DESC:FIELD OF INVENTION
The present invention provides co-crystal of gatifloxacin (I) and process for preparation thereof.
BACKGROUND OF THE INVENTION
Gatifloxacin (I) is a broad-spectrum quinolone antibacterial agent indicated for the treatment of infections caused by Gram-positive and Gram-negative bacteria. It is chemically known as (±)-1-Cyclopropyl-6fluoro-1,4-dihydro-8-methoxy-7-(3-methyl1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid and represented by structural formula given below.

Gatifloxacin (I) was first disclosed in the patent US 4,980,470 and the later patent US 5,880,283 discloses sesquihydrate of gatifloxacin (I). US 5,880,283 mention that gatifloxacin (I) and gatifloxacin (I) hydrochloride tends to form hydrate and hemihydrate because of its strong hygroscopity and that the tablet containing the hemihydrates has poor disintegration and dissolution rates.
The patent application CN 103864751 discloses gatifloxacin (I) lactic acid salt and process for its preparation and also mentions that this salt has good water solubility, high bioavailability, high stability and strong antibacterial property. Another patent application CN 103316350 provides process for preparing gatifloxacin (I) injection which utilizes gatifloxacin (I) salts like mesylate, lactate and hydrochloride.
The patent application CN 1257073 provides organic and inorganic salts of gatifloxacin (I) to improve its solubility. Organic acids selected from formic acid, acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid or p-toluenesulfonic and inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
Thus various salts of gatifloxacin (I) are provided in the literature to increase solubility, bioavailability, stability and antibacterial property. The present invention provides various co-crystals of gatifloxacin (I) to achieve better properties of gatifloxacin (I).
“Co-crystal” means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion when compared to those of the drug and coformer individually. The co-crystals comprise a co-crystal former H-bonded to an API.

Following are the advantages of the co-crystals:
i) control the dissolution rate of API-containing pharmaceutical compositions in water,
ii) increased stability,
iii) improved processability, or preparation of pharmaceutical formulations
iv) increased bioavailability.

The present invention provides various co-crystals of gatifloxacin (I) to achieve the desired properties like better solubility, bioavailability, stability and antibacterial property.
SUMMARY OF THE INVENTION
The present invention provides co-crystals of gatifloxacin (I) with a co-crystal former and process for preparation thereof.
Co-crystal former is selected from oxalic acid, citric acid, DL-tartaric acid, glutaric acid, succinic acid, fumaric acid, malonic acid, salicylic acid and hydroxy benzoic acid.
BRIEF DESCRIPTION OF DRAWINGS

Figure 1- PXRD diffractogram of gatifloxacin: citric acid co-crystal
Figure 2- PXRD diffractogram of gatifloxacin: oxalic acid co-crystal
Figure 3- PXRD diffractogram of gatifloxacin: 4-hydroxy benzoic acid co-crystal
Figure 4- PXRD diffractogram of gatifloxacin: DL-tartaric acid co-crystal
Figure 5- PXRD diffractogram of gatifloxacin: glutaric acid co-crystal
Figure 6- PXRD diffractogram of gatifloxacin: succinic acid co-crystal
Figure 7- PXRD diffractogram of gatifloxacin: fumaric acid co-crystal
Figure 8- PXRD diffractogram of gatifloxacin: malonic acid co-crystal
Figure 9- PXRD diffractogram of gatifloxacin: salicylic acid co-crystal.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides co-crystal of gatifloxacin (I) with co-crystal former selected from oxalic acid, citric acid, DL- tartaric acid, glutaric acid, succinic acid, fumaric acid, malonic acid, salicylic acid, and hydroxy benzoic acid.
In another embodiment the invention provides process for preparation of co-crystal of gatifloxacin (I) with co-crystal former by crystallization method.
Gatifloxacin (I) can be synthesized by methods known in the literature.

The process for preparation of co-crystal of gatifloxacin (I) involves crystallization of gatifloxacin and co-crystal former from a suitable solvent. Suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.

Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane.

In the crystallization process, gatifloxacin and the co-crystal former are mixed in the ratio of 1:1.5, preferably 1:1.

The solvent volume utilized for the crystallization process is 5-10 times by weight/volume of gatifloxacin, preferably 5 times.

