Field Of The Invention
The present invention relates to a novel ethane sulphonate salt of gemifloxacin, process for its preparation, pharmaceutical composition comprising it and method of treatment comprising administration of ethane sulphonate salt of gemifloxacin.
Background Of The Invention
Gemifloxacin, which is chemically 7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, is represented by Formula I

(Formula Removed)

It is a naphthyridine carboxylic acid derivative having potent antibacterial activity and
is known from US patent no. US 5633262.
Ethane sulphonate salt of gemifloxacin is represented by Formula II
(Formula Removed)
It shows potent antibacterial activity against broad pathogenic strains including both gram-positive and gram-negative strains and improved solubility in water.
Several processes for the preparation of gemifloxacin have been described in literature such as those described in US 5633262, WO 01/18002, US 6307059, Journal of Medicinal Chemistry (1997), 40 (22), 3584, which are herein incorporated by reference only. While US 5633262 mentions that the
naphthyridine carboxylic acid derivatives including gemifloxacin can form salts with inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, etc as well as organic acid such as acetic acid, succinic acid, benzoic acid, sulphonic acids, etc, no such salt has been prepared.
US 6723734 discloses methane sulphonic acid salt of gemifloxacin along with its process of preparation. WO 00/17199 and WO 01/18002 disclose improved processes for the preparation of methane sulphonate salt of gemifloxacin and its hydrates.
WO 03/087100 discloses a process for the preparation of acid salts of gemifloxacin, which does not include the ethane sulphonate salt. Although, the application mentions in the specification that the process disclosed is applicable for different acid salts of gemifloxacin such as salts with hydrochloric acid, methane sulphonic acid, sulphuric acid, acetic acid, only methane sulphonic acid salt is prepared specifically.
The methane sulphonic acid salt of gemifloxacin known in the prior art has a low solubility in water and thus the in-vivo antibacterial activity is not so high as the in-vitro activity.
Therefore, there is a need for the preparation of new salt(s) of gemifloxacin having better solubility and antibacterial activity than the methane sulphonic acid salt.
Summary of The Invention
A first aspect of the present invention provides a novel ethane sulphonate salt of gemifloxacin of Formula II.
(Formula Removed)
A second aspect of the present invention provides a process for preparing ethane sulphonate salt of gemifloxacin which comprises contacting gemifloxacin with ethane sulphonic acid in suitable solvent (s) and isolating the ethane sulphonate salt of gemifloxacin.
A third aspect of the invention provides a process for the preparation of gemifloxacin comprising hydrolysis of ethane sulphonic acid salt of gemifloxacin.
A fourth aspect of the present invention provides a pharmaceutical composition comprising ethane sulphonate salt of gemifloxacin along with one or more pharmaceutically acceptable excipients.
A fifth aspect of the invention provides a method of treating bacterial infections comprising administering ethane sulphonate salt of gemifloxacin.
Brief Description Of The Drawings
Figure I depicts the powder X-ray diffraction pattern of gemifloxacin ethane sulphonate. Figure II depicts the DSC thermogram of gemifloxacin ethane sulphonate.
Detailed Description Of The Invention
Gemifloxacin ethane sulphonate is a crystalline solid. Crystalline gemifloxacin ethane sulphonate may be characterized by strong peaks in the X-ray diffraction pattern at about 26.36, 22.26, 18.72, 16.28 and 10.62 ± 0.2 degrees two-theta and weak peaks at about 27.98, 24.68, 18.02, 16.94, 15.98, 11.76, 10.84, 9.14 and 7.08 ± 0.2 degrees two-theta. Gemifloxacin ethane sulphonate of the present invention may also be characterized by DSC thermogram as depicted in Figure II.
Gemifloxacin ethane sulphonate obtained by the present invention has solubility in water at room temperature of at least 1gm in 4 ml water, which is better than the solubility of gemifloxacin methane sulphonate.
The gemifloxacin free base to be used for the preparation of ethane sulphonate salt can be obtained by any of the methods known in the art including those described in US 5633262, WO 01/18002, US 6307059, Journal of Medicinal Chemistry (1997), 40 (22), 3584 which are herein incorporated by reference only. The starting gemifloxacin free base may be obtained as a solution directly from a reaction mixture in which gemifloxacin is formed and used as such without isolation.
