WO2006134491A2

WO2006134491A2 - New crystalline form of moxifloxacin hydrochloride and process for its preparation

Info

Publication number: WO2006134491A2
Application number: PCT/IB2006/001721
Authority: WO
Inventors: Ramesh Dandala; Jayati Mitra; Arun Kumar Gupta; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2005-06-14
Filing date: 2006-06-01
Publication date: 2006-12-21
Also published as: WO2006134491A3

Abstract

The present invention relates to a new crystalline form of 1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid hydrochloride of the Formula I with a moisture content below 2 % w/w (Form A). The present invention also relates to a process of preparing the new crystalline form.

Description

NEW CRYSTALLINE FORM OF MOXIFLOXACTN HYDROCHLORIDE AND PROCESS FOR ITS PREPARATION

FIELD QF THE INVENTION

The present invention relates to a new crystalline form of l-cyclopropyl-6-fluoiO- ] ,4-dihydiO-8-methoxy-7-[(4aiS,7aS)-octahydro-6//-pyrrolo[3,4-&]pyridin-6-yl]-4- oxo-3-quinolinecarboxylic acid hydrochloride of the Formula I with a moisture content below 2 % w/w (Form A). The present invention also relates to a process of preparing the new crystalline form.

_j__iCl Formula I

BACKGROUND QF THE INVENTION

l -CyclopiOpyl-6-fluoro-l ,4-dihydiO-8-methoxy-7-[(4aS',7aiS^r)-octahydiO-6//- pyriOlo[3,4-Λ]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid hydrochloride is generically known as Moxifloxacin hydrochloride. Moxifloxacin hydrochloride, a fluoroquinolone, is a synthetic broad-spectrum anti-bacterial agent and has a methoxy group at the 8-position.

The present invention describes a new crystalline form of Moxifloxacin hydrochloride (Form A). Polymorphism is the property of some molecules and molecular complexes to assume more than one crystalline or amorphous form in solid state. A molecule such as Moxifloxacin of formula I may give rise to a variety of solids having distinct physical properties like 'solubility, melting point, powder X-ray diffraclogram (XRD) etc. The differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula, which may be thought of as analogous to unit cell metallurgy, yet having distinct advantageous and or disadvantageous physical properties compared to other forms in the polymorph family.

Bayer has disclosed Moxifloxacin and its derivatives generically in US Patent No. 4,990,517. It is more specifically claimed in US Patent No. 5,607,942. Moxifloxacin has activity against Gram-negative and Gram -positive organisms, including Streptococcus pneumonia, Staphylococcus aureus, Pseitdomonas aeruginosa, and particularly against the respiratory disease causing pathogens like Mycoplasma pneumonia, Mycobacterium tuberculosis. Chlamydia pneumonia and the activity shown to be unaffected by β-lactamases.

US Patent 5,849,752, claims monohydrated Moxifloxacin monohydrochloride. The monohydrate form, which crystallizes as prisms, can be prepared by suspending anhydrous crystalline Moxifloxacin in ethanol/water mixtures, preferably in ethanol/water at room temperature. The monohydrated Moxifloxacin monohydrochloride as disclosed in US Patent 5,849,752 has a moisture content of about 3.9 % w/w. In this patent, it is also mentioned that the form of Moxifloxacin hydrochloride reported as of the date of filing of US Patent 5,849,752 is anhydrous.

An amorphous form of Moxifloxacin hydrochloride is disclosed in WO 2004/039804 along with a process to prepare the same. The inventors have used the spray drying or freeze-drying technique utilizing the Moxifloxacin hydrochloride solution to prepare amorphous Moxifloxacin hydrochloride. In WO 2004/091619, a new polymorphic form of anhydrous Moxitloxacin monohydrochloride has been described and the inventors have designated this polymorphic form as Form III.

