WO2006134431A1

WO2006134431A1 - Formate salt of gemifloxacin

Info

Publication number: WO2006134431A1
Application number: PCT/IB2006/001061
Authority: WO
Inventors: Neera Tiwari; Hashim Nizar Poovanathil Nagoor Meeran; Vinod George
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2005-05-03
Filing date: 2006-04-28
Publication date: 2006-12-21
Anticipated expiration: 2007-11-03

Abstract

The present invention relates to a novel formate salt of gemifloxacin or its hydrate, processes for its preparation, pharmaceutical compositions comprising the formate salt, and methods of treating that include administrating the formate salt of gemifloxacin.

Description

FORMATE SALT OF GEMIFLOXACIN

Field of the Invention

The present invention relates to a novel formate salt of gemifloxacin or its hydrate, processes for its preparation, pharmaceutical composition incorporating the salt, and methods of treatment comprising administrating the formate salt of gemifloxacin or its hydrate.

Background of the Invention

Gemifloxacin which is chemically 7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-l- pyrrolidinyl]-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-l, S-naphthyridme-S-carboxylic acid, is represented by Formula I

It is a naphthyridine carboxylic acid derivative having potent antibacterial activity and is known from U.S. 5,633,262.

The formate salt of gemifloxacin is represented by Formula II

.HCOOH

B2006/001061

- 2 -

The formate salt of gemifloxacin or its hydrate shows a potent antibacterial activity against broad pathogenic strains, including both gram-positive and gram-negative strains, with comparable solubility in water so as to exhibit a good antibacterial activity in the biological systems. Several processes for the preparation of gemifloxacin have been described in the literature, such as in U.S. 5,633,262, WO 01/18002, U.S. 6307059, Journal of Medicinal Chemistry (1997), 40 (22), 3584, which are herein incorporated by reference. While U.S. 5,633,262 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., it is believed that no such salt has been prepared.

U.S. 6,723,734 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 formate 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, and acetic acid, only the methane sulphonic acid salt is specifically prepared.

In the light of the above prior art, no salt other than methane sulphonic acid has been prepared or characterized earlier and formate salt of gemifloxacin is not known in the literature. The salts known in the prior art have a low solubility in water and thus the in- vivo antibacterial activity is not so high as the in-vitro activity. Accordingly, numerous studies have been regularly conducted to improve the solubility in water and to improve the pharmacokinetic activity. Summary of the Invention

A first aspect of the present invention provides a novel formate salt of gemifloxacin of Formula II

.HCOOH

or its hydrate.

A second aspect of the present invention provides a process for preparing the formate salt of gemifloxacin or its hydrate. The process includes contacting gemifloxacin with formic acid in one or more suitable solvents and isolating the formate salt of gemifloxacin or its hydrate.

A third aspect of the present invention provides a method of treating bacterial infections comprising administering the formate salt of gemifloxacin or its hydrate.

A fourth aspect of the present invention provides a pharmaceutical composition comprising formate salt of gemifloxacin or its hydrate along with one or more pharmaceutically acceptable excipients.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Brief Description of the Drawings

FIG. 1 is a powder X-ray powder diffraction (XRD) pattern of gemifloxacin formate hydrate. - A -

FIG. 2 is a DSC graph of gemifloxacin formate hydrate. FIG. 3 is a TGA graph of gemifloxacin formate hydrate Detailed Description of the Invention

Gemifloxacin formate or its hydrate is a crystalline solid. Crystalline gemifloxacin formate hydrate may be characterized by strong X-ray peaks at about 26.96, 24.52, 23.10, 9.80, 7.62 ± 0.2 degrees two-theta and weak peaks at about 25.30, 25.18, 23.72, 21.36, 14.80, 8.04, 4.88 ± 0.2 degrees two-theta. Crystalline gemifloxacin formate may also be characterized by its DSC and TGA graphs. Gemifloxacin formate obtained by the present invention has an endotherm at about 160°C in the DSC thermogram. The gemifloxacin free base to be used for the preparation of the formate salt can be obtained by any of the methods known in the art including those described in U.S. 5,633,262, WO 01/18002, U.S. 6,307,059, Journal of Medicinal Chemistry (1997), 40 (22), 3584 which are herein incorporated by reference. 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 the formate salt of gemifloxacin or its hydrate are the customary inert solvents that do not change under the reaction conditions. Examples of suitable solvents for carrying out the process include water, water-miscible solvents and mixtures thereof. The term "water-miscible" solvents, as used herein, is meant to include solvents which do not form a two-phase system with water under the given reaction conditions. Examples of water-miscible solvents include alcohols, ketones, nitriles, ethers, dipolar aprotic solvents and mixtures thereof.

