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WO2012001357A1 - Forme cristalline de la prulifloxacine et procédés pour sa préparation - Google Patents

Forme cristalline de la prulifloxacine et procédés pour sa préparation Download PDF

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Publication number
WO2012001357A1
WO2012001357A1 PCT/GB2011/000982 GB2011000982W WO2012001357A1 WO 2012001357 A1 WO2012001357 A1 WO 2012001357A1 GB 2011000982 W GB2011000982 W GB 2011000982W WO 2012001357 A1 WO2012001357 A1 WO 2012001357A1
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Prior art keywords
prulifloxacin
process according
solvent
crystalline form
methyl
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PCT/GB2011/000982
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Inventor
Srinivas Laxminarayan Pathi
Dharmaraj Ramachandra Rao
Rajendra Kankan
Venugopalarao Chinimilli
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Cipla Ltd
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Cipla Ltd
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Priority to GB1301307.3A priority Critical patent/GB2498107A/en
Priority to IN2925MUN2012 priority patent/IN2012MN02925A/en
Publication of WO2012001357A1 publication Critical patent/WO2012001357A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals

Definitions

  • the present invention relates to a crystalline polymorphic form of 6-fluoro-1-methyl-7- ⁇ 4-[(5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl]piperazin-1 -yl ⁇ -4-oxo-4H-[1 ,3]-thiazeto-[3,2- a]-quinoline-3-carboxylic acid (prulifloxacin). More specifically, the invention relates to a crystalline form of prulifloxacin (herein referred to as Form A), and a method for preparing the crystalline Form A. The present invention further provides a pharmaceutical formulation comprising the novel form of prulifloxacin.
  • Prulifloxacin is chemically known as 6-fluoro-1-methyl-7- ⁇ 4-[(5-methyl-2-oxo-1 ,3-dioxol- 4-yl)methyl]piperazin-1-yl ⁇ -4-oxo-4H-[1 ,3]-thiazeto-[3,2-a]-quinoline-3-carboxylic acid, and it has the structure as shown below as formula I:
  • Prulifloxacin has significant antibacterial activity and has been marketed as a synthetic antibacterial agent.
  • Prulifloxacin was first disclosed in US 5,086,049.
  • the patent discloses a process for the preparation of prulifloxacin by the condensation of ulifloxacin with a 4-halomethyl-5- methyl-1 ,3-dioxolen-2-one of formula III wherein X is halo selected form chloro, bromo or iodo, in the presence or absence of an aprotic solvent and a base to obtain prulifloxacin free base which is recrytallised with chloroform-methanol.
  • ethyl 6,7-difluoro-1-methyl-4-oxo-4H- (1 ,3)-thiazeto-(3,2-a)-quinoline-3-carboxylate is condensed with piperazine in the presence of dimethyl formamide and purified by column chromatography followed by basic hydrolysis to give ulifloxacin, which is then converted to prulifloxacin.
  • Prulifloxacin prepared by this method has a purity of 60-65% containing impurities in unacceptable levels. Removal of these impurities by usual purification procedures, such as recrystallisation, distillation and washing, is difficult and requires extensive and expensive multiple purification processes. This further decreases the overall yield.
  • a method involving column chromatographic purifications and multiple purifications cannot be used for large-scale operations, thereby making the process commercially non-viable.
  • EP1626051 A1 mentions that Type I, Type II and Type III crystals of prulifloxacin are obtained by crystallization from acetonitrile as reported in lyakuhin Kenkyu, Vol. 28 (1), (1997), 1-11. However, the conditions of crystallization from acetonitrile for preparing Type I, Type II and Type III crystals are not disclosed in lyakuhin Kenkyu, Vol. 28 (1), (1997), 1-11.
  • EP1626051A1 further mentions that Type III crystals have been marketed by considering the solubility, absorbability, therapeutic effect and the like of the respective crystal forms.
  • US 2007/0149540 discloses a crystal of prulifloxacin acetonitrile solvate (Compound B) which is an intermediate for producing preferentially the type III crystal of prulifloxacin.
  • a crystal of Compound B can be preferentially precipitated by controlling the supersaturation concentration in crystallization using acetonitrile as a solvent, subsequently; the type III crystal of Compound A can be produced by performing desolvation of the crystal.
  • WO 2008/111018 discloses processes for the preparation of Type I, Type II and Type III crystals of prulifloxacin. There is disclosed a process for preparing Type I crystals by controlled cooling over a period of 7 to 9 hours and prolonged drying over 24 hours. The inventors of the present invention have found that Type I and Type III crystals prepared according to the WO 2008/111018 process are unstable and the process is non-reproducible.
