FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"NOVEL POLYMORPH OF MOXIFLOXACIN HYDROCHLORIDE."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, PlotNo.5 Sector-] 9, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL POLYMORPH OF MOXIFLOXACIN HYDROCHLORIDE

FIELD OF THE INVENTION:

The present invention relates to novel polymorph of moxifloxacin hydrochloride hereinafter refer as crystalline form F. The present invention further relates to processes for preparing crystalline form F of moxifloxacin hydrochloride and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION:

Chemically moxifloxacin hydrochloride is monohydrochloride salt of 1-cyclopropyl-7-[(S, S)-2, 8-diazabicyclo [4.3.0] non-8-yl]-6-fluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid having the compound of structural formula I and is known form U.S. Patent No. 5, 607,942.

Formula I

Moxifloxacin hydrochloride is a synthetic broad-spectrum antibacterial agent. The active moiety, moxifloxacin has been shown to be clinically active against most strains of microorganisms such as aerobic gram-positive microorganisms including staphylococcus aureus, streptococcus pneumonia (penicillin-susceptible strains) and streptococcus pyogenes, aerobic gram-negative microorganisms including haemophilus influenza, hemophilus parainfluenzae, klebisiella pneumonia. Moxifloxacin is commercially available under the brand name of AVELOX® marketed by Bayer Healthcare

U.S. Patent No. 5,849,752 discloses moxifloxacin hydrochloride anhydrous and moxifloxacin hydrochloride monohydrate form.

U.S. Patent No. 7,230,006 discloses crystalline form III of anhydrous moxifloxacin hydrochloride and processes for their preparation.

U.S. Patent application no. 2006/252789 discloses moxifloxacin hydrochloride in an amorphous form.

PCT Publication No. 2005/054240 discloses moxifloxacin hydrochloride crystalline form A and moxifloxacin hydrochloride crystalline form B.

PCT Publication No. 2007/148137 discloses moxifloxacin hydrochloride in a stable hydrated form.

PCT Publication No. 2008/059223 discloses moxifloxacin hydrochloride crystalline polymorphic form C.

Our own Indian patent application no. 2700/MUM/2010 discloses anhydrous moxifloxacin hydrochloride crystalline form E.

PCT Publication No. 2009/087151 discloses hydrate crystalline forms of moxifloxacin hydrochloride designated as α1 and α2 form.

PCT Publication No. 2006/134491 discloses crystalline moxifloxacin hydrochloride Form A having water content below 2% weight / weight.

PCT Publication No. 2007/010555 discloses crystalline forms X and Y of anhydrous moxifloxacin hydrochloride.

PCT Publication No. 2008/028959 discloses moxifloxacin hydrochloride sesquihydrate form.

PCT Publication No. 2010/052726 discloses polymorph IV of moxifloxacin hydrochloride monohydrate form.

Spanish Patent No. 2316270 discloses crystalline form IV of moxifloxacin hydrochloride anhydrous form.

U.S. Patent application no. 2006/0264635 discloses moxifloxacin hydrochloride pseudohydrate form.

PCT Publication No. 2008/095964 discloses crystalline form of moxifloxacin base.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Therefore, there is a need for additional solid state forms of moxifloxacin hydrochloride.

The present applicant of the patent has surprisingly found a new crystalline polymorphic form of moxifloxacin hydrochloride, which is designated as form F.

SUMMARY OF THE INVENTION:

A first aspect of the present invention is to provide a novel polymorphic form of moxifloxacin hydrochloride hereinafter refer as crystalline form F.

A second aspect of the present invention is to provide processes of preparing crystalline form F of moxifloxacin hydrochloride.

A third aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form F of moxifloxacin hydrochloride.

A fourth aspect of the present invention is to provide a process of preparing crystalline form F of moxifloxacin hydrochloride comprising the steps of:
a. providing a solution of moxifloxacin base in an alcohol solvent,
b. treating the solution of moxifloxacin base obtained from step a, with an alcoholic hydrochloric acid and
c. isolating crystalline form F of moxifloxacin hydrochloride.

DETAIL DESCRIPTION OF THE INVENTION:

A crystalline form F of moxifloxacin hydrochloride may be characterized by X-ray diffraction pattern having peaks at 4.1, 7.0, 7.2, 8.3, 8.5, 10.8, 11.1, 13.9, 15.2, 15.5, 15.7, 17.2, 18.9, 19.5, 19.9, 23.2, 23.7, 27.1, 27.8, 29.0, 29.6 ± 0.2 degrees two theta.

A crystalline form F of moxifloxacin hydrochloride may be characterized by X-ray diffraction pattern as depicted in Figure 1.