US Patent No. 5,157,1 17 discloses (l-cyclopropyl-βJ-difluoro-l Λ-dihydiO-δ- methoxy-4-oxo-3-quinolinecarboxylic acid-0³,C/)bis(acetate-(9)borate and a process for its preparation by reacting ethyl l-cyclopropyl-6,7-difluoiO-l ,4- dihydro-8-methoxy-4-oxo~3-quinolinecarboxylate with boric acid and acetic anhydride in presence of zinc chloride and its conversion to Gatifloxacin hydrochloride.

WO 96/33992 Al PCT publication discloses a process for the preparation of 1 - cyclopiOpyl-6,7-difl Lioro- l,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid boron difluoride chelate, but further conversion to Moxifloxacin hydrochloride is not discussed in this publication.

US 4,990,517, US 5,639,886, and EP 550,903 disclose the preparation of Moxifloxacin hydrochloride involving the condensation of l-cyclopropyl-6,7- diIluoro~l ,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid or its esters with (LS¹,iS')-2,8-Diazabicyclo[4.3.0]nonane in presence of a base and its conversion to hydrochloride at higher temperatures. This process not only produces desired Moxifloxacin but also its positional isomer namely l-cyclopropyl-7-fluoro-l,4- clihydro-8-methoxy-6-(4a5',7aS^r)-octahydiO-6//-pynOlo[3,4-δ]pyridin-6-yl)]-4-oxo- quinolinecarboxylic acid (II) as a major impurity.

Formula II

Λs the impurity and Moxifloxacin are positional isomers, it is very difficult to separate them. Purification of Moxifloxacin to remove this isomer results in lower yields thereby increasing the product cost.

We have now found that, in the process of the present invention the formation of undesired isomer is reduced to a level within the acceptable limits.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a new crystalline form of

Moxifloxacin hydrochloride with a moisture content less than 2 % w/w (Form A).

Another objective of the present invention is to provide a simple and effective process for the preparation of crystalline form of Moxifloxacin hydrochloride of high purity on a commercial scale.

SUMMARY OF INVENTION

The present invention provides a new crystalline form of Moxifloxacin hydrochloride with moisture content below 2 % w/w (Form A) and its process for the preparation.

The present invention provides a new crystalline form of Moxifloxacin hydrochloride having a moisture content of 1 to 2 % w/w amounting closely to hemihydrate and is herein referred to as Moxifloxacin hydrochloride (Form A).

The new crystalline polymorphic Form A of the present invention shows X-ray diffraction peaks at the diffraction angles of about 6.36 ± 0.2, 8.39 ± 0.2, 10.02 ± 0.2, 12.28 ± 0.2, 13.28 ± 0.2, 13.64 ± 0.2, 14.90 ± 0.2, 15.39 ± 0.2, 15.79 ± 0.2,

16.71 ± 0.2, 17.69 ± 0.2, 18.23 ± 0.2, 19.09 ± 0.2, 20.07 ± 0.2, 20.71 ± 0.2, 21.44 ± 0.2, 22.25 ± 0.2, 23.60 ± 0.2, 24.18 ± 0.2, 24.61 ± 0.2, 25.98 ± 0.2, 26.90 ± 0.2, 27.83 ± 0.2, 28.67 ± 0.2, 29.90 ± 0.2, 30.40 ± 0.2, 31 .17 ± 0.2, 32.01 ± 0.2, 32.85 ± 0.2, 38.24 ± 0.2

Further, the new crystalline polymorphic Form A can be characterized by an endolherm at about 64.9 ⁰C and a melting endotherm with a peak temperature at about 241 .7 ⁰C in the Differential Scanning Calorimetiy (DSC) thermogram.

The new crystalline polymorphic Form A can be characterized by infrared absorption spectrum pattern having characteristic peaks at 1455, 1515, 1621, 1701 , 3521 and 3354 cm^{" 1}.

