)-3-
(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid is further converted to
pharmaceutically acceptable salts, preferably (R,S)-7- [(4Z)-3-(aminomethyl)-4-
(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-
[l,8]naphthyridine-3-carboxylic acid mesylate.

In accordance with yet another embodiment of the present invention there is provided a crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-l,4- dihydro-4-oxo-[l,8]naphmyridine-3-carboxylic acid mesylate polymorphic Form A characterized by powder x-ray diffraction having peaks at 5.26, 9.98, 10.52, 15.06, 15.93, 16.37, 17.13, 17.62, 18.65, 19.53, 20.04, 21.77,22.68,25.68 and 26.28 ± 0.2 29 values.

In accordance with still another embodiment of the present invention there is provided
a process for producing the crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-
(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-
[l,8]naphthyridine-3-carboxylic acid mesylate Form A comprising suspending (R,S)-
7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-
1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid in a mixture of water
miscible organic solvent and water, adding methane sulphonic acid in presence of a
solvent, and isolating crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-
1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l ,8]naphthyridine-3-
carboxylic acid polymorphic mesylate Form A.

In accordance with an alternate embodiment of the present invention there is provided
a process for producing crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-
(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-
[l,8]naphthyridine-3-carboxylic acid mesylate Form A comprising dissolving (R,S)-
7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-
1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate in a mixture of
water miscible organic solvent and water, optionally seeding with Form-A, and
isolating crystalline (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 mesylate crystalline Form A.

In accordance with still another embodiment of the present invention there is provided
a process for producing crystalline (R,S)-7- [(42)-3-(aminomethyl)-4-
(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate Form A comprising suspending (R,S)-
7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-
1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate in a polar solvent
and isolating the crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-
pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l ,8]naphthyridine-3-
carboxylic acid mesylate Form A.

In accordance with still another embodiment of the present invention, there is
provided a crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-
pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[ 1,8]naphthyridine-3-
carboxylic acid mesylate Form G characterized by powder x-ray diffraction having peaks at 4.62, 8.29,9.68,10.49,25.64 and 27.08 ± 0.2 20 values.

In accordance with yet another embodiment of the present invention, there is provided
a process for producing crystalline (R,S)-7- [(4Z)-3-(arninomethyl)-4-
(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-
[l,8]naphthyridine-3-carboxylic acid mesylate Form G wherein the crystalline (R,S)-
7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-
1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate Form G is
produced by a process comprising treating (R,S)-7- [(42)-3-(aminomethyl)-4-
(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-
[l,8]naphthyridine-3-carboxylic acid mesylate in 5- 20 volumes (w/v) water,
removing the water and isolating the crystalline (R,S)-7- [(42)-3-(aminomethyl)-4-
(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-l,4- dihydro-4-oxo-
[l,8]naphthyridine-3-carboxylic acid Form G.

In accordance with yet another alternate embodiment of the present invention, there is
provided a process for producing crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-
(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-
[l,8]naphthyridine-3-carboxylic acid mesylate Form G comprising dissolving (R,S)-7- [(4Z)-3-(aminomethyI)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate in a mixture of water miscible organic solvent and water, removing the solvent mixture and isolatingcrystalline (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 Form G.

Brief Description of the Drawings Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:

Figure 1 illustrates the powder XRD pattern of Form A of (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid (gemifloxacin) mesylate Figure 2 illustrates the Differential Scanning Calorimetric (DSC) thermogram of Form A of gemifloxacin mesylate

Figure 3 illustrates the Thermo Gravimetric Analysis (TGA) thermogram of Form A of gemifloxacin mesylate

Figure 4 illustrates the powder XRD pattern of Form B of gemifloxacin mesylate Figure 5 illustrates the powder XRD pattern of Form C of gemifloxacin mesylate Figure 6 illustrates the powder XRD pattern of Form D of gemifloxacin mesylate Figure 7 illustrates the powder XRD pattern of Form E of gemifloxacin mesylate Figure 8 illustrates the powder XRD pattern of Form F of gemifloxacin mesylate Figure 9 illustrates the powder XRD pattern of Form G of gemifloxacin mesylate Figure 10 illustrates the Differential Scanning Calorimetric (DSC) thermogram of Form G of gemifloxacin mesylate

Figure 11 illustrates the Thermo Gravimetric Analysis (TGA) thermogram of Form G of Gemifloxacin mesylate

Detail Description of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The present invention discloses an improved process for the preparation of (R,S)-7-[(4Z)-3 -(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid (gemifloxacin) and its pharmaceutically acceptable salts thereof.

