WO2011121596A2 - Crystal modification of moxifloxacin hydrochloride - Google Patents

Crystal modification of moxifloxacin hydrochloride Download PDF

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Publication number
WO2011121596A2
WO2011121596A2 PCT/IN2010/000220 IN2010000220W WO2011121596A2 WO 2011121596 A2 WO2011121596 A2 WO 2011121596A2 IN 2010000220 W IN2010000220 W IN 2010000220W WO 2011121596 A2 WO2011121596 A2 WO 2011121596A2
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moxifloxacin hydrochloride
moxifloxacin
crystalline
according
form β
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PCT/IN2010/000220
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French (fr)
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WO2011121596A3 (en
Inventor
Arul Ramakrishnana
Sreenivasulu Pamujula
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Neuland Laboratories Ltd.
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Publication of WO2011121596A3 publication Critical patent/WO2011121596A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Abstract

The present invention related to novel polymorphic forms of Moxifloxacin hydrochloride and an improved industrially viable, cost effective process for their manufacturing.

Description

CRYSTAL MODIFICATION OF

MOXIFLOXACIN HYDROCHLORIDE

FIELD OF THE INVENTION

The present invention relates to novel crystal modifications of Moxifloxacin hydrochloride, processes for their preparation and their pharmaceutical composition.

BACKGROUND OF THE INVENTION

Moxifloxacin of formula I is an antibiotic from the class of the fluoroquinolonecarboxylic acids. It is chemically known as l-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-l,4- dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid.

Figure imgf000002_0001

I

It is a synthetic broad spectrum, anti-infective agent, widely used in the treatment of infections by antibiotic -resistant bacteria and highly effective against bacteria which are resistant to penicillin's and macrolides.

Moxifloxacin was first described for the first time in EP-A-0 350 733. However, EP0350733 does not describe any crystal modification of it. The hydrochloride salt of Moxifloxacin is the marketed salt whose preparation is disclosed in EP550903A.

US5849752 discloses two crystal modification of Moxifloxacin hydrochloride, anhydrous and specific monohydrate form of Moxifloxacin and their process for preparation. This patent also mentions that the anhydrous modification is not entirely satisfactory in the preparation of various medicament forms. Moxifloxacin hydrochloride is hygroscopic and absorbs water under adverse storage conditions and during pharmaceutical formulation. On the other hand monohydrate form doesn't have disadvantage of being hygroscopic and can be prepared in crystalline prism form, which is significantly more free-flowing than the monohydrate in the needle form.

WO 2004091619 describes a polymorphic Form III of anhydrous Moxifloxacin hydrochloride. An amorphous form of Moxifloxacin hydrochloride and its process for preparation by using a spray- drying or freeze-drying technique of a Moxifloxacin hydrochloride solution is disclosed in WO2004039804.

WO2005054240 describes two anhydrous crystalline forms Form A and Form B of Moxifloxacin hydrochloride and their preparation. WO2006134491 reports a crystalline form of Moxifloxacin hydrochloride, designated as Form A, having a moisture content of 1 to 2 % w/w amounting closely to hemihydrate. A process for the preparation of this crystalline Form A involving an environmentally hazardous boron difluoride chelate, is also disclosed.

WO2007010555 provides two anhydrous . crystalline forms of Moxifloxacin hydrochloride, designated as Form X and Form Y, and processes for their preparation. WO2007/148137 discloses a hydrate form of Moxifloxacin hydrochloride and a process for the preparation thereof comprising humidification of one or more forms of Moxifloxacin hydrochloride.

WO 2008/028959 discloses a sesquihydrate form of moxifloxacin hydrochloride and a process for the preparation thereof.

The discovery of novel polymorphic forms of a pharmaceutically useful compound is always desired to improve the performance characteristics of a pharmaceutical product. The present inventors found that Moxifloxacin hydrochloride can be converted into new monohydrate crystalline modification, which has better stability, as compared to the known forms, and are particularly suitable for the preparation of stable pharmaceutical formulations, and have better flowability and suitable rate of dissolution in aqueous fluid.