According to an embodiment, the present invention also provides a process for the preparation of this new crystalline Form A, comprising, i) reacting (l-cyclopropyl-6,7-difluoiO-l,4-dihydiO-8-methoxy-4-(oxo-/cO)-

3-quinolinecarboxylato-/cO^J)difluoroboiOn (III)

Formula III

with (4aS,7aS)octahydro-lH-pyriOlo[3,4-Zy|pyridine (IV)

Formula IV

in presence of a base (s) in an organic solvent (s) to produce (1- cyclopropyl-6-fluoiO-l,4-dihydro-8-methoxy-7-[(4a5',7a₁S^f)-octahydiO- 6/-/-pynOlo[3,4-Λ]pyridin-6-yl]-4-(oxo-AO)-3-quinolinecarboxylato-

( Moxilloxacin boron difluoride chelate (V)),

Formula V

ii) cleaving of boron difluoride chelate (V) using an organic base in a solvent to produce Moxifloxacin, which on reaction with dry hydrogen chloride in presence of solvent gives Moxifloxacin hydrochloride Form A;

OH _J , p J Formula 1

In another embodiment, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the new crystalline Moxifloxacin hydrochloride Form A and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of new crystalline Moxifloxacin hydrochloride Form A.

Figure 2 is an infrared spectrum in KBr of crystalline Moxifloxacin hydrochloride Form A. Figure 3 is differential scanning caloiϊmetry thermogram of crystalline Moxifloxacin hydrochloride Form A.

DETAILED DESCRIPTION OF THE INVENTION

The process for the preparation of a new crystalline form of Moxifloxacin hydrochloride comprises; suspending (l -cyclopropyl-6,7-difluoro-l,4-dmydro-8-methoxy-4-(oxo-/cϋ)-3- quinolinecarboxylato-/c0³)difluoroboiOn (III) in an organic solvent selected from acetonitrile, methanol, ethanol, isopropanol, butanol etc, preferably methanol with (4a&7aS)octahydiO-l H-pyiτolo[3,4-6]pyridine (IV) in the presence of an organic or inorganic base preferably organic base selected from the group consisting of DBU, triethylamine, N,N-diisopropylethylamine etc preferably triethylamine, at temperatures 20⁰C to about 6O⁰C, preferably 30⁰C to about 35°C for about 2 hr to about 10 hrs, preferably 2 to 3 hr. After the completion of reaction, as ascertained by the known methods such as HPLC, the product (l-cyclopiOpyl-6-fluoro-l ,4- dihydro-8-methoxy-7-[(4a5',7aiS)-octahydiO-6//-pyπOlo[3,4-ό]pyridin-6-yl]-4- (oxo-£O)-3-quinolinecarboxylato-£O^J)diflιιoroboron (Moxifloxacin boron di fluoride chelate (V)) is filtered and washed with solvent selected from acetonitrile, methanol, ethanol, isopropanol, butanol.

Compound of formula (V) is dissolved in an organic solvent selected from methanol, ethanol, isopropanol, butanol,, etc, preferably methanol and treated with organic or inorganic base preferably organic base selected from triethylamine, diisopropylamine, DBU, DABCO, is added and heated to reflux temperature, preferably 60⁰C to about 65°C, for 6 to 30 hrs, preferably 20 to 24 hrs. After the completion of reaction, as ascertained by the known methods such as HPLC, solvent and excess of base are distilled off, and the residue containing Moxilloxacin is taken into a solvent mixture selected from the group consisting of water, methylene chloride, ethylacetate, toluene, preferably water and methylene chloride. The reaction mass is neutralized with base selected from sodium hydroxide, potassium hydroxide, aqueous ammonia, preferably aqueous sodium hydroxide, organic layer is separated and distilled off. The residue containing Moxifloxacin is taken into a solvent mixture selected from the group consisting of acetonilrile, methanol, ethanol or lower alcohols and hydrochloric acid. The reaction mass is stirred for 10 min to about 2 his, preferably 30 minutes at 1 O⁰C to about 5O⁰C, preferably 2O⁰C to about 25°C, and thereafter cooled further to O⁰C to about 2O⁰C, preferably 0⁰C to about 5°C, and maintained for 1 to about 4 hrs preferably 2 hrs at O⁰C. The product formed is separated by conventional means, washed with solvent and is dried at 30⁰C to about 7O⁰C, preferably at 45°C to about 5O⁰C to constant weight.

