WO2013153558A1 - Forme anhydre de chlorhydrate de moxifloxacine - Google Patents

Forme anhydre de chlorhydrate de moxifloxacine Download PDF

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Publication number
WO2013153558A1
WO2013153558A1 PCT/IN2013/000231 IN2013000231W WO2013153558A1 WO 2013153558 A1 WO2013153558 A1 WO 2013153558A1 IN 2013000231 W IN2013000231 W IN 2013000231W WO 2013153558 A1 WO2013153558 A1 WO 2013153558A1
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WO
WIPO (PCT)
Prior art keywords
moxifloxacin hydrochloride
anhydrous form
hygroscopic
moxifloxacin
hygroscopic anhydrous
Prior art date
Application number
PCT/IN2013/000231
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English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Bandi Vamsi Krishna
Original Assignee
Hetero Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2013153558A1 publication Critical patent/WO2013153558A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic 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
    • C07D471/02—Heterocyclic 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel non-hygroscopic anhydrous Form of moxifloxacin hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
  • Moxifloxacin and its salts are antibacterial agents, which were disclosed in European patent no. 550,903.
  • Moxifloxacin, chemically l-cyclopropyl-6-fluoro-l ,4- dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl]-4-oxo-3- quinolinecarboxylic acid, is represented by the following structure:
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
  • polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules.
  • Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
  • Moxifloxacin and its hydrochloride salt can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • U.S. patent no. 7,230,006 disclosed anhydrous Form III of moxifloxacin hydrochloride and 2 ⁇ values are 5.6, 7.1 , 8.4, 8.8, 10.0, 10.4, 1 1.4, 12.2, 13.1 , 13.9, 14.4, 14.7, 16.6, 16.9, 17.2, 17.7, 18.5, 19.1, 19.2, 19.8, 20.1, 20.3, 21.1 , 21.5, 22.1, 22.6, 22.9, 23.5, 24.0, 24.6, 24.9, 25.8, 26.2, 26.6, 26.9, 27.2, 28.7, 29.1, 29.7, 30.1, 31.4, 32.1, 37.3, 39.0, 40.8, 41.5, 42.2 and 43.1 ⁇ 0.09 degrees.
  • WO patent application publication No. 04/039804 disclosed amorphous form of moxifloxacin hydrochloride.
  • WO 2005/054240 disclosed two novel crystalline forms which were designated as Form A and Form B of moxifloxacin hydrochloride.
  • WO patent application publication No. 2007/010555 disclosed two crystalline forms which were Form X and Form Y of moxifloxacin hydrochloride. According to '555 patent, Form Y was obtained by crystallization of moxifloxacin hydrochloride from the mixture of methanol and water in the ratio of about 9: 1 by volume.
  • WO patent application publication No. 2007/148137 ( ⁇ 37 patent) disclosed hydrate form of moxifloxacin hydrochloride.
  • moxifloxacin hydrochloride monohydrate was obtained by crystallization moxifloxacin hydrochloride by humidification of moxifloxacin hydrochloride at 50-90 % relative humidity at 25-60°C for 8 to 24 hours.
  • WO patent application publication No. 2008/028959 disclosed crystalline form of moxifloxacin hydrochloride.
  • moxifloxacin hydrochloride was obtained by dissolving moxifloxacin hydrochloride in a mixture of methanol and water and adding acetone and recovering moxifloxacin hydrochloride crystalline form.
  • WO patent application publication No. 2008/059521 disclosed process for the preparation of anhydrous crystalline form I of moxifloxacin hydrochloride.
  • WO patent application publication No. 2008/095964 disclosed crystalline form of moxifloxacin base.
  • novel non-hygroscopic anhydrous Form of moxifloxacin hydrochloride is stable, reproducible and so, the novel non-hygroscopic anhydrous Form is suitable for formulating moxifloxacin hydrochloride.
  • an object of the present invention is to provide a novel non-hygroscopic anhydrous Form of moxifloxacin hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention there is provided a novel non-hygroscopic anhydrous Form of moxifloxacin hydrochloride designated as Form HI characterized by powder x-ray diffractogram (PXRD) having peaks expressed as 2 ⁇ at about 5.7, 7.2, 8.8, 10.5, 11.4, 14.4, 14.7, 17.7, 19.3 and 24.6 ⁇ 0.2 degrees.
  • a process for the preparation of moxifloxacin hydrochloride non-hygroscopic anhydrous Form HI which comprises:
  • step (b) drying the solid obtained in step (b) at about 80 to 110°C under reduced pressure to obtain moxifloxacin hydrochloride non-hygroscopic anhydrous Form HI .
  • the present invention provides a pharmaceutical composition comprising non-hygroscopic anhydrous Form HI of moxifloxacin hydrochloride and pharmaceutically acceptable excipients.
  • Figure 1 is an X-ray powder diffraction spectrum of moxifloxacin hydrochloride non-hygroscopic anhydrous Form HI .
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.019 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
  • room temperature refers to temperature at about 25 to 35°C.
  • Form HI a novel non- hygroscopic anhydrous Form of moxifloxacin hydrochloride designated as Form HI characterized by powder x-ray diffractogram (PXRD) having peaks expressed as 2 ⁇ at about 5.7, 7.2, 8.8, 10.5, 11.4, 14.4, 14.7, 17.7, 19.3 and 24.6 ⁇ 0.2 degrees..
  • PXRD powder x-ray diffractogram
  • the Form HI may be identified and differentiated from the known polymorphs by its characteristic PXRD pattern.
  • a peak at 8.4 ⁇ 0.09 and 10.0 ⁇ 0.09 degrees 2 ⁇ are absent in the PXRD of the Form HI of the present invention, but are present in the PXRD of the moxifloxacin hydrochloride anhydrous Form III disclosed in the US Patent No. 7,230,006.
  • a peak at 7.2 ⁇ 0.2 degrees 2 ⁇ is present and a peaks at 8.5 ⁇ 0.2 and 10.1 ⁇ 0.2 degrees 2 ⁇ are absent in the PXRD of the Form HI of the present invention, but the peak at 7.2 ⁇ 0.2 degrees 2 ⁇ is absent and a peaks at 8.5 ⁇ 0.2 and 10.1 ⁇ 0.2 degrees 2 ⁇ are present in the PXRD of the moxifloxacin hydrochloride monohydrate disclosed in the US Patent No. 5,849,752.
  • step (b) drying the solid obtained in step (b) at about 80 to 1 10°C under reduced pressure to obtain moxifloxacin hydrochloride non-hygroscopic anhydrous Form HI .
  • the solid may be isolated in step (b) by methods known such as filtration or centrifugation.
  • Drying in step (c) may preferably be carried out at about 90 to 100°C under reduced pressure.
  • the drying may be performed under vacuum.
  • reduced pressure refers to a pressure of less than 100 mmHg.
  • a pharmaceutical composition comprising non-hygroscopic anhydrous Form HI of moxifloxacin hydrochloride and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the anhydrous Form HI may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • Moxifloxacin hydrochloride monohydrate (25 gm; Moisture content: 3.4 - 3.6%) was dissolved in n-butanol (125 ml) and then heated to reflux. The solution was maintained for 4 hours at reflux and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid thus obtained was then dried at 90 to 95°C under vacuum for 7 hours to obtain 22 gm of moxifloxacin hydrochloride non-hygroscopic anhydrous Form HI.
  • Example 2 Example 2:
  • Moxifloxacin hydrochloride anhydrous Form (5 gm) as obtained by the process described in US 5,849,752 was dissolved in n-butanol (24 ml) and then heated to reflux. The solution was maintained for 4 hours at reflux and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid thus obtained was then dried at 95 to 100°C under vacuum for 6 hours to obtain 4.5 gm of moxifloxacin hydrochloride non-hygroscopic anhydrous Form H I .
  • Moxifloxacin hydrochloride anhydrous Form (5 gm) as obtained by the process described in US 7,230,006 was dissolved in n-butanol (25 ml) and then heated to reflux. The solution was maintained for 4 hours at reflux and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid thus obtained was then dried at 90 to 95°C under vacuum for 6 hours to obtain 4.4 gm of moxifloxacin hydrochloride non-hygroscopic anhydrous Form HI .
  • the p H of the reaction mass was adjusted to 7.5 to 8.0 with ammonia and then the layers were separated.
  • the aqueous layer was extracted with methylene chloride. Combined organic layer were then concentrated to obtain a residual solid.
  • To the residual solid was added water (50 ml) and methanol (210 ml).
  • the pH of the reaction mass was adjusted to 1.0 to 2.0 with hydrochloric acid and maintained for 1 hour 30 minutes at room temperature.
  • the reaction mass was then cooled to 0 to 5°C and then added n-butanol (250 ml).
  • the reaction mass was then heated to reflux and maintained for 4 hours.
  • the solution was then cooled to room temperature and stirred for 1 hour.
  • the separated solid was filtered and then dried at 90 to 95°C under vacuum for 5 hours to obtain 43 gm of moxifloxacin hydrochloride non-hygroscopic anhydrous Form HI .