SUMMARY OF THE INVENTION

The principal aspect of the invention is to provide a novel crystal modification of Moxifloxacin hydrochloride monohydrate, herein referred to as Form β. The Moxifloxacin hydrochloride monohydrate crystalline Form β is characterized by an XRPD (X-ray powder diffraction) pattern comprising peaks at about 5.8024, 8.4866, 10.0924, 10.4429, 1 1.5849, 13.4039, 14.4529, 14.7400, 15.5922, 16.9760, 17.3841, 17.91 19, 18.5255, 19.0767, 19.6279, 20.3619, 21.0970, 22.6650, 22.9170, 23.6037, 24.0888, 24.4682, 25.0633, 25.9257, 26.4559, 27.4564, 27.7408, 28.4188, 28.8227, 29.1421, 29.6222, 30.0545, 30.7650, 31.3923, 32.5137, 33.3306,34.1244, 35.1223, 36.7192, 37.5152, 38.5604, 39.2922, 39.8568, 40.7870, 41.8697, 44.2453,45.0861, 45.5579, 46.2635, 49.1749 ± 0.2° 2Θ. It is further characterised by having a solid-state 13C NMR spectrum with chemical shift (δ) at about 21.881, 34.205, 39.199, 46.126, 48.865, 51.765, 55.148, 58.531, 63.042, 65.539, 104.283, 106.539, 1 15.721, 1 16.688, 134.328, 136.584, 139.886, 142.625, 148.988, 150.438, 166.709, and 174.764 ppm. It may be further characterised by a DSC endotherm maximum peak at about 252.42 °C.

Another aspect of the invention is to provide a novel crystal modification of anhydrous Moxifloxacin hydrochloride, herein referred to as Form γ. The anhydrous Moxifloxacin hydrochloride crystal Form γ is characterized by an XRPD pattern comprising peaks at about 3.2267, 6.4004, 8.4426, 10.0809, 12.3330, 12.7358, 13.3286, 13.7186, 14.9276, 15.4333, 15.9454, 16.7090, 16.8625, 17.7161, 18.2921, 19.0993, 20.1476, 20.5470, 20.7709, 21.5376, 22.2521, 22.7464, 23.6324, 24.1976, 24.6930, 25.2964, 26.0932, 26.7327, 26.9714, 27.3137, 27.8648, 28.6805, 29.9685, 30.3799, 31.1279, 32.0863, 32.8637, 34.3804, 34.8566, 35.3924, 36.4482, 38.3063, and 39.6230 ± 0.2° 2Θ. It is further characterised by a DSC endotherm maximum peak at about 254.34 °C.

Another aspect of the invention is to provide a process for the preparation of Moxifloxacin hydrochloride monohydrate crystal Form β comprising:

a) converting moxifloxacin base to moxifloxacin hydrochloride;

b) dissolving moxifloxacin hydrochloride in an aqueous alcohol;

c) optionally treating with activated carbon;

d) washing with alcohol and water;

e) heating the obtained product to make a solution and adding hydrochloric acid; f) cooling the product slowly, filtering and washing with chilled aqueous alcohol; and g) drying and sieving the material to obtain Form β of moxifloxacin hydrochloride monohydrate.

Another aspect of the invention is to provide a process for the preparation of anhydrous Moxifloxacin hydrochloride crystal Form γ comprising:

a) converting moxifloxacin base to moxifloxacin hydrochloride;

b) dissolving moxifloxacin hydrochloride in an aqueous alcohol;

c) optionally treating with activated carbon; d) washing with alcohol and water;

e) heating the obtained product to make a solution;

f) cooling the product slowly, filtering and washing with chilled aqueous alcohol; and g) drying and sieving the material to obtain Form γ of anhydrous moxifloxacin hydrochloride.

Another aspect of the invention is to provide use of Moxifloxacin hydrochloride monohydrate Form β for the preparation of a medicament for the treatment of infections.

Yet another aspect of the invention is to provide a pharmaceutical composition comprising the Moxifloxacin hydrochloride monohydrate Form β optionally with at least one pharmaceutically acceptable excipients.

Another aspect of the invention is to provide use of anhydrous Moxifloxacin hydrochloride Form γ for the preparation of a medicament for the treatment of infections.

Yet another aspect of the invention is to provide a pharmaceutical composition comprising ihe anhydrous Moxifloxacin hydrochloride Form γ optionally together with at least one pharmaceutically acceptable excipients.

Brief Description of the Drawings

Figure 1 shows an XRPD pattern of Form β of Moxifloxacin hydrochloride monohydrate;

Figure 2 shows a DSC thermogram of Form β of Moxifloxacin hydrochloride monohydrate; Figure 3 shows a solid-state 13C NMR spectrum of Moxifloxacin hydrochloride monohydrate Figure 4 shows IR spectrum of Moxifloxacin hydrochloride monohydrate

Figure 5 shows an XRPD pattern of Form γ of anhydrous Moxifloxacin hydrochloride;

Figure 6 shows a DSC thermogram of Form γ of anhydrous Moxifloxacin hydrochloride;

Detailed description of the invention

Accordingly in an embodiment, the present invention provides a novel crystalline Moxifloxacin hydrochloride monohydrate herein designated as Form β and a process for its preparation.