Alternatively it is possible to proceed for the preparation of Moxifloxacin hydrochloride without the isolation of the intermediate (l-cyclopropyl-6-fluoro- l ,4-dihydro-8-methoxy-7-[(4a5',7a6)-octahydiO-6//-pyπOlo[3,4-δ]pyridin-6-yI]-4- (oxo-AO)-3-quinolinecarboxylato-/cO' )difluoroboiOn (V). This is accomplished by adding base selected from triethylamine, diisopropylamine, DBLJ, DABCO, preferably triethylamine to the reaction mass containing (l-cyclopropyl-6-fluoro- l ,4-dihydro-8-methoxy-7-[(4a5',7a5^<)-octahydiO-o//-pynOlo[3,4-/7]pyridin-6-yl]-4- (oxo-/fO)-3-quinolinecarboxylato-/cO³)difluoiOboron (V) at 30⁰C and the suspension is heated to reflux temperature preferably 60 to about 65°C for 12 to about 20 hours, preferably 15 hrs. After the completion of reaction, solvent and excess of base are distilled off, and the residue containing Moxifloxacin is taken into a solvent mixture selected from the group consisting of acetonitrile, methanol, ethanol, propanol, isopropanol, butanol etc; and neutralized with hydrochloric acid. The reaction mass is stirred for 10 min to about 2 hrs, preferably 30 minutes at 10⁰C to about 50⁰C, preferably 20⁰C to about 25°C. The clear filtrate obtained is acidified with hydrochloric acid. The product formed is separated by conventional means, washed with solvent and is dried at 30⁰C to about 7O⁰C, preferably at 60°C to about 7O⁰G to constant weight. The new crystalline form of Moxifloxacin hydrochloride (Form A) can alternatively be prepared by the process, which comprises, suspending Moxilloxacin hydrochloride in a solvent mixture selected from water, methylene chloride, chloroform, ethylacetate, toluene, preferably in a mixture of water and methylene chloride and treated with base selected from sodium hydroxide, potassium hydroxide, aqueous ammonia, preferably aqueous sodium hydroxide. The organic layer containing Moxifloxacin is concentrated and the residue is treated with dry hydrogen chloride in a solvent selected from methanol, ethanol, propanol, isopropanol, butanol, preferably methanol. The precipitated Moxi floxacin hydrochloride crystalline form is Filtered and dried under vacuum till Moxifloxacin hydrochloride (Form A) is obtained.

The present invention also provides a novel intermediate, (l-cyclopropyl-6- rluoiO-l ,4-dihydiO-8-methoxy-7-[(4aiS¹,7aiS0-octahydiO-6H-pyiτolo[3,4-b]pyi"idin- 6-yI]-4-(oxo-/tO)-3-quinolinecarboxylato-/cO ^J)difluoroboron (V) (Moxifloxacin boron difluoride chelate (V)).

The powder X-ray diffraction of new crystalline form of Moxifloxacin hydrochloride (Form A), was determined on Seifert XRD 3003 TT system using a copper X-ray tube, a nickel filter and the sample was placed in a pyrex glass holder. The scan rate was 1.8 degrees, two theta per minute, the step size of 0.03 degrees two theta over the range from 5 to 50°.

This new crystalline form of Moxifloxacin hydrochloride is characterized by an X-ray powder diffraction pattern shown in Table 1. Comparison of XRD data of Form A with anhydrous form and the monohydrate form reported in literature.