Suitable solvents for preparing ethane sulphonate salt of gemifloxacin are the customary inert solvents that do not change under the reaction conditions. Examples of suitable solvent(s) for carrying out the process may include water, water-miscible solvents and mixtures thereof. The term "water-miscible" solvents, as used herein, is meant to include solvents that do not form a two-phase system with water under the given reaction conditions. Examples of water-miscible solvents may include alcohols, ketones, nitriles, ethers, dipolar aprotic solvents and mixtures thereof.
Examples of alcohols may include straight and branched-chain lower alcohols such as methanol, ethanol, isopropanol and mixtures thereof. Examples of ketones may include acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof. Examples of ethers may include tetrahydofuran. Examples of dipolar aprotic solvents may include nitriles, dimethylformamide, dimethyl sulphoxide and mixtures thereof.
In some particular embodiments, mixture of water and alcohol may be used. Preferably, water and isopropanol or water and ethanol may be used in some particular embodiments. The ratio of water and alcohol may be from 1:1 to 1:5, preferably 1:3.
Ethane sulphonic acid used for the preparation of gemifloxacin ethane sulphonate may be in the range of about 0.8 to about 1.5 equivalents.
The term "contacting" includes dissolving, slurrying, stirring or a combination thereof.
The mixture of gemifloxacin free base, ethane sulphonic acid and solvent (s) may be heated to room temperature to reflux temperature to obtain a clear solution for a time period sufficient to complete the reaction, preferably for about 20 to 40 minutes.
The solution of gemifloxacin free base, ethane sulphonic acid and solvent(s) may be treated with a decolorizing agent such as activated charcoal before precipitation.
Generally, ethane sulphonate salt of gemifloxacin precipitates out of the solution or the reaction mixture. The precipitation may be spontaneous depending upon the solvent used and reaction conditions. The precipitation may also be facilitated by adding seeds of ethane sulphonate salt of gemifloxacin. The seeds of gemifloxacin ethane sulphonate may be added at a temperature range of about 25°C to 35°C. The precipitation may also be induced by reducing the temperature.
Isolation of the ethane sulphonate salt of gemifloxacin may be accomplished by concentration, precipitation, cooling, filtration or centrifugation or a combination thereof followed by drying.
The precipitated ethane sulphonate salt of gemifloxacin may be isolated in a solid state by conventional methods such as filtration or centrifugation. The isolated product may be optionally washed followed by drying. The product may be purified by recrystallization for better purity.
The ethane sulphonate salt of the present invention has purity greater than 99% by HPLC.
The hydrolysis of ethane sulphonic acid salt of gemifloxacin may be carried out in a basic or neutral medium.
Solvates, hydrates and isomers of ethane sulphonate salt of gemifloxacin are also included within the scope of the present invention.
The ethane sulphonate salt of gemifloxacin has a broad antibacterial activity in comparison with the early stage antibacterial compounds, and therefore, has been widely and practically used for treatment of diseases in clinical field such as acute bacterial exacerbation of chronic bronchitis and community-acquired pneumonia. The salt is usually administered as part of a pharmaceutical composition. Accordingly, in a further aspect, there is provided a pharmaceutical composition that comprises ethane
sulphonate salt of gemifloxacin, and one or more pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. The salt may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example peroral or parental.
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. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Methods
Powder XRD
X-Ray Difractometer, Rigaku Coorperation, RU-H3R
Goniometer CN2155A3
X-Ray tube with Cu target anode
Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1 0
Power: 40 KV, 100 mA
Scanning speed: 2 deg/min step: 0.02 deg
Wavelength: 1.5406 A
DSC
Mettler Toledo instrument
Example 1
To a suspension of (R, S)-7-(3-aminomethyl-4-synmethoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-
oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid (100 g) in a mixture of isopropanol (1200 ml) and
water (400 ml) was added ethane sulphonic acid (28 g) at 45-55°C. To the resulting solution was added
activated charcoal (20 g) and the solution was stirred at the same temperature for 30 minutes and then
filtered. The filtrate was allowed to cool to 30°C and seed crystals of ethane sulphonate salt (0.5 g) were
added. The suspension was cooled to 5°C, stirred for 2 hours and filtered. The precipitate was washed
with isopropanol: water (3:1) mixture (200 ml) and then with isopropanol (200 ml). The wet material was
dried at 50-55°C to give the ethane sulphonate salt of gemifloxacin.