  • WO 2010/0084508 discloses processes for the preparation of Type I, Type II and Type III crystals of prulifloxacin.
  • WO 2008/059512 discloses a process for the preparation of prulifloxacin using novel intermediates.
  • WO 2008/111016 discloses a process for the preparation of prulifloxacin having purity of about 99% or above. It would be a significant contribution to the art to provide a crystalline form of prulifloxacin, which is consistent and to provide industrially viable methods of preparation, pharmaceutical formulations, and methods of use thereof.
  • the object of the present invention is to provide a novel crystalline polymorphic form of prulifloxacin.
  • Another object of the present invention is to provide an improved process for the synthesis of a novel crystalline polymorphic form of prulifloxacin.
  • the present invention provides novel crystalline polymorphic Form A of prulifloxacin, a method of preparing the novel form of prulifloxacin and an improved process for producing prulifloxacin in high purity and high yield.
  • the present invention also provides pharmaceutical compositions comprising the novel form and the known forms of prulifloxacin prepared by the novel processes.
  • the advantages of the process include simplicity, eco-friendliness and suitability for commercial use. Further, the crystalline forms are produced without adding seed crystals.
  • the invention relates to a crystalline prulifloxacin Form A.
  • crystalline Form A of prulifloxacin there is provided crystalline Form A of prulifloxacin.
  • the crystalline Form A of prulifloxacin is characterized by having an XRD pattern comprising characteristic peaks at 6.1 , 13.7, 16.5, 19.8 and 26.8 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • crystalline Form A of prulifloxacin is characterized by having an XRD pattern as shown in Figure 1.
  • Crystalline Form A of prulifloxacin may also be characterized by having an IR spectrum comprising characteristic IR spectra peaks at about 2940 cm “1 , 2821 cm “1 , 1812 cm *1 , 1739 cm “1 , 1706 cm '1 , 1631 cm “1 , 1598 cm *1 , 1497 cm “1 , 1450 cm *1 , 1380 cm “1 , 1325 cm *1 , 1308 cm “1 , 1288 cm “1 , 1206 cm “1 , 1125 cm “1 , 1102 cm *1 , 1049 cm “1 , 1002 cm '1 , 937 cm '1 , 892 cm “1 , 862 cm “1 , 822 cm *1 and 804 cm “1 ⁇ 2cm '1 .
  • crystalline Form A of prulifloxacin is characterized by having an IR spectrum as shown in Figure 2.
  • a process for preparing crystalline Form A of prulifloxacin comprising dissolving prulifloxacin in a solvent of D F or DMSO at a temperature ranging from room temperature (about 20°C to about 25 °C) to the boiling point of the solvent, quenching the solution in water, filtering the solids, suspending the solids in an alcohol or water or a mixture thereof for a period sufficient to crystallize Form A of prulifloxacin.
  • the solvent is DMSO.
  • the alcoholic solvent may be selected from methanol, ethanol, isopropanol, t-butanol and isobutanol.
  • the solvent is methanol.
  • the reaction mass may be stirred at 25-30°C, for a period of time ranging from 30 minutes to about 3 days.
  • the period of time may range from about 30 minutes to about 5 hours, preferably from about 30 minutes to about 3 hours, more preferably from about 1 hour to about 3 hours, most preferably from about 1 hour to about 2 hours.
  • the suspension may be stirred at a temperature ranging from about 25° to about 30°C, for a period of time ranging from 30 minutes to 2 days.
  • the period of time may range from about 30 minutes to about 5 hours, preferably from about 30 minutes to about 3 hours, more preferably from about 1 hour to about 3 hours, most preferably from about 1 hour to about 2 hours.
  • the precipitated Form A may be isolated by filtration, for example by gravity or suction.
  • the precipitate may be dried at room temperature and/or in vacuum to obtain Form A.
  • the polar solvent is DMSO
  • the prulifloxacin is dissolved in the DMSO at a temperature ranging from about 70°C to about 100°C, preferably from about 80°C to about 90°C, quenching in water, filtering and the filtered solids are suspended in water or an aqueous solution of methanol for a period of time ranging from about 30 minutes to about 3 hours, preferably from about 1 hour to about 2 hours, to crystallize Form A of prulifloxacin.
  • the prulifloxacin starting material may be in any polymorphic form or in a mixture of any polymorphic forms.
  • the prulifloxacin is in Type I crystal form.