According to an embodiment of the present invention, there is provided an improved and high yielding process for producing gemifloxacin comprising condensing 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylicacid with 4-amino-methylpyrrolidin-3-one-O-methyloxime oxalate salt in the presence of a base in a mixture of water and a water miscible organic solvent to produce gemifloxacin.

The base employed according to the invention during the condensation reaction is selected from the group consisting of trimethylamine, triethylamine, diisopropylamine. The water miscible organic solvent organic solvent used in the condensation is selected from the group of methanol, ethanol, propanol and isopropanol or mixture thereof.

The present invention further discloses novel polymorphic forms of gemifloxacin mesylate hereafter designated as gemifloxacin mesylate polymorphic Form A, B, C, D, E, F and G. In addition the present invention relates to a process for the preparation of novel polymorphic forms of gemifloxacin mesylate. The polymorphic forms differ from other prior art polymorphs in its physical properties, spectral data and method of preparation and are characterized by its X-ray powder diffraction pattern.
Powder X-rav 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 9/6 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 26 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 TA Q1000 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 pans covered by lids with three pin holes were used.

Thermo gravimetric Analysis (TGA)

The TGA measurements were carried out on TA Q5000 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 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 polymorphic Form A is characterized by powder X-ray diffraction pattern as shown in Figure 1 with peaks at 5.26, 9.98, 10.52, 15.06, 15.93, 16.37, 17.13, 17.62, 18.65, 19.53, 20.04, 21.77, 22.68, 25.68 and 26.28 ± 0.2 29 values.
The crystalline gemifloxacin mesylate polymorphic Form A is further characterized by Differential Scanning Calorimetric (DSC) thermogram as shown in Figure 2 and by Thermo Gravimetric Analysis (TGA) thermogram as shown in Figure 3. The water content of crystalline gemifloxacin mesylate polymorphic Form A is determined by Karl-Fisher method and is about 4 to 6 %.

The present invention provides a process for producing the crystalline gemifloxacin mesylate polymorphic Form A, the process comprising dissolving the gemifloxacin mesylate in a mixture of water miscible organic solvent and water, optionally seeding with the Form A and isolating the crystalline gemifloxacin mesylate polymorphic Form A.

The water miscible organic solvent is selected from methanol, ethanol, propanol, isopropyl alcohol or mixture thereof.

According to an alternate process of the present invention, there is provided a process for the preparation of crystalline gemifloxacin mesylate Form A comprising suspending gemifloxacin free base in a mixture of water miscible organic solvent and water, adding methane suiphonic acid in a solvent, and isolating the crystalline gemifloxacin mesylate polymorphic Form A. The water miscible organic solvent employed is selected from methanol, ethanol, propanol and isopropyl alcohol or mixture thereof. The solvent used in the above process according to the present invention is preferably acetonitrile.

According to an alternate embodiment of the invention, the gemifloxacin mesylate polymorphic Form A is prepared by suspending gemifloxacin mesylate in a polar solvent and isolating gemifloxacin mesylate polymorphic Form A. The gemifloxacin mesylate employed for producing gemifloxacin mesylate Form A is preferably gemifloxacin mesylate Form F or Form G. The polar solvent employed according to the present invention is selected from acetonitrile and methanol.

The crystalline gemifloxacin mesylate polymorphic Form B of the present invention is characterized by powder X-ray diffraction pattern as shown in Figure 4 with peaks at 4.84, 7.44, 8.54, 9.87, 10.75, 15.98, 16.47, 18.40, 18.94, 19.49, 24.95 and 26.04 ± 0.2 20 values.

The present invention provides a process for the preparation of crystalline gemifloxacin mesylate Form B comprising dissolving gemifloxacin mesylate in a mixture of 1,4-dioxane and water, adding obtained clear solution to 1,4-dioxane and isolating gemifloxacin mesylate polymorphic Form B.

According to an embodiment of the present invention, the 1,4-dioxane employed in the above process is preferably more than 2 volumes of gemifloxacin mesylate taken in step a (w/v).

The crystalline gemifloxacin mesylate polymorphic Form C of the present invention is characterized by powder X-ray diffraction pattern as shown in Figure 5 with peaks at 7.49,16.03 and 18.33 ± 0.2 26 values .