A crystalline form F of moxifloxacin hydrochloride may be characterized by X-ray diffraction pattern having following peaks:

Pos. [°2Th.] Height [cts] Area [cts*°2Th.] FWHM [°2Th.] d-spacing [Å] Rel. Int. [%]
4.1851 265.87 65.81 0.1673 21.09637 16.88
5.8684 8.42 2.08 0.1673 15.04819 0.53
7.0782 556.70 55.12 0.0669 12.47855 35.35
7.2109 865.89 107.16 0.0836 12.24930 54.98
8.3618 664.49 115.13 0.1171 10.56565 42.20
8.5202 365.56 54.29 0.1004 10.36966 23.21
10.8210 312.99 30.99 0.0669 8.16942 19.88
11.1276 711.76 193.79 0.1840 7.94501 45.20
13.9671 1021.90 252.94 0.1673 6.33553 64.89
15.2027 841.24 291.51 0.2342 5.82325 53.42
15.5923 563.23 41.82 0.0502 5.67863 35.77
15.7613 593.63 73.47 0.0836 5.61810 37.70
17.2130 824.08 268.98 0.1632 5.14744 52.33
17.9050 135.19 44.13 0.1632 4.95001 8.58
18.5155 103.66 21.15 0.1020 4.78816 6.58
18.9524 431.24 87.97 0.1020 4.67875 27.38
19.5591 338.84 165.89 0.2448 4.53497 21.52
19.9486 243.70 79.54 0.1632 4.44730 15.48
21.0015 66.13 43.17 0.3264 4.22664 4.20
21.4312 151.64 123.74 0.4080 4.14287 9.63
21.7610 129.95 26.51 0.1020 4.08081 8.25
23.2067 337.71 220.45 0.3264 3.82975 21.44
23.7341 282.36 34.56 0.0612 3.74584 17.93
24.5773 119.05 14.57 0.0612 3.61920 7.56
25.2033 163.26 186.51 0.5712 3.53070 10.37
27.1630 1574.78 449.76 0.1428 3.28027 100.00
27.8251 391.51 223.63 0.2856 3.20369 24.86
29.0771 160.35 52.34 0.1632 3.06854 10.18
29.6793 178.40 160.13 0.4488 3.00764 11.33
31.9691 57.17 37.32 0.3264 2.79724 3.63
32.7094 128.14 15.68 0.0612 2.73560 8.14
33.0899 101.61 49.75 0.2448 2.70501 6.45
34.8757 31.71 25.88 0.4080 2.57048 2.01
36.8760 51.47 50.40 0.4896 2.43551 3.27
38.1016 48.48 23.73 0.2448 2.35994 3.08

The moxifloxacin base may be provided by neutralizing the solution of moxifloxacin hydrochloride in halogenated aliphatic hydrocarbon solvent with an aqueous solution of alkali metal hydroxide.

The moxifloxacin hydrochloride used in the present invention may be formed by methods known in the art such as those described in U.S.Patent nos. 5,849,752; 7,230,006 and PCT Publication nos. 2005/054240; 2007/148137 or 2008/059223, which are incorporated herein by reference only.

The examples of halogenated aliphatic hydrocarbon solvents may include but not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.

The examples of alkali metal hydroxides may include but not limited to sodium hydroxide, lithium hydroxide or potassium hydroxide.

The moxifloxacin base may be isolated by separating organic layer, followed by washing with water, dried over anhydrous sodium sulfate and concentrating under reduced pressure.

The solution of moxifloxacin base in an alcohol solvent may be formed by dissolving moxifloxacin base in an alcohol solvent at a temperature in the range of 25C to 120C.

The examples of alcohol solvent may include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof.

A solution of moxifloxacin base in alcohol solvent may contain moisture content about 0.15% weight / weight to 1.5% weight / weight.

The solution of moxifloxacin base in an alcohol solvent may be treated with an alcoholic hydrochloric acid at a temperature in the range of 0C to 30C to get a solution of moxifloxacin hydrochloride in an alcohol solvent.

The example of alcoholic hydrochloride solutions may include methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride or n-butanolic hydrochloride.

The alcoholic hydrochloride solution may contain hydrochloric acid in the range of 5% weight / weight to 15% weight / weight.

The crystalline form F of moxifloxacin hydrochloride may be formed by stirring the solution of moxifloxacin hydrochloride in an alcohol solvent at a temperature in the range of 0C to 30C for a period of 30 minutes to 8 hours.

The crystalline form F of moxifloxacin hydrochloride may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.