In another embodiment, the present invention provides a novel crystalline anhydrous Moxifloxacin hydrochloride herein designated as Form γ and a process for its preparation.

In another embodiment, the crystalline Form β of Moxifloxacin hydrochloride monohydrate as well as Form γ of anhydrous Moxifloxacin hydrochloride are stable and non-hygroscopic. These forms don't absorb moisture under adverse storage conditions and during pharmaceutical processing of the active ingredient into medicament forms. They have good handling properties and higher physical stability compared with the prior art known anhydrous crystal modification. They have considerable advantages in the formulation of a medicament. The use of this non-hygroscopic crystalline form provides a good dosing accuracy during the preparation of medicaments, which in turn increases safety and minimizes the risk to the patient.

In another embodiment, the novel crystalline Form β has a water content of about 3.5-4.2 % w/ w, preferably 4.00% w/w as analysed by Karl Fisher method where as the water content of anhydrous Moxifloxacin hydrochloride Form γ has water content less than 0.1% preferably it is less than 0.7%. ,

In another embodiment, the novel crystalline Form β of Moxifloxacin hydrochloride monohydrate is characterised by XRPD, DSC, solid state 13C NMR and IR analysis and novel crystalline Form γ of anhydrous Moxifloxacin hydrochloride is characterised by XRPD and DSC. XRPD analysis was performed on a PANALYTICAL Xpert Pro powder automatic diffractometer at 20 °C temperature, using a CuK a tube (45 kV, 40 mA, λ = 1.5418 A) as the X-ray source. Data collection was made in 2Θ step scan mode, at a scan speed of 0.02% in the range of 2.5° to 50° in 2Θ. Approximately 100 mg samples were accurately grinded and placed on an aluminium sampler.

DSC thermal analysis was performed on a Perkin Elmer Jade differential scanning calorimeter. Samples were placed in aluminium pans and heated from 50 to 300 °C in a dry nitrogen atmosphere at a heating rate of 10°C/minute.

The 13C NMR spectra were measured on a Bruker Avance 400 MHz NMR spectrometer, equipped with a 4 mm MAS probe. Data points were acquired with a recycling time of 5 seconds, using a contact time of 400 microseconds and a spinning rate of 12 KHz. The IR spectrum was measured by KBr pellet using a Perkin-Elmer Spectrum one FT-IR spectrometer.

In another embodiment of the invention, the novel crystalline moxifloxacin hydrochloride monohydrate Form β is characterized by XRPD (X-ray powder diffraction) pattern comprising peaks at about 5.8024, 8.4866, 10.0924, 10.4429, 1 1.5849, 13.4039, 14.4529, 14.7400, 15.5922, 16.9760, 17.3841, 17.9119, 18.5255, 19.0767, 19.6279, 20.3619, 21.0970, 22.6650, 22.9170, 23.6037, 24.0888, 24.4682, 25.0633, 25.9257, 26.4559, 27.4564, 27.7408, 28.4188, 28.8227, 29.1421, 29.6222, 30.0545, 30.7650, 31.3923, 32.5137, 33.3306,34.1244, 35.1223, 36.7192, 37.5152, 38.5604, 39.2922, 39.8568, 40.7870, 41.8697, 44.2453,45.0861, 45.5579, 46.2635, 49.1749 ± 0.2° 2Θ, as depicted in Figure 1. It is further characterised by having a solid-state 13C NMR spectrum with chemical shift (δ) at about 21.881, 34.205, 39.199, 46.126, 48.865, 51.765, 55.148, 58.531, 63.042, 65.539, 104.283, 106.539, 1 15.721, 116.688, 134.328, 136.584, 139.886, 142.625, 148.988, 150.438, 166.709, and 174.764 ppm, as depicted in Figure 3. It may be further characterised by a DSC endotherm maximum peak at about 252.42 °C, as depicted in Figure 1. The Form β is still additionally characterised by an infrared spectrum having the peaks at 3529.09, 3471.24, 2952.48, 2926.45, 2810.77, 2830.03, 2796.28, 2775.06, 2745.17, 2693.1,2672.86, 2634.29, 261 1.14, 2567.75, 2524.36, 2454.94, 2426.01, 1708.62, 1622.8, 1515.78, 1455.03, 1394.28, 1372.1 , 1352.82, 1320.04, 1281.47, 1262.18, 1247.72, 1 184.08, 1162.87, 11 14.65, 1105.01, 1081.87, 1045.23, 1024.98, 994.125, 970.983, 956.52, 937.235, 912.165, 888.059, 874.56, 860.096, 834.062, 803.206, 773.315, 733.782, 721.247, 682.677, 649.893, 635.43, 625.788, 592.039, 568.898, 555.398, 544.792, 525.507, 513.936, 494.652, 475.367,458.01 1, and 418.477 cm"1 as depicted in Figure 4.