The present invention further provides a process for the preparation of the crystalline gemifloxacin mesylate polymorphic Form C comprising dissolving gemifloxacin mesylate in a mixture of 1,4-dioxane and water, adding obtained clear solution to 1,4-dioxane and isolating the crystalline gemifloxacin mesylate polymorphic Form C. The gemifloxacin mesylate and 1,4-dioxane employed in the above process is in 1:1 (w/v) ratio .

The present invention additionally provides a process for the preparation of crystalline gemifloxacin mesylate Form C comprising suspending gemifloxacin base in a mixture of 1,4-dioxane and water, adding methane sulphonic acid and 1,4-dioxane and isolating the crystalline gemifloxacin mesylate polymorphic Form C.

The crystalline gemifloxacin mesylate polymorphic Form D according to the present invention is characterized by powder X-ray diffraction pattern as shown in Figure 6 with peaks at 4.77, 6.67, 7.85, 8.47, 9.78, 10.68, 17.82, 18.51, 18.77, 19.09, 19.62, 20.06,25.79,26.00 and 27.19 ± 0.2 29 values.

Furthermore, the present invention provides a process for the preparation of crystalline gemifloxacin mesylate polymorphic Form D comprising treating the gemifloxacin mesylate with ethyl acetate and isolating the crystalline gemifloxacin mesylate polymorphic Form D.

The crystalline gemifloxacin mesylate polymorphic Form E is characterized by powder X-ray diffraction pattern as shown in Figure 7 with peaks at 7.63, 12.27, 13.68, 15.36, 16.42, 17.73, 18.06, 19.05, 19.38, 19.69, 20.23, 20.76, 21.77, 22.35, 23.37, 24.63, 25.17, 25.48, 26.03, 27.12, 27.50, 28.54, 28.95, 29.28, 30.34, 31.90, 37.16,42.92 and 45.79 ± 0.2 20 values .

Moreover, the present invention provides a process for preparation of the crystalline gemifloxacin mesylate polymorphic Form E comprising dissolving gemifloxacin mesylate in a mixture of 1,4-dioxane and water, and isolating the crystalline gemifloxacin mesylate polymorphic Form E.

According to the present invention, amorphous gemifloxacin mesylate polymorphic Form
F is characterized by powder X-ray diffraction pattern as shown in Figure 8 with peaks at 4.81 and 27.03 ± 0.2 20 values.

The present invention further provides a process for the preparation of the amorphous gemifloxacin mesylate polymorphic Form F comprising dissolving the gemifloxacin mesylate in 20-100 volumes (w/v) of water, removing water by lyophilization and isolating the amorphous gemifloxacin mesylate polymorphic Form F.

According to an exemplary process of the present invention, the amorphous gemifloxacin mesylate polymorphic Form F is prepared by treating the gemifloxacin mesylate in 2 volumes (w/v) of water, removing water by spray drying and isolating the amorphous gemifloxacin mesylate polymorphic Form F.

The crystalline gemifloxacin mesylate polymorphic Form G is characterized by powder X-ray diffraction pattern as shown in Figure 9 with peaks at 4.62, 8.29, 9.68, 10.49,25.64 and 27.08 ± 0.2 20 values.

The crystalline gemifloxacin mesylate polymorphic Form G is further characterized by Differential Scanning Calorimetric (DSC) thermogram as shown in Figure 10 by Thermo Gravimetric Analysis (TGA) thermogram as shown in Figure 11. The water content of the crystalline gemifloxacin mesylate polymorphic Form G determined by Karl-Fisher method is about 6 to 8 %.

The present invention additionally provides a process for producing the crystalline gemifloxacin mesylate Form G comprising treating the gemifloxacin mesylate in 5-20 volumes (w/v) water, removing water and isolating the crystalline gemifloxacin polymorphic Form G. According to the present invention, water is removed by lyophilization, spray-drying or distillation to produce the crystalline gemifloxacin polymorphic Form G.

According to an alternate embodiment of the invention, the crystalline gemifloxacin mesylate polymorphic Form G is prepared by dissolving the gemifloxacin mesylate in a mixture of water miscible organic solvent and water, removing solvent mixture and isolating the crystalline gemifloxacin polymorphic Form G.

According to an embodiment of the present invention, the water miscible organic solvent employed in this process is selected from methanol, ethanol, propanol, isopropyl alcohol or mixtures thereof. The solvent is removed by spray-drying to produce the crystalline gemifloxacin mesylate polymorphic Form G.

According to another embodiment of the present invention, gemifloxacin mesylate is gemifloxacin mesylate hydrate Form.