The isolated crystalline form F of moxifloxacin hydrochloride may be dried at a temperature in the range of 45°C to 150°C for a period of 4 hours to 20 hours under reduced pressure.

The moxifloxacin hydrochloride Form F may contain moisture content 0.15% weight / weight to 2.0% weight / weight as determined by Karl-Fischer titration method.

A pharmaceutical composition of moxifloxacin hydrochloride comprising crystalline form F of moxifloxacin hydrochloride and pharmaceutically acceptable excipients

BRIEF DESCRIPTION OF THE DRAWING:

Figure 1 illustrates a powder X-ray diffraction pattern of moxifloxacin hydrochloride Form F.

XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: continuous;
Step size [°2-theta]: 0.0170°;
Scan step time[s]: 51.04 seconds;
Sample spin: 15 rpm;
Sample holder: glass;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha [Å]: 1.54060

Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

EXAMPLE:

In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example 1: Preparation of crystalline form F of moxifloxacin hydrochloride

A solution of moxifloxacin hydrochloride (10gm) in dichloromethane (50ml) was added an aqueous solution of 2N sodium hydroxide (20ml) and the resulting solution was stirred for 15 minutes. The organic layer was separated, washed with water (3x50ml), dried over anhydrous sodium sulfate (5gm) and then concentrated under reduced pressure to get a residue of moxifloxacin base. The obtained residue of moxifloxacin base was dissolved in n-butanol (50ml) at 116 and resulting reaction mixture was stirred for 10 minutes. The reaction mixture was cooled to 25C and then n-butanolic hydrochloric acid solution (10ml, 15% weight/weight) was added and resulting solution of moxifloxacin hydrochloride was stirred for 1 hour at 25C. The resulting solids were filtered, washed with n-butanol (25ml) and then first dried at 60C for 8 hours and then at 100C for 3 hours.
Yield: 9.9gm
Purity: 99.98% (By HPLC)
XRD: As illustrate in Figure 1

WE CLAIM:

1. A compound which is crystalline form F of moxifloxacin hydrochloride having substantially the same X-ray diffraction pattern as depicted in Figure 1.

2. The moxifloxacin hydrochloride form F according to claim no. 1, is further characterized by X-ray diffraction pattern comprising peaks at 4.1, 7.0, 7.2, 8.3, 8.5, 10.8, 11.1, 13.9, 15.2, 15.5, 15.7, 17.2, 18.9, 19.5, 19.9, 23.2, 23.7, 27.1, 27.8, 29.0, 29.6 ± 0.2 degrees two theta.

3. A process of preparing crystalline form F of moxifloxacin hydrochloride comprising the steps of:
a. providing a solution of moxifloxacin base in an alcohol solvent,
b. treating the solution of moxifloxacin base obtained from step a, with an alcoholic hydrochloric acid and
c. isolating crystalline form F of moxifloxacin hydrochloride.

4. The process according to claim no. 3, wherein moxifloxacin base is provided by neutralizing the solution of moxifloxacin hydrochloride in halogenated aliphatic hydrocarbon solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof with an aqueous solution of alkali metal hydroxide such as sodium hydroxide, lithium hydroxide or potassium hydroxide.

5. The process according to claim no. 3, wherein moxifloxacin base is isolated by separating organic layer, followed by washing with water, dried over anhydrous sodium sulfate and concentrating under reduced pressure.

6. The process according to claim no. 3, wherein solution of moxifloxacin base in an alcohol solvent is formed by dissolving moxifloxacin base in an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof at a temperature in the range of 25C to 120C.

7. The process according to claim no. 3, wherein solution of moxifloxacin base in an alcohol solvent is treated with an alcoholic hydrochloric acid such as methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride or n-butanolic hydrochloride at a temperature in the range of 0C to 30C to get a solution of moxifloxacin hydrochloride in an alcohol solvent.

8. The process according to claim nos. 3 and 7, wherein alcoholic hydrochloride solution is contain hydrochloric acid in the range of 5% weight / weight to 15% weight / weight.

9. The process according to claim no. 3, wherein crystalline form F of moxifloxacin hydrochloride is formed by stirring the solution of moxifloxacin hydrochloride in an alcohol solvent at a temperature in the range of 0C to 30C for a period of 30 minutes to 8 hours and isolated by the steps of filtration, centrifugation, washing followed by dried at a temperature in the range of 45°C to 150°C for a period of 4 hours to 20 hours under reduced pressure.

10. A pharmaceutical composition of moxifloxacin hydrochloride comprising crystalline form F of moxifloxacin hydrochloride and pharmaceutically acceptable excipients.