In another embodiment of the invention, the novel crystalline anhydrous moxifloxacin hydrochloride Form γ is characterized by XRPD (X-ray powder diffraction) pattern comprising peaks at about 3.2267, 6.4004, 8.4426, 10.0809, 12.3330, 12.7358, 13.3286, 13.7186, 14.9276, 15.4333, 15.9454, 16.7090, 16.8625, 17.7161, 18.2921, 19.0993, 20.1476, 20.5470, 20.7709, 21.5376, 22.2521, 22.7464, 23.6324, 24.1976, 24.6930, 25.2964, 26.0932, 26.7327, 26.9714, 27.3137, 27.8648, 28.6805, 29.9685, 30.3799, 31.1279, 32.0863, 32.8637, 34.3804, 34.8566, 35.3924, 36.4482, 38.3063, and 39.6230 ± 0.2° 2Θ, as depicted in Figure 5. It may be further characterised by a DSC endotherm maximum peak at about 254.32 °C, as depicted in Figure 6.

In further embodiment moxifloxacine base used for the preparation of crystalline Moxifloxacin hydrochloride monohydrate Form β and crystalline anhydrous Moxifloxacin hydrochloride Form γ, is prepared as per the process available in prior art or according to the process disclosed by the applicant in PCT publication WO2009/12545. Moxifloxacin base is converted to moxifloxacin hydrochloride in presence of an aqueous alcoholic solvent, hydrochloric acid and (Ethylenedinitrilo) tetraacetic acid disodium salt (EDTA disodium salt). The alcoholic solvent used in this process is selected from methanol, ethanol, propanol, isopropanol and the like. Preferably the alcoholic solvent is methanol. Most preferably the solvent used is 50 % aqueous methanol. Moxifloxacin base, hydrochloric acid and EDTA disodium salt are heated in aqueous alcoholic solvent in the temperature range of 25 to 60 oC preferably in the range of 30 to 50 oC and most preferably in the range of 34-38 oC. Further the content is cooled to 0-5 °C and maintained for 2 hours preferably 1 hour. The obtained product is filtered and washed with chilled methanol to obtain moxifloxacin hydrochloride as wet material. The obtained wet material is further dissolved in mixture of water and an alcoholic solvent preferably methanol in the temperature range of 50 to 75 °C, preferably in 55-60 °C. The activated carbon is used optionally to remove the color impurity.

In still further embodiment in step (e) the product is heated to about 55 °C to get a clear solution and cooled slowly to 40- 45 °C and hydrochloric acid is added. The content is slowly cooled to 0-5 °C and maintained for 1 hour. The product is filtered and washed repeatedly with chilled aqueous methanol, dried at 50-55 °C and sieved and again dried at 45-55 °C to obtain Moxifloxacin hydrochloride monohydrate Form β with HPLC purity greater than 99.5 % and less than 0.5 % of the other isomer.

In still further embodiment in step (e) the product is heated to about 55 °C to get a clear solution and cooled slowly to 40- 45 °C. The content is slowly cooled to 0-5 °C and maintained for 1 hour. The product is filtered and washed repeatedly with chilled aqueous methanol, dried at 50-55 °C and sieved and again dried at 45-55 °C to obtain anhydrous Moxifloxacin hydrochloride Form γ with HPLC purity greater than 99.5 % and less than 0.5 % of the other isomer.