Table-l

This new crystalline form has moisture content of about 2 % w/w as analysed by Karl Fisher method (determined on 0.1 g, w/w), which shows it to be different from the monohydrate (moisture content 3.9 % w/w). This form was also characterized by IR spectrum measured by KBr transmission. The absorption bands in the region of OH vibrations differ from that of the monohydrate and anhydrous forms (Figure 2).

Comparing XRD data in the Table 1, it is apparent that certain peaks provide the best way of characterizing the new crystalline Moxifloxacin hydrochloride Form A and of differentiating it from the monohydrate and anhydrous forms. Very few of such peaks are needed to allow for such characterization and differentiation. Thus, the crystalline Moxifloxacin hydrochloride (Form A) may be characterized by an X-ray powder diffraction pattern with characteristic peaks at 6.36 ± 0.2, 8.39 ± 0.2, 10.02 ± 0.2. These prominent peaks are absent in the previously reported monohydrate and anhydrous forms.

The differential scanning calorimetry (DSC) thermogram of monohydrate as described by the inventors shows a broad endothermal peak at 260 ⁰C that are absent in the new crystalline form of Moxifloxacin hydrochloride (Figure 3).

The new crystalline form of Moxifloxacin hydrochloride of the present invention exhibits infrared absorption peaks tabulated in Table 2. The infrared absorption pattern clearly differentiates the present form with the forms reported in the prior art references. Comparative table of IR data of Form A, anhydrous form and monohydrate form.

Table 2

It is evident from the above data that the new crystalline form of Moxifloxacin hydrochloride of the present invention is different from the polymorphic forms reported in the prior-art.

5 Further the new crystalline polymorph showed good handling properties and stability that are desirable for formulation.

The following examples to Moxifloxacin Hydrochloride (Form A) illustrate the nature of the invention and are provided for illustrative purpose only and should I O not be construed to limit the scope of the invention:

EXAMPLE 1

Stage I

15 Preparation of (l-cycIopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4aiS',7a>S')- octahydro-6H-pyrrolo[3,4-Z>]pyridin-6-yl]-4-(oxo-/r0)-3- quinolinecarboxylato- /rO³)difluoroboron (Moxifloxacin boron difluoride chelate (V)).

Boron difluoride chelate derivative (III) (5 g; 0.0146 moles) was suspended in 0 acetonitrile (25 ml) and (4a5\7a5)octahydro-lH-pyrrolo[3,4-/>]pyridine (2.2 g, 0.0175 moles) followed by triethylamine (3.4 g, 0.0335 moles) were added. The reaction mass was heated to reflux and maintained at 70-80⁰C for 1 h. After completion of reaction, the reaction mass was cooled to 40-45⁰C and solvent was distilled off under reduced pressure to get residue. 5 [ A small portion of the reaction mixture was filtered, washed with acetonitrile and dried and the solid product was analysed]

'Η NMR (DMSO-dr.) δ ppm: 0 8.95 (s, 1 Η), 7.79 (d, J=14Η_Z, IH), 4.35 (m, IH), 4.07-3.95 (m, 2H), 3.58 (s, 3H), 3.48-3.3 (m. 3H), 2.86 (m, I H), 2.50 (m, IH), 2.28 (m, IH), 1.73-1.63 (m, IH), 1.44 (m, I H), 1.30-1.25 (m, 2H), 1.06-1.01 (m, 2H). m/z 450 I M+H I

IR (KBr, cm^-l): 3337, 3080, 2958, 2932, 2853, 1903, 1717, 1629, 1567,1522, 1503, 1471 , 1461 , 1436, 1371 , 1336, 1306, 1296, 1284, 1253, 1220, 1 189, 1 150, 1060, 1033, 985, 974.