Yield: 85 g
HPLC purity: 99.40%
Melting point: 214-215°C
1HNMR (DMSO), ppm: 8.55 (s, 1H); 8.03 (d, 1H); 7.93 (brs, 2H); 4.57(brs, 2H), 4.37(m, 1H); 3.90(s, 3H),
3.80(brs, 1H); 3.70(m, 1H); 3.41(m, 1H); 3.17(m, 2H); 2.38(q, 2H), 1.22(m, 2H),
1.07(m, 2H), 1.02(t, 3H) XRD pattern and DSC thermogram were similar to those as shown in Figure I and Figure II respectively.
Example 2
To a suspension of (R,S)-7-(3-aminomethyl-4-synmethoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (100 g) in a mixture of ethanol (1200 ml) and water
(400 ml) was added ethane sulphonic acid (28 g) at 45-50°C. To the resulting solution was added
activated charcoal (20 g) and the contents were stirred for 30 minutes at 45-50°C and then filtered. Seed
crystals of ethane sulphonate salt (0.5 g) were added to the filtrate. The suspension was cooled to 5°C,
stirred for 5 hours and filtered. The precipitate was washed with ethanol: water (3:1) mixture (200 ml) and
then with ethanol (200 ml). The wet material was dried at 50-55°C to give the ethane sulphonate salt of
gemifloxacin.
Yield: 80 g
HPLC purity: 99.50%
Melting point: 214-215°C
1HNMR (D2O), ppm: 8.55 (s, 1H); 8.03 (d, 1H); 7.93 (brs, 2H); 4.57(brs, 2H), 4.37(m, 1H); 3.90(s, 3H),
3.80(brs, 1H); 3.70(m, 1H); 3.41(m, 1H); 3.17(m, 2H); 2.38(q, 2H), 1.22(m, 2H),
1.07(m,2H), 1.02(t,3H) XRD pattern and DSC thermogram were similar to those as shown in Figure I and Figure II respectively.

WE CLAIM:
1. Ethane sulphonate salt of gemifloxacin of Formula II.
(Formula Removed)
2. The ethane sulphonate salt of gemifloxacin of claim 1 having X-ray powder diffraction pattern as depicted in Figure I.
3. The salt according to claim 1, which is in a crystalline form and is characterized by a powder X-ray diffraction pattern with strong peaks at about 26.36, 22.26, 18.72, 16.28 and 10.52 ± 0.2 degrees two-theta and weak peaks at about 27.98, 24.68, 18.02, 16.94, 15.98, 11.76, 10.84, 9.14 and 7.08 ± 0.2 degrees two-theta.
4. The ethane sulphonate salt of gemifloxacin of claim 1 having a DSC thermogram as depicted in Figure II.
5. The salt according to claim 1, which has solubility of at least 1 g in 4 ml water at room temperature.
6. Ethane sulphonate of gemifloxacin having purity greater than 99% by HPLC.
7. A process for preparing ethane sulphonate salt of gemifloxacin, which comprises contacting gemifloxacin free base with ethane sulphonic acid in suitable solvent (s) and isolating ethane sulphonate salt of gemifloxacin.
8. The process according to claim 7, wherein gemifloxacin freebase, obtained as a solution directly from a reaction mixture, is used.
9. The process according to claim 7, wherein the ethane sulphonic acid is added in the range of about 0.8 to about 1.5 equivalents.
10. The process according to claim 7, wherein the suitable solvent(s) is selected from the group comprising of water, and water-miscible solvents.
11. The process according to claim 10, wherein the water-miscible solvent is selected from the group comprising of alcohols, ketones, nitriles, ethers, dipolar aprotic solvents and/ or mixtures thereof.
12. The process according to claim 11, wherein the alcohol is selected from the group comprising of methanol, ethanol, isopropanol, butanol and/ or mixtures thereof.
13. The process according to claim 7, wherein the suitable solvent is a mixture of water and alcohol in a ratio of 1:3.
14. A process for the preparation of gemifloxacin comprising hydrolysis of ethane sulphonic acid salt of gemifloxacin.
15. The process according to claim 14, wherein the hydrolysis is carried out in neutral or basic medium.
16. A pharmaceutical composition comprising ethane sulphonate of gemifloxacin and one or more pharmaceutical^ acceptable carriers, diluents or excipients.
17. A method of treating bacterial infections comprising administering ethane sulphonate salt of gemifloxacin.
18. A process for the preparation of ethane sulphonate salt of gemifloxacin of formula II as herein described and illustrated by the examples.