In still further embodiment this invention also relates to pharmaceutical formulations, which comprises Moxifloxacin hydrochloride monohydrate Form β according to this invention. The formulation can be in the form of suspension, emulsion, tablets, coated tablets, coated tablets cores, suppositories, hard or soft gelatin capsules and the like. The moxifloxacin hydrochloride monohydrate Form β can be used along with one or more pharmaceutical excipients to form a formulation. The pharmaceutical compositions containing Moxifloxacin hydrochloride monohydrate Form β can be prepared in a manner well known in the art. The amount of the compound actually needed to administer will be typically determined by the physician according to the relevant circumstances, including the condition to be treated, the chosen route of administration and and age , weight and response of the individual patient. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose. The invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example-1: Preparation of Form β of Moxifloxacin hydrochloride monohvdrate

Moxifloxacin base (85 g) was taken in methanol (428 mL) and purified water (258 mL) followed by the addition of Hydrochloric acid (29.1 g) and EDTA disodium salt (95 mg).The content was heated to 34-38 °C and maintained for one hour. The content was cooled to 0-5 °C and maintained for 1 hour. The product was filtered and washed with chilled methanol (85 mL) to obtain a wet material. The obtained wet material was heated in methanol (428 mL) and water (428mL) to 55-60 °C. Activated carbon (8.5 g) was added and the content was maintained at 55-60 °C for 30 min. The content was filtered hot and washed with hot methanol- water mixture (44 mL+44 mL). The filtrate was again heated to 55 °C to get a clear solution, cooled slowly to 40-45 °C and hydrochloric acid (11.2 g) was added. The content was cooled slowly to 0-5°C and maintained for 1 hour. The product was filtered, washed with chilled methanol & water thrice and dried at 50 to 55 °C for two hours. The material was sieved and dried further under vacuum at 45to 55 °C for 30 hours.

Dry weight (90 g) and yield (72.43%)

Example-2: Preparation of Form γ of anhydrous Moxifloxacin hydrochloride

Moxifloxacin base (200 g) was taken in methanol (1000 mL) and purified water (600 mL) followed by the addition of Hydrochloric acid (68.8 g) and EDTA disodium salt (240 mg).The content was heated to 35-38 °C and maintained for one hour. The content was cooled to 0-5°C and maintained for 1 hour. The product was filtered and washed with chilled methanol (200 mL) to obtain a wet material. The obtained wet material was heated in methanol (1000 mL) and water (600 mL) to 55-60 °C. Activated carbon (20 g) was added and the content was maintained at 55-60 °C for 30 min. The content was filtered hot and washed with hot methanol (200 mL). The filtrate was cooled to 20-25 °C. and stirred for 1 hr at this temperature. The content was further cooled to 0-5°C and maintained for 1 hour. The product was filtered; suck dried and stirred it into 200 mL methanol for 30 minutes. The compound was filtered, washed with chilled methanol (50 mL) and dried at 80 to 85 °C for twelve hours. The material was sieved and dried further under vacuum at 80 to 85 °C for 36 hours.

Dry weight (108 g) and yield (54.0%)