Stage II

Preparation of Moxifloxacin hydrochloride

The residue obtained from step Il was dissolved in a mixture of methanol (50 ml) and lrielhylamine (7.4 g, 0.0733 moles) and was heated to reflux at 60-65⁰C for 6 h. Alter the completion of reaction, solvent and excess of triethylamine were distilled off at 40-50⁰C under reduced pressure to obtain a residue, which was suspended in a mixture of acetonitrile (20 ml) and methanol (20 ml) and concentrated hydrochloric acid (4.0 ml) was added at 20-25⁰C. The reaction mass was stirred for 30 niin at 20-25⁰C and thereafter cooled further to 0-5⁰C. After stirring for 2 h at 0-5⁰C, the resulting product Moxifloxacin hydrochloride was filtered and washed with acetonitrile-methanol mixture (1 : 1 , 5 ml). The product was dried at 45-50⁰C till moisture content was less than < 2% w/w. The dry weight of the product 3.5 g (55%).

EXAMPLE 2

Stage-I

Preparation of (l-cycIopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4aiS',7a5)- octahydro~6H-pyrrolo[3,4-£]pyridin-6-yl]-4~(oxo-AO)-3- quinolinecarboxylato- Λ6>³)difluoroboron (Moxifloxacin boron difluoride chelate (V))

l -CyclopiOpyl-6,7-difluoiO-8-methoxy-4-oxo-l,4-diliydroquinoline-3-carboxylic acid borondifluoride chelate (III) (275 g; 0.80 moles) was suspended in acetonitrile (550 ml) and triethylamine (186.3 g, 1.84 moles) was added. (4a₁S'.7a₁S')octahydro-l /-/-pyπOlo[3,4-/?]pyridine (121.3 g, 0.96 moles) was added dropwise and the reaction mixture was stirred for 2 hrs at 30 to 35°C. After completion of reaction, the product obtained was filtered, washed with acetonitrile ( ! 38 ml) and dried at 50 to 55⁰C under reduced pressure. (Yield, 331 g (92%))

Stage II

Preparation of l-cycIopropyI-6-fluoiO-l,4-dihydro-8-methoxy-7-|(4aS',7a.S)- octahydro-6H-pyrrolo[3,4-6]pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid hydrochloride (Moxiiloxacin hydrochloride)

The Moxifloxacin borondifluoride chelate (V) obtained as above (310 g, 0.69 moles) was suspended in methanol (1240 ml), triethylamine (69.8 g, 0.69 moles) was added and the mixture was heated to reflux for twenty-four hours. After cooling, the methanol was distilled off under reduced pressure and the solid residue was suspended in water (2480 ml) and dichloromethane (2480 ml). This reaction mixture was neutralized with 10 % aqueous sodium hydroxide solution and organic layer was separated and the aqueous layer was further extracted with dichloromethane (930 ml). The combined organic layer was distilled under reduced pressure at 30-35⁰C and the crude solid residue was suspended in a mixture of acetonitrile-methanol [(1 :1), 1240 ml]. Concentrated hydrochloric acid (216 g, 2.01 moles) was added dropwise at 0-5⁰C. The precipitated yellow crystals were stirred for one hour at O⁰C to 5°C, filtered and dried under vacuum at 60-65⁰C (224 g, 74%). Stage HI

Preparation of l-cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4a5,7a5)- octahydro-6H-pyrrolo[3,4-6)pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid hydrochloride (Moxifloxacin hydrochloride( Form A))

Moxifloxacin hydrochloride (175 g, 0.4 moles) obtained as above was suspended in water (2480 ml) and methylene chloride (2480 ml) and basified with 10% aqueous sodium hydroxide solution (160 ml, 0.4 moles). The layers were separated and aqueous layer was further extracted with methylene chloride (525 ml). The combined organic layer was distilled off under reduced pressure at 30- 35°C to obtain a residue. The solid residue was suspended in methanol (525 ml) and dry hydrogen chloride (146 g, 4 moles) was bubbled into the stirred reaction 5 mixture at 0°C. The precipitated solid was stirred at 0-5⁰C for two hours, filtered and dried under vaccum at 70-75⁰C to produce Moxifloxacin hydrochloride (Form A) (I l O g, 62.8 %).

