CLIAMS:We Claim:

1. A stable amorphous Gatifloxacin.

2. The compound of claim 1, wherein said stable amorphous Gatifloxacin comprises Gatifloxacin or its combination with a pharmaceutically acceptable carrier.

3. A stable pharmaceutical composition comprising stable amorphous Gatifloxacin of claim 1 along with one or more pharmaceutically acceptable excipient.

4. A process of preparing a stable amorphous Gatifloxacin which process comprises removal of solvent from the solution of Gatifloxacin or its combination with a pharmaceutically acceptable carrier/excipient in a solvent.

5. The process of claim 4, wherein said solvent is a mixture of methanol and methylene chloride.

6. The process of claim 4, wherein said pharmaceutically acceptable carrier/excipient is selected from group of polyvinylpyrrolidones, hydroxypropyl methylcelluloses, and the like.

7. The process of claim 4, wherein said removal of solvent from the solution by using suitable techniques such as spray drying, freeze drying (lyophilization), agitated thin film drying ("ATFD").
,TagSPECI:DESCRIPTION

The present invention provides a stable amorphous Gatifloxacin and process for preparation. Further, it provides stable pharmaceutical compositions of amorphous Gatifloxacin along with other pharmaceutically acceptable excipients. The inventors have observed when amorphous Gatifloxacin is prepared by using spray drying with or without combination of pharmaceutically acceptable excipients, leads to a stable amorphous form which does not get converted to crystalline form.

Gatifloxacin of Formula I is chemically known as (±)-1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid sesquihydrate, which is a synthetic broad-spectrum antibacterial agent for oral or intravenous administration.

Formula I
Gatifloxacin is marketed under the trade name Tequin by Bristol-Myers Squibb. Tequin is available in a dosage of 200 mg and 400 mg in the form of a vial or a tablet, which can be either injected or taken orally. Gatifloxacin is currently available in the US and Canada as an ophthalmic solution.

U.S. Pat. No. 5,880,283 discloses that Gatifloxacin forms a hygroscopic hemihydrate. The crystalline hemihydrate (a pseudopolymorph) is reported to be easily formed upon crystallization of gatifloxacin from water-containing organic solvents.

U.S. Pat. No. 6,413,969 discloses at least 12 different polymorphs or pseudopolymorphs of Gatifloxacin and discloses the x-ray powder diffraction diagrams of at least 10 of these. The hexahydrate, pentahydrate and sesquihydrate are crystallized directly from aqueous solvents. Other crystalline forms are crystallized from a molten phase or by solid-solid phase transformations. The pentahydrate form is, according to the disclosure of WO 02/22126 A1, the most thermodynamically stable form and has the lowest aqueous solubility at room temperature.

Various other patent/applications discloses crystalline forms of Gatifloxacin, for example, WO 03/0864402, WO 03/94919, WO 03/105851, WO 04/12739 and WO 05/118546.

Many pharmaceutical actives are known to exist in different polymorphic forms. Different polymorphic forms of the same compound may have completely different properties, specially when compared with an amorphous form of the same active. Amorphous materials have properties that can be of advantage in the preparation of solid dosage forms, such as solubility/dissolution rate, bioavailability, functional mechanics and adhesively. However, the increased reactivity of an amorphous solid, with a consequent high propensity to spontaneously transform to the crystalline state at a certain conditions such as for example relative humidity, force and temperature among others, may negatively affect the physical and chemical stability of the pharmaceutical preparation. The present invention is to provide potential advantage, especially to affect the stability of amorphous form of Gatifloxacin.

The present invention provides a stable amorphous Gatifloxacin, which comprises removal of solvent from solution of Gatifloxacin or in combination with pharmaceutically acceptable excipient in a suitable solvent by Spray drying.

In an aspect, the present invention is to provide a stable amorphous Gatifloxacin comprising Gatifloxacin or its combination with pharmaceutically acceptable excipient.

In an embodiment, the present invention provides a stable amorphous Gatifloxacin, which comprise Gatifloxacin, prepared by spray drying technique.

In another embodiment, the present invention provides a stable amorphous Gatifloxacin, which comprises solid dispersion of Gatifloxacin and pharmaceutically acceptable excipient, prepared by spray drying technique.

The solid dispersion of a stable amorphous Gatifloxacin has a weight ratio of Gatifloxacin to the pharmaceutically acceptable excipient from about 1:1 to about 1:10.

Accordingly, the present invention provides a thermodynamically stable amorphous form of Gatifloxacin having amorphous X-ray powder diffraction pattern, which is depicted in the Figure.1.