The crystallization process can be carried out at a temperature of 0-100°C, preferably 20-40°C.

In yet another embodiment the present invention provides process for preparation of co-crystal of gatifloxacin (I) by grinding gatifloxacin (I) and co-crystal former in presence of suitable solvent.

Suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.

Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane.

In the grinding process, gatifloxacin (I) and the co-crystal former are mixed in the ratio of 1:1.5, preferably 1:1.

The solvent volume utilized for the grinding process is 1-5 times by weight/volume of gatifloxacin (I), preferably 1-2 times.

The co-crystal of gatifloxacin (I) can be isolated after crystallization or grinding process by techniques known in art like filtration, evaporation, concentration.

The co-crystals of gatifloxacin (I) are characterized by their powder X-ray crystallography (PXRD), differential scanning calorimetry (DSC), and IR spectroscopy.

Provided herein below is a table for the characteristic PXRD peaks, characteristic absorptions in IR spectrum data for the different co-crystals of gatifloxacin (I).

Table 1: Characteristic data for co-crystals:

Serial No. Co-crystal former characteristic PXRD peaks degree 2? (±0.2) characteristic absorptions in IR spectrum (cm-1) (± 5 cm-1)
1 Citric acid 6.11,10.34,15.81,18.51,25.33 3427,2972,2489,1720,1623
2 Oxalic Acid 5.0,6.56,10.49,20.32,20.65,27.66 3442,2986,2467,1728,1623
3 4-Hydroxy benzoic acid 4.36,21.89,22.58,23.47,25.0,27.89 3405,3179,2502,1700,1622
4 DL-Tartaric acid 9.1,10.48,11.61,14.43,16.65 3456,3076,2486,1727,1623
5 Glutaric Acid 5.28,10.0,10.49,13.39,21.86 3419,2944,2468,1731,1623

6 Succinic acid 5.34,10.58,16.0,21.94,28.65 3414,2849,2489,1731,1623
7 Fumaric acid 4.78,10.67,14.35,19.8 3446,2989,2513,1737,1621

8 Malonic acid 5.09,10.43,14.40,20.77,27.63
3453,2993,2486,1733,1624

9 Salicylic acid 4.56,9.87,11.55,14.97,22.48,23.71 3584,2981,2491,1733,1623

The co-crystals of gatifloxacin (I) are further characterized by Differential Scanning Calorimetry (DSC). Following characteristic data was observed for the gatifloxacin (I) co-crystals:
Gatifloxacin: citric acid, endotherm at onset temperature of 202.42°C and peak at 209.30°C;
Gatifloxacin: oxalic Acid, minor endotherm at onset temperature of 242.76°C, peak at 245.46°C and major endotherm at onset temperature of 249.93°C, peak at 252.32°C followed by decomposition;
Gatifloxacin: 4-Hydroxy benzoic acid, endotherm at onset temperature of 231.75°C, peak at 234.31°C;
Gatifloxacin: DL-Tartaric acid one endotherm at onset temperature of 222.91°C, peak at 232.06°C, second endotherm at onset temperature of 245.69°C, peak at 253.0°C.
Gatifloxacin: glutaric Acid, major endotherm at onset temperature of 220.23°C, peak at 222.23°C and minor endotherm at onset temperature of 224.52°C, peak at 228.80°C;
Gatifloxacin: succinic acid, endotherm at onset temperature of 238.86°C, peak at 240.85°C;
Gatifloxacin: fumaric acid, endotherm at onset temperature of 254.88°C, peak at 262.32°C.
Experimental:
The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.

FTIR spectrum was obtained using a Perkin Elmer Precisely Spectrum 400 instrument using KBr pellet method.