Abstract

La présente invention concerne une nouvelle forme anhydre et non hygroscopique de chlorhydrate de moxifloxacine, un procédé pour sa préparation et une composition pharmaceutique la contenant.
PCT/IN2013/000231 2012-04-09 2013-04-08 Forme anhydre de chlorhydrate de moxifloxacine WO2013153558A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1397CH2012 2012-04-09
ININ1397/CHE/2012 2012-04-09

Publications (1)

Publication Number Publication Date
WO2013153558A1 true WO2013153558A1 (fr) 2013-10-17

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050137227A1 (en) * 2003-04-09 2005-06-23 Dr. Reddy's Laboratories Limited Crystalline form III of anhydrous moxifloxacin hydrochloride and a process for preparation thereof
EP2083010A1 (fr) * 2008-01-08 2009-07-29 Chemo Ibérica, S.A. Formes polymorphes d'hydrochlorure de moxifloxacine et leurs procédés de préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050137227A1 (en) * 2003-04-09 2005-06-23 Dr. Reddy's Laboratories Limited Crystalline form III of anhydrous moxifloxacin hydrochloride and a process for preparation thereof
EP2083010A1 (fr) * 2008-01-08 2009-07-29 Chemo Ibérica, S.A. Formes polymorphes d'hydrochlorure de moxifloxacine et leurs procédés de préparation

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