FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
PROV1SINAL SPECIFICATION
(See section 10 and rule 13)

Title of the invention
"CRYSTALLINE FORM OF MOXIFLOXACIN HYDROCHLORIDE"

Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17th floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, Pin Code: 400705 India.

1. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

CRYSTALLINE FORM OF MOXIFLOXACIN HYDROCHLORIDE
FIELD OF THE INVENTION:
The present invention relates to the crystalline polymorphic form of moxifloxacin hydrochloride. The polymorphic form is designated as Form E of moxifloxacin hydrochloride. The present invention also relates to processes for the preparing of the polymorphic Form E of Moxifloxacin hydrochloride and pharmaceutical compositions that include the moxifloxacin hydrochloride Form E.
BACKGROUND OF THE INVENTION:
Chemically moxifloxacin hydrochloride is monohydrochloride salt of l-cyclopropyl-7-[(S, S)-2, 8-diazabicyclo [4.3.0] non-8-yI]-6-fluoro-8-methoxy-l, 4-dihydro-4-oxo-3-quinoline carboxylic acid having the 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.
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.
PCT Publication No. 2009/087151 discloses hydrate crystalline forms of moxifloxacin hydrochloride designated as αl and α2 form.
PCT Publication No. 2006/134491 discloses crystalline moxifloxacin hydrochloride Form A.
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 disclosed crystalline form IV of moxifloxacin hydrochloride anhydrous form.

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 E.
SUMMARY OF THE INVENTION:
In one embodiment, the present invention encompasses crystalline moxifloxacin hydrochloride Form E characterized by data selected from a group consisting of: powder XRD pattern having peaks at 5.7, 8.4, 10.0, 14.4, 15.6, 16.9, 17.3, 17.9, 18.5, 20.3, 23.4, 23.6, 24.1, 26.4, 26.7, 27.3, 27.5, 29.2 ± 0.1 degrees two-theta; a PXRD pattern depicted in Figure 1; and any combination thereof.
In another embodiment the present invention encompasses a process for preparing crystalline moxifloxacin hydrochloride Form E, which comprises the following steps:
1. moxifloxacin hydrobromide is reacted with an aqueous alkali solution,
2. extracting moxifloxacin base by chlorinated hydrocarbons solvent,
3. treating the solution of moxifloxacin base in chlorinated hydrocarbon solvent with an alcoholic hydrochloride solution and
4. isolating moxifloxacin hydrochloride Form E.
In yet another embodiment the present invention encompasses moxifloxacin hydrobromide in a solid form.
In yet another embodiment the present invention encompasses a process for preparing substantially pure moxifloxacin hydrochloride which comprises the following steps:
1. treating crude moxifloxacin base with a hydrobromic acid in an alcoholic solvent
2. isolating moxifloxacin hydrobromide in solid form and
3. converting moxifloxacin hydrobromide in a substantially pure moxifloxacin hydrochloride.
In yet another embodiment the present invention encompasses a pharmaceutical composition that includes the moxifloxacin hydrochloride Form E.

DETAILED DESCRIPTION OF THE INVENTION:
Moxifloxacin hydrochloride Form E characterized by data selected from a group consisting of: powder XRD pattern having peaks at 5.7, 8.4, 10.0, 14.4, 15.6, 16.9, 17.3, 17.9, 18.5, 20.3, 23.4, 23.6, 24.1, 26.4, 26.7, 27.3, 27.5, 29.2 ± 0.1 degrees two-theta.

Pos. [°2Th.] Height [cts]; Area [cts*°2Th.] FWHM
[°2Th.] d-spacing Rel. Int. [%]
5.7 1030.50 102.03 0.0669 15.22998 25.69
8.4 3593.94 444.79 0.0836 10.40582 89.60
10.0 4010.99 496.40 0.0836 8.76026 100.00
14.4 2611.04 452.40 0.1171 6.10665 65.10
15.6 1672.13 248.33 0.1004 5.67208 41.69
16.9 1605.42 198.69 0.0836 5.22049 40.03
17.3 1947.99 289.30 0.1004 5.10861 48.57
17.9 1054.77 182.75 0.1171 4.93693 26.30
18.5 1070.58 211.99 0.1338 4.77943 26.69
20.3 2241.56 721.28 0.2175 4.35267 55.89
23.4 1487.26 110.44 0.0502 3.78782 37.08
23.6 2379.74 294.52 0.0836 3.76087 59.33
24.1 2083.86 361.06 0.1171 3.68905 51.95
26.4 1306.72 194.06 0.1004 3.37073 32.58
26.7 2796.32 553.72 0.1338 3.32764 69.72
27.3 2749.91 476.46 0.1171 3.26013 68.56
27.5 3204.07 793.07 0.1673 3.23895 79.88
29.2 1827.48 497.57 0.1840 3.05546 45.56

Moxifloxacin hydrochloride Form E is physically stable and does not substantially transform to any other crystal form when exposed to 100% relative humidity (RH) or less, for one week, or stored at 40°C and 75% RH for 3 months. After exposure to 100% RH or less, for one week, there is no significant gain of moisture in Form E (not significant means that it absorbs less than about 0.2% water). "Substantially transforms to any other crystal form" means that more than about 1% of the crystal form converts or rearranges to any other crystal form.
Crude moxifloxacin base may be prepared by methods known in the art such as those described in European Patent Nos. EP550903A1, EP1832587B1 and PCT Publication nos. 2009/125425 2008/059521, which are incorporated herein by reference only.
Crude moxifloxacin base obtained by following the prior-art methods always contaminated with following impurities of general formula II, III and IV.