According to another embodiment of the present invention, gemifloxacin mesylate is dissolved in a mixture of water miscible organic solvent and water at elevated temperatures, preferably at 45-60 °C. Further the resulting solution is cooled to 0-10 °C and isolated the solid by filtration.

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.

Example 1

Process for the preparation of 4-amino-methvlpvrrolidin-3-one-Q-methyloxime
Oxalate 100 g of 4-amino-methylpyrrolidin-3-one-0-methyloxime sulphonate was suspended in methanol (1100 ml) under stirring. 62 g of triethylamine was added to the reaction mass. 41 g of oxalic acid was dissolved in methanol (400 ml) and added to the above reaction mass at 20-25° C. The separated solid was filtered and washed with methanol to give 4-amino-methylpyrrolidin-3-one-0-methyloxime oxalate.

Example 2

Process for the preparation of Gemifloxacin

100 g of l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid was suspended in a mixture of DM water (500 ml) and ethanol (500 ml). The reaction mass was cooled and 160 g of triethylamine was added under stirring. 91 g of 4-amino-methylpyrrolidin-3-one-(9-methyloxime oxalate was added to the reaction mass and maintained for 24 hr. The separated solid was filtered and washed with water to give the gemifloxacin.

Example 3

Process for the preparation of gemifloxacin mesylate.

100 g of Gemifloxacin free base was suspended in a mixture of ethanol (180 ml) and dichloromethane (1150 ml) at room temperature. 22.2 g of methanesulfonic acid was added to the reaction mixture and stirred for 3 hr at 25-30° C. The reaction mass was then cooled slowly to 10-20° C. The separated solid was filtered and washed with dichloromethane to give the gemifloxacin mesylate.

Example 4

Process for the preparation of gemifloxacin mesylate sesquihydrate. 100 g of Gemifloxacin mesylate was suspended in a mixture of isopropanol (545 ml) and purified water (275 ml) and heated to 50-55° C to obtain a clear solution. The solution was then cooled slowly to 30-35° C and seed crystals of Gemifloxacin mesylate sesquihydrate to the reaction mass. The solution was then cooled slowly to room temperature and maintained for 18 hr and further cooled to 0-5° C and maintained for 2 hr. The separated solid was filtered and washed with isopropanol (110 ml) to Gemifloxacin mesylate sesquihydrate.

Example 5
Preparation of Gemifloxacin mesylate Form A 1g of Gemifloxacin mesylate sesquihydrate was suspended in mixture of IP A (30ml)\ and water (8 ml) at room temperature. The reaction mass was then heated at 50-55°C to obtain a clear solution. The solution was then cooled slowly to room temperature and further cooled to 0-4°C and maintained for lhr. The solid obtained was identified as the gemifloxacin mesylate Form A XRD of the sample showed it to be Form A

Example 6
Preparation of Gemifloxacin mesylate Form A by seeding 1g of Gemifloxacin mesylate sesquihydrate was suspended in mixture of IPA (30ml) and water (15ml) at room temperature. The reaction mass was then heated at 50-55°C to obtain a clear solution. The solution was then slowly cooled to 34°C and seeded with 2% gemifloxacin mesylate Form A. Further the reaction mass was cooled to 0-4°C and maintained for 2hr. The solid obtained was isolated and dried at 45-50°C under vacuum. The product obtained was identified as the gemifloxacin mesylate Form A.

XRD of the dried sample showed it to be Form A

Example 7
Preparation of Gemifloxacin mesylate Form A
5g of gemifloxacin mesylate sesquihydrate was suspended in a mixture of methanol (20ml) and water (5ml) at 25-30°C. The mass was then heated at 50-55°C to obtain a clear solution and stirred for 15 min. The clear solution was then filtered through hyflow to remove any undissolved particulates. The clear filtrate was then again heated to 50-55°C and seeded with gemifloxacin mesylate Form-A. To this solution acetonitrile (100ml) was added at 50-55°C and stirred for 10 min. The mass was then cooled slowly to 25-30°C and stirred for 5 hrs. The solid obtained was isolated and identified as the gemifloxacin mesylate Form A. XRD of the sample showed it to be Form A

Example 8
Preparation of gemifloxacin mesylate Form A
5g of Gemifloxacin base was suspended in methanol (20ml) and water (5ml) at room temperature. To this slurry the mixture of methanesulfonic acid (1.2g) and acetonitrile (100ml) was added and stirred for 30min to get a clear solution. After 10min the material was precipitated out. The mass was stirred for 5hrs at room temperature and the solid obtained was isolated and identified as the gemifloxacin mesylate Form A. XRD of the sample showed it to be Form A