Examples of alcohols include straight and branched-chain lower alcohols such as methanol, ethanol, isopropanol and mixtures thereof. Examples of ketones include acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof. Examples of ethers include tetrahydofuran. Examples of dipolar aprotic solvents include nitriles, dimethylformamide, dimethyl sulphoxide and mixtures thereof.

In some particular embodiments, mixture of water and alcohol may be used. Preferably, water and isopropanol may be used in some particular embodiments. The ratio of water and isopropanol maybe from 1:1 to 1:5, preferably 1:2. Formic acid used for the preparation of gemifloxacin formate may be in the range of about 0.8 to about 2.5 equivalents.

The term "contacting" includes dissolving, slurrying, stirring or a combination thereof. The mixture of gemifloxacin free base, formic acid and solvent may be heated from room temperature to 60°C to obtain a clear solution for a time period sufficient to complete the reaction, preferably for about 5 to 15 minutes.

The solution of gemifloxacin free base, formic acid and solvent may be treated with a decolorizing agent such as activated charcoal before precipitation. Generally the formate salt of gemifloxacin or its hydrate may be precipitated 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 the formate salt of gemifloxacin or its hydrate. The seeds of gemifloxacin formate may be added at a temperature range of about 25⁰C to 35°C. The precipitation may also be induced by reducing the temperature.

Isolation of the formate salt of gemifloxacin may be accomplished by concentration, precipitation, cooling, filtration or centrifugation or a combination thereof followed by drying.

The precipitated formate salt of gemifloxacin or its hydrate may be isolated in a solid state by conventional methods such as filtration or centrifugation, optionally followed by washing and/or drying and may be purified by crystallization.

It has been observed that the formate salt of gemifloxacin of the present invention has a better solubility and stability as compared to the methane sulphonic acid salt of gemifloxacin reported earlier. The gemifloxacin formate salt of the present invention has a solubility of at least 1 gm in 15 ml water at room temperature.

Solvates and isomers of formate salt of gemifloxacin are also included within the scope of this invention.

The formate salt of gemifloxacin or its hydrate 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 fields such as acute bacterial exacerbation of chronic bronchitis and community acquired pneumonia.

The salt is usually administered as part of a pharmaceutical composition which comprises the formate salt of gemifloxacin or its hydrate, 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 and several variants of these examples would be evident to persons ordinarily skilled in the art.

Methods Powder XRD

X-Ray Difractometer, Rigaku Corporation, RU-H3R

Goniometer CN2155 A3

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

Wave length: 1.5406 A

TGA

Perkin Elmer T4A-7 instrument DSC

Mettler Toledo instrument Example 1

To a suspension of (R, S)-7-(3-aminomethyl-4-5>'nmethoxyiminopyrrolidm-l-yl)- l-cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid (100 g) in a mixture of isopropanol (800 ml) and water (400 ml) was added formic acid (11.8 g) at 45-55°C and stirred for 10 minutes. To the resulting solution was added activated charcoal (20 g) and the solution was again stirred for 30 minutes at 45-55°C and then filtered. The filtrate was allowed to cool to 35⁰C and seed crystal of formate salt (0.5 g) was added. The suspension was cooled to 25⁰C and stirred at 20-25°C for 6-8 hours. It was further cooled to 5°C for 1 hour and then filtered. The precipitate was washed with an isopropanol:water (2:1) mixture (200 ml) and then with isopropanol (200 ml). The wet material was dried at 50-55⁰C to give the formate salt of gemifloxacin.