Claims

We claim:
1. Crystalline Moxifloxacin hydrochloride monohydrate Form β characterized by an XRPD (X-ray powder diffraction) pattern comprising peaks at about 5.8024, 8.4866, 10.0924, 10.4429, 11.5849, 13.4039, 14.4529, 14.7400, 15.5922, 16.9760, 17.3841, 17.9119, 18.5255, 19.0767, 19.6279, 20.3619, 21.0970, 22.6650, 22.9170, 23.6037, 24.0888, 24.4682, 25.0633, 25.9257, 26.4559, 27.4564, 27.7408, 28.4188, 28.8227, 29.1421, 29.6222, 30.0545, 30.7650, 31.3923, 32.5137, 33.3306,34.1244, 35.1223, 36.7192, 37.5152, 38.5604, 39.2922, 39.8568, 40.7870, 41.8697, 44.2453,45.0861, 45.5579, 46.2635, 49.1749 ± 0.2° 2Θ and having a solid-state 13C NMR spectrum with chemical shift (δ) at about 21.881, 34.205, 39.199, 46.126, 48.865, 51.765, 55.148, 58.531, 63.042, 65.539, 104.283, 106.539, 115.751, 116.688, 134.328, 136.584, 139.886, 142.625, 148.988, 150.438, 166.709, and 174.764 ppm.
2. Crystalline Moxifloxacin hydrochloride monohydrate Form β according to claim 1, characterised by X-ray powder diffraction pattern substantially in accordance with figure 1.
3. Crystalline Moxifloxacin hydrochloride monohydrate Form β according to claim 1, characterised by a solid -state 13C NMR Spectrum substantially in accordance with figure 3.
4. Crystalline Moxifloxacin hydrochloride monohydrate Form β according to claim 1, characterised by differential scanning calorimetry endothermic maximum peak at about 252.42 °C.
5. Crystalline Moxifloxacin hydrochloride monohydrate Form β according to claim 1 to 4, characterised by a differential scanning calorimetry thermogram substantially in accordance with figure 2.
6. A process for the preparation of crystalline Moxifloxacin hydrochloride monohydrate Form β according to claim 1, which comprises:
a) converting moxifloxacin base to moxifloxacin hydrochloride;
b) dissolving moxifloxacin hydrochloride in an aqueous alcohol;
c) treating with activated carbon optionally;
d) washing with alcohol and water;
e) heating the obtained product to make solution and adding hydrochloric acid; f) cooling the product slowly, filtering and washing with chilled aqueous alcohol; and g) drying and sieving the material to obtain Form β of moxifloxacin hydrochloride monohydrate.
7. A process according to claim 6 wherein, moxifloxacin base is converted to moxifloxacin hydrochloride in presence of an aqueous alcoholic solvent, hydrochloric acid and EDTA disodium salt.
8. A process according to claim 6 to 7 wherein, the alcoholic solvent is selected from methanol, ethanol, propanol and isopropanol.
9. A process according to claim 6 to 8 wherein, the alcoholic solvent is methanol.
10. Crystalline anhydrous Moxifloxacin hydrochloride Form γ characterized by an XRPD (X-ray powder diffraction) pattern comprising peaks at about 3.2267, 6.4004, 8.4426, 10.0809, 12.3330, 12.7358, 13.3286, 13.7186, 14.9276, 15.4333, 15.9454, 16.7090, 16.8625, 17.7161, 18.2921, 19.0993, 20.1476, 20.5470, 20.7709, 21.5376, 22.2521, 22.7464, 23.6324, 24.1976, 24.6930, 25.2964, 26.0932, 26.7327, 26.9714, 27.3137, 27.8648, 28.6805, 29.9685, 30,3799, 31.1279, 32.0863, 32.8637, 34.3804, 34.8566, 35.3924, 36.4482, 38.3063, and 39.6230 ± 0.2° 2Θ and/or characterised by differential scanning calorimetry endothermic maximum peak at about 254.34 °C.
1 1. Crystalline anhydrous Moxifloxacin hydrochloride Form γ according to claim 10, characterised by X-ray powder diffraction pattern substantially in accordance with figure 5. >
12. Crystalline anhydrous Moxifloxacin hydrochloride Form γ according to claim 10 to 11, characterised by a differential scanning calorimetry thermogram substantially in accordance with figure 6.
13. A process for the preparation of crystalline anhydrous Moxifloxacin hydrochloride Form γ according to claim 10, which comprises:
h) converting moxifloxacin base to moxifloxacin hydrochloride;
i) dissolving moxifloxacin hydrochloride in an aqueous alcohol;
j) treating with activated carbon optionally;
k) washing with alcohol and water;
1) heating the obtained product to make solution;
m) cooling the product slowly, filtering and washing with chilled aqueous alcohol; and n) drying and sieving the material to obtain Form β of moxifloxacin hydrochloride monohydrate.
14. A process according to claim 13 wherein, moxifloxacin base is converted to moxifloxacin hydrochloride in presence of an aqueous alcoholic solvent, hydrochloric acid and EDTA disodium salt.
15. A process according to claim 13 to 14 wherein, the alcoholic solvent is selected from methanol, ethanol, propanol and isopropanol.
16. A process according to claim 13 to 15 wherein, the alcoholic solvent is methanol.
17. Use of the Moxifloxacin hydrochloride monohydrate Form β according to claim 1 to 5 for the preparation of medicament for the treatment of infections.
18. A pharmaceutical composition comprising Moxifloxacin hydrochloride monohydrate Form β according to any of claim 1 to 5 , optionally together with at least one pharmaceutically acceptable excipients.
19. Use of the anhydrous Moxifloxacin hydrochloride Form γ according to claim 10 to 12 for the preparation of medicament for the treatment of infections.
20. A pharmaceutical composition comprising anhydrous Moxifloxacin hydrochloride. Form γ according to claim 10 to 12 for, optionally together with at least one pharmaceutically acceptable excipients.
PCT/IN2010/000220 2010-04-01 2010-04-01 Crystal modification of moxifloxacin hydrochloride WO2011121596A2 (en)

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CN108690021A (en) * 2018-07-09 2018-10-23 宋雪萍 A kind of preparation method and its pharmaceutical composition of moxifloxacin hydrochloride

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