Example 9
Preparation of Gemifloxacin mesylate Form A
lg of gemifloxacin mesylate was slurred in appropriate solvents in appropriate volumes at 25-30°C and maintained under stirring for 24 hours. The results obtained are displayed in the Table 1.
Table 1

Example 10
Preparation of Gemifloxacin mesylate Form B
lg of gemifloxacin mesylate sesquihydrate was suspended in 1,4-dioxane and water
(2.6:2.6 v/v) at room temperature and heated at 40°C to obtain a clear solution. Add
this solution to 1, 4-dioxane (2.6ml) at room temperature for 30minutes followed by
cooling to 0-5°C and maintained for lhr. The clear solution was further stirred for
12hrs at room temperature and isolated the precipitated gemifloxacin mesylate Form
B.

XRD of the sample showed it to be Form B

Example 11
Preparation of gemifloxacin mesylate Form C
lg of Gemifloxacin mesylate sesquihydrate was suspended in a mixture of 1,4-
dioxane and water (2.6:2.6 v/v) at room temperature and heated to 40°C to obtain a
clear solution. This solution is added to 1,4-dioxane (1ml) at room temperature for 30
minutes followed by cooling to 0-5°C and maintained forlhr. The clear solution was
further stirred for 12 hrs at room temperature and the precipitated Gemifloxacin
mesylate Form C was isolated.

XRD of the sample showed it to be Form C

Example 12
Preparation of Gemifloxacin mesylate Form C
5g of Gemifloxacin base was suspended in a mixture of 1, 4-dioxane (13ml) and water (13ml) at room temperature. To this slurry the mixture of methanesulfonic acid (0.8ml) and 1,4-dioxane (10ml) was added at 25-30°C and stirred for 10 min to get the clear solution at 25-30°C. The solid was precipitated out after lhr stirring at 25-30°C and was further maintained under stirring for 3hrs. The resulting solid was isolated and identified as the gemifloxacin mesylate Form C. XRD of the sample showed it to be Form C.

Example 13
Preparation of gemifloxacin mesylate Form D
lg of Gemifloxacin mesylate trihydrate was suspended in ethyl acetate (15ml) at room
temperature. The reaction mass was heated to reflux temperature for 30 minutes
followed by cooling to room temperature and maintained forlhr. The solid obtained
was filtered and dried at room temperature. The product isolated was identified as
crystalline gemifloxacin mesylate Form D.

XRD of the sample showed it to be Form D

Example 14
Preparation of Gemifloxacin mesylate Form E
lg of Gemifloxacin mesylate sesquihydrate was suspended in 2:1 v/v ratio of 1,4-dioxane and water mixture at room temperature. The reaction mass was heated to 50°C to obtain a clear solution followed by cooling to room temperature. The resulting solution was stirred at room temperature for 18 hours and cooled to 0-5°C under stirring for 0.5 hours. The solid obtained was filtered and dried at room temperature. The product isolated was identified as crystalline Gemifloxacin mesylate FormE.

XRD of the dried sample showed it to be Form E

Example 15
Preparation of Gemifloxacin mesylate Form F by Lyophilization
Gemifloxacin mesylate sesquihydrate (lg) was dissolved in water (20ml). The clear
solution was filtered through hyflow to remove the undissolved particulate. The
resulting solution was then subjected to freeze drying (Model: Virtis Genesis SQ
Freeze Dryer) at -104°C and below 200 Torr vacuum. The solid obtained was
identified as amorphous Gemifloxacin mesylate Form F.

XRD of the sample showed it to be Form F

Example 16
Preparation of Gemifloxacin mesylate Form F by Spray drying
A 50% aqueous solution of Gemifloxacin mesylate sesquihydrate was subjected to
spray drying in a Mini Spray Dryer (Model Buchi - 290) at a temperature of 100-
105°C using nitrogen gas. The obtained solid was identified as crystalline
Gemifloxacin mesylate Form F.

XRD of the sample showed it to be Form F

Example 17
Preparation of Gemifloxacin mesylate Form G by Spray-drying
A 20% aqueous solution of Gemifloxacin mesylate sesquihydrate was subjected to
spray drying in a Mini Spray Dryer (Model Buchi - 290) at a temperature of 100-
105°C using nitrogen gas. The obtained solid was identified as crystalline
gemifloxacin mesylate Form G.
XRD of the sample showed it to be Form G

Example 18
Preparation of Gemifloxacin mesylate Form G
Gemifloxacin mesylate sesquihydrate (lg) was dissolved in water (5ml) and the
solution was filtered through hyflow to remove the undissolved particulate. The
resulting solution was completely distilled off under vacuum at 50°C leaving white
crystalline gemifloxacin mesylate Form G.