Differential scanning calorimetry (DSC) was done using Diamond DSC Perkin Elmer instrument. The scans were recorded between 50 and 300 °C at a constant heating rate of 10°C/min.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
Example 1: Preparation of gatifloxacin: oxalic acid dihydrate co-crystal:
A mixture of gatifloxacin (10 g) and oxalic acid dihydrate (3.35 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 89.8%.
Example 2: Preparation of gatifloxacin: oxalic acid dihydrate co-crystal:
A mixture of gatifloxacin (5 g) and oxalic acid dihydrate (1.67 g) was grinded in a mortar pestle using methanol (2 ml) at 25-30°C. Yield: 86%.
Example 3: Preparation of gatifloxacin: salicylic acid co-crystal:
A mixture of gatifloxacin (10 g) and salicylic acid (3.68 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 93.6%.
Example 4: Preparation of gatifloxacin: glutaric acid co-crystal:
A mixture of gatifloxacin (10 g) and glutaric acid (3.52 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 76.2%.
Example 5: Preparation of gatifloxacin: succinic acid co-crystal:
A mixture of gatifloxacin (10 g) and succinic acid (3.14 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 80.6%.
Example 6: Preparation of gatifloxacin: citric acid monohydrate co-crystal:
A mixture of gatifloxacin (10 g) and citric acid monohydrate (5.6 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 86%.
Example 7: Preparation of gatifloxacin: citric acid monohydrate co-crystal:
A mixture of gatifloxacin (5 g) and citric acid monohydrate (2.88 g) was grinded in a mortar pestle using methanol (2 ml) at 25-30°C. Yield: 74.3%.
Example 8: Preparation of gatifloxacin: fumaric acid co-crystal:
A mixture of gatifloxacin (10 g) and fumaric acid (3.09 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 88.9%.
Example 9: Preparation of gatifloxacin: malonic acid co-crystal:
A mixture of gatifloxacin (10 g) and malonic acid (2.77 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 92.4%.
Example 10: Preparation of gatifloxacin: 4-hydroxy benzoic acid co-crystal:
A mixture of gatifloxacin (10 g) and 4-hydroxy benzoic acid (3.68 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 94.3%.
Example 11: Preparation of gatifloxacin: DL-tartaric acid co-crystal:
A mixture of gatifloxacin (10 g) and DL-tartaric acid (4.0 g) in methanol (50 ml) was stirred for 4 hours at 25-30°C. The solid was filtered, washed with methanol (20 ml) and dried under vacuum. Yield: 95.7%.
,CLAIMS:1. A gatifloxacin co-crystal selected from gatifloxacin: citric acid co-crystal, gatifloxacin: oxalic acid co-crystal, gatifloxacin: 4-hydroxy benzoic acid co-crystal, gatifloxacin: DL-tartaric acid co-crystal, gatifloxacin: glutaric acid co-crystal, gatifloxacin: succinic acid co-crystal, gatifloxacin: fumaric acid co-crystal, gatifloxacin: malonic acid co-crystal and gatifloxacin: salicylic acid co-crystal.

2. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is citric acid co-crystal characterized by X-ray diffraction of figure 1 and DSC having peak at 209.30°C.

3. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is oxalic acid co-crystal characterized by X-ray diffraction of figure 2 and DSC having peak at 245.46°C and at 252.32°C.

4. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is 4-hydroxy benzoic acid co-crystal characterized by X-ray diffraction of figure 3 and DSC having peak at 234.31°C.

5. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is DL-tartaric acid co-crystal characterized by X-ray diffraction of figure 4 and DSC having peak at 232.06°C and 253.0°C.

6. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is glutaric acid co-crystal characterized by X-ray diffraction of figure 5 and DSC having peak at 222.23°C and 228.80°C.

7. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is succinic acid co-crystal characterized by X-ray diffraction of figure 6 and DSC having peak at 240.85°C.

8. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is fumaric acid co-crystal characterized by X-ray diffraction of figure 7 and DSC having peak at 262.32°C.

9. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is a malonic acid co-crystal characterized by X-ray diffraction of figure 8.

10. A gatifloxacin co-crystal according to claim 1, wherein co-crystal is salicylic acid co-crystal characterized by X-ray diffraction of figure 9.

11. A process for preparation of co-crystal of gatifloxacin comprising crystallizing gatifloxacin and co-crystal former from a suitable solvent.

12. A process for preparation of co-crystal of gatifloxacin comprising grinding gatifloxacin and co-crystal former in a suitable solvent.

13. A process according to claim 11 and 12, wherein suitable solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, acetone, methyl isobutyl ketone, methyl isopropyl ketone, methanol, ethanol, isopropanol, n-butanol, toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform, hexane, cyclohexane and mixtures thereof.