In another aspect, the present invention provides a process for the preparation of stable amorphous Gatifloxacin which comprises removal of solvent from the solution of Gatifloxacin or its combination with a pharmaceutically acceptable carrier/excipient in a solvent.

A solution of Gatifloxacin may be provided by dissolving in a solvent or a mixture of solvents. Any polymorphic form may be used in the preparation of solution, such as crystalline forms including solvates and hydrates.

Gatifloxacin and the pharmaceutically acceptable excipient may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture.

Pharmaceutically acceptable carrier/excipient that may be used for the preparation of amorphous Gatifloxacin (solid dispersions) containing include, but are not limited to, pharmaceutical hydrophilic carriers such as polyvinylpyrrolidones (homopolymers of N-vinylpyrrolidone, called povidones), copolymers of N-vinylpyrrolidone, gums, cellulose derivatives (including hydroxypropyl methylcelluloses (Hypromellose), HPMC), hydroxypropyl celluloses, mannitol and others), cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives, and the like. The use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

Solvents which may be used for dissolving Gatifloxacin include, but are not limited to, alcohols such as methanol, ethanol, isopropyl alcohol and butanol; halogenated solvents like dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; ketones such as acetone, and the like; or mixtures thereof. Specific examples of solvents that may be utilized for the present invention include methanol, dichloromethane (methylene chloride), and mixtures thereof. The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.

The desired temperatures can range from about 20°C to about 100°C, depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution of Gatifloxacin and excipient is provided.

Optionally, the solution obtained above may be filtered to remove any undissolved particles, prior to further processing. The undissolved particles may be removed suitably by filtration, centrifugation, decantation, and other techniques. The solution may be filtered by passing through paper (for example, Whatman filter paper), glass fiber, or other membrane material, or a bed of a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The solvent removal is performed by using spray drying technique to provide a stable amorphous Gatifloxacin with or without pharmaceutically acceptable excipient. The other suitable techniques, which may be used for solvent removal include distillation using a rotational evaporator device such as freeze drying (lyophilization), agitated thin film drying ("ATFD") and the like.

Evaporation of the solvent may be conducted under a vacuum at temperatures such as about -20°C to about 100°C. Any temperature and vacuum conditions may be used as long as there is no increase in the impurity levels of the product. For example, spray drying is more suitable for industrial scale production with batch sizes of about 100 g or about 1 Kg, or greater at about 50 °C to 100 °C.

According to the present invention the obtained amorphous form from spray drying, ATFD and lyophilization is quickly dissolved for pharmaceutical compositions.

The amorphous material can be collected from the equipment using techniques such as by scraping, or by shaking the container, or using techniques specific to the particular apparatus, optionally under an inert gas atmosphere.

Optionally, drying of solid product may be carried out under suitable conditions to afford stable gatifloxacin in an amorphous form, substantially free of residual solvents.

In an embodiment, the amorphous Gatifloxacin of present invention is retained its physical stability when stored at different conditions, for example, at 50-55% relative humidity and at room temperature.

The stable amorphous form of Gatifloxacin of present invention may be utilized for the pharmaceutical composition because of their advantages, for example, its high stability. The effective amount of stable amorphous form of present invention can be used to prepare pharmaceutical composition in association with one or more non toxic pharmaceutically acceptable carriers and/or diluents thereof.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES

Example -1: Preparation of stable amorphous Gatifloxacin

Gatifloxacin (10 gm) was dissolved in a mixture of methylene chloride (300 ml) and Methanol (300 ml) at RT and then filtered. The resultant filtrate was subjected lot wise for Spray drying at elevated temperature. After completion of the spray drying, the spray dryer was cooled to RT and then collected amorphous solid under nitrogen atmosphere. The solid was dried under vacuum in vacuum tray dryer to afford the title compound (Figure 1).
Yield: 4.5 to 9.5 gm.

Parameters for spray dryer
Inlet temperature : 85±1.5°C
Outlet temperature : 42±5 °C
Drying gas flow rate (Aspirator) : 36 ±2 m3/hr (100 %)
Feed rate : 1000 ± 10 ml/hr (60%)
Automization pressure (Nitrogen) : 5.5 ± 0.5 Kg/cm2
Vacuum in system : - 65 ± 10 mbar

Example -2: Sable amorphous Gatifloxacin

The obtained amorphous solid material was exposed to different conditions to ascertain physical stability. The results are summarized with their XRPD pattern in the below table.

Initial sample obtained by spray drying/ATFD/ yophilization After holding 5 days After exposing sample to Air at 36 % relative humidity for 6 days After holding at 2-8 °C for 22 days After holding for 22 days at 25-30 °C
Amorphous Amorphous and no change in the purity