XRD of the sample showed it to be Form G

Example 19
Preparation of Gemifloxacin mesylate Form G by Spray-drying
20g of Gemifloxacin mesylate Sesquihydrate was dissolved in a mixture of water
(150ml) and IP A (200ml) at 60°C. The clear solution was then filtered through hyflow
to remove the undissolved particulate. The resulting solution was then subjected to
Spray drying in a mini spray drier (model buchi-290) at 100°C outlet temperature with
flow rate of 1-5% using nitrogen gas. The obtained solid was identified as
gemifloxacin mesylate Form G.

XRD of the sample showed it to be Form G
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

We Claim:

1. An improved process for producing (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid (Gemifloxacin) comprising condensing 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro[ 1,8]naphthyridine-3-carboxylic acid with 4-amino-methylpyrrolidin-3-one-O-methyloxime oxalate salt in presence of a base in a mixture of water and a water miscible organic solvent.

2. The process according to claim 1, wherein the base is selected from a group
consisting of trimethylamine, triethylamine and diisopropylamine.

3. The process according to claim 1, wherein the water miscible organic solvent is selected from a group consisting of methanol, ethanol, propanol and isopropanol or mixture thereof.

4. The process according to claim 1, wherein the process further comprising converting the (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[ 1,8]naphthyridine-3-carboxylic acid to its pharmaceutically acceptable salt.

5. The process according to claim 4, wherein the pharmaceutically acceptable salt prepared is preferably mesylate salt.

6. A crystalline (R,S)-7- [(42)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[ 1,8]naphthyridine-3-carboxylic acid mesylate Form A, wherein the crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate Form A is characterized by powder x-ray diffraction having peaks at 5.26, 9.98, 10.52, 15.06, 15.93, 16.37,

7. A process for producing crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-

[l,8]naphthyridine-3-carboxylic acid mesylate Form A comprising suspending (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid in a mixture of water miscible organic solvent and water, adding methane sulphonic acid in presence of a solvent, and isolating the resultant crystalline Form A.

8. The process according to claim 7, wherein the water miscible organic solvent is selected from a group consisting of methanol, ethanol, propanol and isopropyl alcohol or mixture thereof.

9. The process according to claim 7, wherein the solvent used is acetonitrile.

10. A process for producing crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate polymorphic Form A comprising dissolving the (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1-cyclopropyl-6-fluoro-l ,4- dihydro-4-oxo-[l ,8]naphthyridine-3-carboxylic acid mesylate in a mixture of water miscible organic solvent and water, optionally seeding with Form A, and isolating the resultant crystalline Form A.

11. The process according to claim 10, wherein the water miscible organic solvent is selected from a group consisting of methanol, ethanol, propanol and isopropyl alcohol or mixture thereof.

12. A process for producing (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate polymorphic Form A, which comprises suspending (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo- [ 1,8]naphthyridine-3 -carboxylic acid mesylate in a polar solvent and isolating the resultant crystalline Form A.

13. The process according to claim 12, wherein the (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4-

dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate employed is selected
from (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 mesylate polymorphic Form F or Form G.

14. The process according to claim 12, wherein the polar solvent is selected from acetonitrile and methanol.

15. A crystalline (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 mesylate Form G, wherein the crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate Form G is characterized by powder x-ray diffraction having peaks at 4.62, 8.29, 9.68, 10.49, 25.64 and 27.08 ± 0.2 20 values.

16. A process for producing crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate Form G comprsing treating the (R,S)-7- [(4Z)-3 -(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate in 5- 20 volumes (w/v) water, removing the water and isolating the resultant crystalline Form G.

17. A process for producing crystalline (R,S)-7- [(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate Form G comprising dissolving the (R, S)-7- [(4Z)-3 -(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyl] -1 -cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-[l,8]naphthyridine-3-carboxylic acid mesylate in a mixture of water miscible organic solvent and water, removing the solvent mixture and isolating the resultant crystalline Form G.

18. The process according to claim 17, wherein the water miscible organic
solvent is selected from a group consisting of methanol, ethanol, propanol, isopropyl
alcohol or mixture thereof.

19. The process according to claim 17, wherein the solvent is removed by
using spray drying.