FonnulaII Fomula III formula Iv
The term substantially pure moxifloxacin hydrochloride means moxifloxacin hydrochloride contain less than 0.1% wt/wt of above mentioned impurities of general formula II, III and IV.
The reaction of crude moxifloxacin base may be reacted with a hydrobromic acid in alcoholic solvents at a temperature in the range of 25°C to 82°C.
Examples of alcoholic solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof.

The reaction of crude moxifloxacin base may be reacted with a hydrobromic acid in alcoholic solvents may be carried out for a period of 30 minutes to 4 hours.
The moxifloxacin hydrobromide salt may be isolated from the reaction mixture by the steps of cooling, filtration, centrifugation, washing, drying or combinations thereof.
The isolated moxifloxacin hydrobromide salt may be crystalline or amorphous in nature.
The isolated moxifloxacin hydrobromide may be substantially free from the compounds of general formula II, III and IV.
The moxifloxacin hydrobromide salt may be converted into substantially pure moxifloxacin hydrochloride by reacting moxifloxacin hydrobromide salt with an aqueous alkali solution.
Examples of alkali include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate or lithium hydroxide.
The moxifloxacin base may be extracted by chlorinated hydrocarbon solvent at a temperature in the range of 25°C to 30°C.
The examples of chlorinated hydrocarbon solvent may include dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof.
The solution of moxifloxacin base in chlorinated hydrocarbon solvent may be concentrated under reduced pressure up to the half of initial volume and then it may be reacted with an alcoholic hydrochloride solution at a temperature in the range of 25°C to 65°C for a period of 30 minutes to 6 hours.
Examples of alcoholic hydrochloride solution include methanolic hydrochloric acid, ethanolic hydrochloric acid or isopropanolic hydrochloric acid.

The concentration of alcoholic hydrochloride solution may be in the range of 5% wt/wt to 15% wt/wt.
The crystalline moxifloxacin hydrochloride Form E may be isolated from the reaction mixture by the steps of cooling, filtration, centrifugation, washing, drying or the combinations thereof.
The isolated crystalline moxifloxacin hydrochloride Form E may be dried at a temperature in the range of 75°C to 150°C for a period of 4 hours to 20 hours under reduced pressure.
The isolated crystalline moxifloxacin hydrochloride Form E may be characterized by XRD pattern as illustrate in Figure 1.
The isolated crystalline moxifloxacin hydrochloride Form E may contain moisture content up to
1% wt/wt.
The isolated crystalline moxifloxacin hydrochloride Form E is physically stable and does not substantially transform to any other crystal form when exposed to 100% relative humidity (RH) or less, for one week, or stored at 40°C and 75% RH for 3 months. After exposure to 100% RH or less, for one week, there is no significant gain of moisture in Form E (not significant means that it absorbs less than about 0.2% water). "Substantially transforms to any other crystal form" means that more than about 1% of the crystal form converts or rearranges to any other crystal form.
The pharmaceutical composition of crystalline moxifloxacin hydrochloride Form E may contain crystalline moxifloxacin hydrochloride Form E and pharmaceutically acceptable excipients.

Brief Description of the Drawing:
Figure 1 illustrates a powder X-ray diffraction pattern of crystalline moxifloxacin hydrochloride salt designated form E.
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 [A]: 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.
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: Preparation of crystalline moxifloxacin hydrochloride Form E
Step 1: Preparation of moxifloxacin hydrobromide salt
A solution of crude moxifloxacin base (20 gm) in isopropanof (90 ml) was added a solution of
hydrobromic acid (9.2 gm) in isopropanol (10 ml) at 30°C. The resulting reaction mixture was
stirred for one hour and then resulting solids were filtered, washed with isopropanol (10 ml) and
dried at 50°C under reduced pressure for 12 hours.
Yield: 15 gm
Step 2: Preparation of crystalline moxifloxacin hydrochloride Form E
The solution of moxifloxacin hydrobromide (15 gm) in water (100 ml) was treated with sodium hydroxide solution in water (10 ml, 20%wt/wt). The resulting reaction mixture was extracted with dichloromethane (50 ml), the organic layer was dried by sodium sulphate (l0gm) and then it was concentrated under reduced pressure up to half of initial volume. The resulting solution was treated with isopropanolic hydrochloric acid (10 ml, 10% wt/wt) and then it was stirred for 5 hours at 25°C. The resulting solids were filtered, dried at 150°C. Yield: 11 gm; Purity: 99.70% (By HPLC)
Compound of Formula II: 0.05[Limit of detection (herein after referred as LOD): 0.001% wt/wt; Limit of quantitation (herein after referred as LOQ): 0.05% wt/wt]
Compound of Formula III: Not detected [LOD: 0.005% wt/wt; LOQ: 0.05% wt/wt]
Compound of Formula IV: 0.06 [LOD: 0.025% wt/wt; LOQ: 0.01% wt/wt]
XRD: As illustrate in Figure 1