EXAMPLE 3 I U

Preparation of 1 -cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-f (4aS,7aS)- octahydro-όH-pyrroloP^-^lpyridin-ό-ylJ^-oxo-S-quinoIinecarboxylic acid hydrochloride (Moxifloxacin hydrochloride Form A)

1 5 Moxifloxacin ( 1 g) was suspended in absolute alcohol (20 ml) and cooled to

0-5⁰C with stirring. Dry hydrogen chloride gas was bubbled into the reaction mixture till saturation upon which a clear solution resulted. After stirring for 1 hour at 0-10 ⁰C the reaction mixture turned hazy and crystallization of product was observed. The reaction was maintained for another hour at 0-10 ⁰C, the 0 solution concentrated under reduced pressure and further dried for 12 hours at 75- 80 ⁰C under reduced pressure (-10 mm Hg) to yield a new crystalline form of Moxifloxacin hydrochloride (Form A) (1.1 g).

Example 4 5

Preparation of l-cycIopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4a5^>,7a5')- octahydro-6H-pyrroIo[3,4-£]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid hydrochloride (Moxifloxacin hydrochloride (Form A))

0 l-CyclopiOpyl-6,7-difluoiO-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid boron difluoride chelate (III) (150g, 0.44 moles) was suspended in methanol (750 ml) and (4£uS',7ai9)octahydiO-l//-pynOlo[3,4-6]pyridino (66 g, 0.52 moles) followed by triethylamine (60.9g, 0.60 moles) were added. The reaction mixture was stirred at 3O⁰C for 10 h. Thereafter triethylamine (220.8 g, 2.19 moles) was added and the suspension was heated to reflux for 22 h. After completion of

> reaction the solvent and excess triethylamine were distilled off under reduced pressure at 40-50°C. The crude residue was suspended in a mixture of acetonitrile (600 ml) and methanol (600 ml) and concentrated hydrochloric acid was added till a clear solution was formed at pH ~7. Carbon (7.5 g) was added, the reaction mixture was stirred at 20-25⁰C and filtered. The clear filtrate was slowly

) acidified with the remaining amount of concentrated hydrochloric acid ( 136 g, 1.3 moles) at 2O⁰C and the precipitated solid was stirred at 20-25⁰C for 2h followed by another hour at 0-5⁰C. The product was filtered under nitrogen atmosphere, washed with a mixture of acetonitrile-methanol (1 :1, 150 ml) and dried under reduced pressure at 60-70⁰C till moisture content was less than 2 %. The dry i weight of the product was 97 g, with chromatographic purity >99.7 %.

Claims

WE CLAIM

1 . Λ new crystalline Form A of l -cyclopiOpyl-6-fluoiO-l ,4-diydro-8-mcthoxy-7- | (4aΛ',7a.S')-ociahychO-6/-/-pyπOlo[3,4-Λ]pyridin-6-yl]-4-oxo-3-quinoline having water content below 2% w/w.

2. The new crystalline form as claimed in claim 1 having the following the X-ray diffraction spectrum of which shows peaks at the diffraction angles of about 6.36 ± 0.2, 8.39 ± 0.2, 10.02 ± 0.2, 12.28 ± 0.2, 13.28 ± 0.2, 13.64 ± 0.2, 14.90 ± 0.2, 15.39 ± 0.2, 15.79 ± 0.2, 16.71 ± 0.2, 17.69 ± 0.2, 18.23 ± 0.2, 19.09 ± 0.2, 20.07 ± 0.2, 20.71 ± 0.2, 21.44 ± 0.2, 22.25 ± 0.2, 23.60 ± 0.2, 24.18 ± 0.2, 24.61 ± 0.2, 25.98 ± 0.2, 26.90 ± 0.2, 27.83 ± 0.2, 28.67 ± 0.2, 29.90 ± 0.2, 30.40 ± 0.2, 31 .17 ± 0.2, 32.01 ± 0.2, 32.85 ± 0.2, 38.24 ± 0.2 two theta degrees.