Yield: 92 g HPLC purity: 99%

¹HNMR (D₂O), ppm: 8.61 (s, IH); 8.49 (s, IH); 7.68 (d, IH); 4.66(brs, 2H), 4.45(m,lH); 4.04(s,3H),3.85(brs,lH);3.71(m,lH);3.60(m,lH); 3.45(m,2H);

1.36(m, 2H), 1.10(m, 2H)

XRD, DSC and TGA graphs of the material were similar to those shown in Figs. I, II and III, respectively.

Example 2 To a suspension of (R,S)-7-(3 -aminomethyl-4-synmethoxyiminopyrrolidin- 1 -yl)- 1 - cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylic acid (100 g) in a mixture of ethanol (800 ml) and water (400 ml) was added formic acid (11.8 g) at 45-50⁰C and stirred for 10 minutes. To the resulting solution was added activated charcoal (20 g) and the solution was again stirred for 30 minutes at 45-50⁰C and then filtered. The filtrate was allowed to cool to 35°C and seed crystal of formate salt (0.5 g) was added. The suspension was further cooled to 25°C and stirred at 20-25⁰C for about 10 hours. It was further cooled to 5°C and stirred at 0-5⁰C for 1 hour and then filtered. The precipitate was washed with an ethanol:water (2:1) mixture (200 ml) and then with ethanol (200 ml). The wet material was dried at 50-55⁰C to give the formate salt of gemifloxacin. Yield: 80 g HPLC purity: 99%

¹HNMR (D₂O), ppm: 8.61 (s, IH); 8.49 (s, IH); 7.68 (d, IH); 4.66(brs, 2H), 4.45(m, IH);

4.04(s. 3H), 3.85(brs, IH); 3.71(m, IH); 3.60(m, IH); 3.45(m, 2H); 1.36(m₅ 2H), 1.10(m, 2H) XRD, DSC and TGA graphs of the material were similar to those shown in Figs. I, II and III, respectively.

While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. For example, the formate salt of gemifloxacin can be included in a pharmaceutical composition and administered to treat a bacterial infection. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

Claims

We claim: 1. A formate salt of gemifloxacin of Formula II,

.HCOOH

or its hydrate.

2. The formate salt according to claim 1 having X-ray powder diffraction pattern as shown in Figure I.

3. The formate salt according to claim 1 being in a crystalline form and characterized by a powder X-ray diffraction pattern with strong peaks at about 26.96, 24.52, 23.10, 9.80, 7.62 ± 0.2 degrees two-theta and weak peaks at 25.3, 25.18, 23.72, 21.36, 14.80, 8.04, 4.88 ± 0.2 degrees two-theta.

4. The formate salt of according to claim 1 having a DSC thermogram as shown in Figure II.

5. The formate salt according to claim 1 having an endotherm at about 16O⁰C in its DSC thermogram.

6. The formate salt according to claim 1, having a solubility of at least 1 g in 15 ml water at room temperature.

7. A process for preparing the formate salt of gemifloxacin or its hydrate, the process comprising contacting gemifloxacin free base with formic acid in one or more suitable solvents and isolating the formate salt of gemifloxacin or its hydrate.

8. The process according to claim 7, wherein the gemifloxacin free base is used as a solution obtained directly from a reaction mixture.

9. The process according to claim 7, wherein the formic acid is added in the range of about 0.8 to about 2.5 equivalents.

10. The process according to claim 7, wherein the suitable solvent is water or water- miscible solvents selected from the group comprising alcohols, ketones, nitriles, ethers, dipolar aprotic solvents and mixtures thereof.

11. The process according to claim 7, wherein the suitable solvent is a mixture of water and isopropanol in a ratio of 1 :2.

12. The process according to claim 7, wherein the suitable solvent is a mixture of water and ethanol in a ratio of 1 :2.

13. A method of treating bacterial infections comprising administering a formate salt of gemifloxacin or its hydrate.

14. An antibacterial composition comprising a formate salt of gemifloxacin or its hydrate and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. A process for the preparation of formate salt of gemifloxacin of formula II or its hydrate as herein described and illustrated by the examples herein.