3. Crystalline Moxifloxacin hydrochloride (Form A) of claim 1 which is characterized by infrared absorption spectrum pattern having characteristic peaks at 1455, 1515, 1621 , 1701 , 3521 and 3354 cm^"1

4. Crystalline Moxifloxacin hydrochloride (Form A) of claim 1 , having an endotherm at 64.9 ⁰C and melting endotherm at 241.7 ⁰C.

5. A process for the preparation of the new crystalline form of Moxifloxacin hydrochloride (Form A) with moisture content below 2% w/w, comprising;

OH _HC| Formula

reacting (l-cyclopiOpyl-6J-difluoro-l,4-dihydro-8-methoxy-4-(oxo-/cO)- 3-quinolinecarboxylato-/t0³)di(luoroboiOn (111)

⁷ormula III

with (4a5,7a,S^<)octahydiO- lH-pyiτolo[3,4-&]pyridine (IV)

Formula IV

in presence of a base (s) in an organic solvent (s) to produce (1- cyclopiOpyl-6-fluoiO-l,4-dihydiO-8-methoxy-7-[(4aLS^r,7a5')-octahydiO- 6/-/-pyrrolo[3,4-6]pyridin-6-yl]-4-(oxo-/c(9)-3-quinolinecarboxylato- /cO^J)difluoroboiOn ( Moxifloxacin boron difluoride chelate (V)),

Formula V

cleaving of Moxifloxacin boron difluoride chelate (V) using an organic base in a solvent to produce Moxifloxacin, which on reaction with hydrochloric acid in presence of solvent mixture gives Moxifloxacin hydrochloride Form A;

6. The process of claim 5 wherein the organic solvent used in step (i) is selected from acetonitrile, methanol, ethanol, isopropanol, butanol.

8. The process of claim 5 wherein the organic base used in step (i) is selected from triethylamine, diisopropylamine, DBU, DABCO.

9 The process of claim 5 wherein the solvent used in step (ii) is selected from methanol, ethanol, isopropanol, butanol.

10 The process of claim 5 wherein the preferred solvent mixture used in hydrochloride preparation is selected from acetonitrile, methanol, ethanol, propanol, isopropanol, butanol or mixtures thereof.

1 1. The process of claim 5, wherein the Moxifloxacin borondifluoride chelate (V) is isolated before converted to Moxifloxacin.

12. The process of claim 5, wherein the Moxifloxacin borondifluoride chelate (V) is not isolated from the reaction mixture and directly converted to Moxifloxacin.

13. A process for the preparation of the new crystalline form of Moxifloxacin hydrochloride (Form A) with moisture content below 2% w/w, comprising; i) ^' suspending Moxifloxacin hydrochloride in a solvent -mixture; ii) treating the mixture with base; iii) separating the layers and distilled off the solvent to produce residue; iv) treating the residue with dry hydrochloric acid in a solvent; v) isolating crystalline Form A of Moxifloxacin. 14^'. '[^'he process of claim 13, wherein solvent mixture selected from water, methylene chloride, chloroform, ethylacetate, tolune.

15. The process of claim 13, wherein the base is selected from inorganic base such 5 as sodium hydroxide, potassium hydroxide, aqueous ammonia.

16. The process of claim 13, wherein solvent used in step (iv) is selected from methanol, ethanol, propanol, butanol, isopropanol.

17. ( 1 -cyclopropyl-ό-fluoro-l ,4-dihydiO-8-methoxy-7-[(4a5',7a_lS^r)-octahydro-6//- [ 0 pyriOlo[3,4-6]pyridin-6-yl]-4-(oxo-A-O)-3-quinolinecarboxylato-/fO³)- difluoro boron of Formula (V)

Γ rormu .la v V

18. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of Moxifloxacin hydrochloride according, to claim 1 and a 15 pharmaceutically acceptable carrier.