  • the Type I crystals may be prepared by dissolving/suspending prulifloxacin in a polar aprotic solvent at a temperature ranging from room temperature to boiling point of the solvent, cooling the solution/suspension under stirring for a period sufficient to crystallize Type I crystals of prulifloxacin.
  • the temperature of the solution/suspension is reduced to 0°C.
  • the polar aprotic solvent is selected from tetrahydrofuran, acetone, 1 ,4-dioxane, dimethylformamide (DMF), dimethylsulfoxide and N-methyl-2-pyrolidone.
  • the solvent is DMF.
  • a process for preparing Type I crystals of prulifloxacin comprising: (a) dissolving or suspending prulifloxacin in DMF at a temperature ranging from about 70°C to about 90°C,
  • the process comprises:
  • the process comprises:
  • the process comprises:
  • the prulifloxacin starting material may be in any polymorphic form (for example Type II or Type III crystals) or in a mixture of any polymorphic forms.
  • the inventors have surprisingly and advantageously found that the process described above is consistent in preparing Type I crystals of prulifloxacin that are stable. In the prior art crystallization involving acetonitrile, any of the Type I, II or III crystals may be formed, and the resulting polymorphs are not stable. However, the Type I crystals prepared by the process described above are stable. According to another aspect of the present invention, there is provided Type I crystals of prulifloxacin prepared by the process described above.
  • Type I crystals of prulifloxacin are characterized by having an XRD pattern comprising peaks at 7.13, 12.3, 12.8, 14.3, 16.28, 17.8, 21.9, 23.1 , 23.7 and 25.1°2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may comprise further peaks at 11.81, 18.8, 20.3, 21.0, 24.6, and 25.8°2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRD pattern comprise still further peaks at 15.48, 27.0, 27.7, 28.5, 28.8,30.7,32.7 and 32.9 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Type I crystals of prulifloxacin are characterized by having an XRD pattern as shown in Figure 3.
  • Type I crystals of prulifloxacin may also be characterized by having an IR spectrum comprising characteristic IR spectra peaks at about 2922 cm “1 , 2854 cm “1 , 1814 cm “1 , 1709 cm “1 , 1628 cm “1 , 1601 cm “1 ' 1496 cm “1 , 1467 cm “1 , 1371 cm “1 , 1349 cm “1 , 1332 cm “ ⁇ 1304 cm “1 , 1283 cm “1 , 1250 cm “1 , 1232 cm '1 , 1205 cm “1 , 1133 cm “1 , 1097 cm '1 , 1046 cm “1 , 1007 cm “1 , 930 cm “1 , 894 cm “1 , 862 cm “1 , 847 cm “1 and 806cm “1 ⁇ 2.
  • Type I crystals of prulifloxacin is characterized by having an IR spectrum as shown in Figure 4.
  • Type I crystals of prulifloxacin to prepare Form A of prulifloxacin.
  • a process for preparing prulifloxacin comprising: a) condensation of 5,6-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto-[3,2-a]-quinoline-3- carboxylic acid ethyl ester (formula II)
  • the ethyl ester (II) may be in the form of a different alkyl ester, for example a Ci-C 6 , preferably Ci-C straight- or branched-chain alkyl ester.
  • the alkyl ester is a methyl, ethyl, n-propyl or i-propyl ester.
  • the ester is the ethyl ester depicted above.
  • the Hal group is preferably chloro or bromo, more preferably bromo.
  • the crystallization step d) is carried out, and the step d) comprises the process for preparing crystalline Form A of prulifloxacin as described above.
  • crystalline prulifloxacin Form A prepared by a process according to the process described above.
  • a pharmaceutical composition comprising crystalline prulifloxacin Form A as described above, together with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is in the form of a tablet suitable for oral delivery.
  • crystalline prulifloxacin Form A as described above for use in medicine.
  • crystalline prulifloxacin Form A as described above for use in treating infectious diarrhea, including travelers' diarrhea, which can be caused by a broad range of bacteria.
  • crystalline prulifloxacin Form A as described above for use in the manufacture of a medicament for treating infectious diarrhea, including travelers' diarrhea.
  • a method of treating infectious diarrhea including travelers' diarrhea comprising administering to a patient in need thereof a therapeutically effective amount of crystalline prulifloxacin Form A as described above.
  • Figure 1 Powder X-ray diffractogram (XRD) of crystalline Form A of prulifloxacin of the present invention.
  • Figure 2 Infra-Red (IR) absorption spectra of crystalline Form A of prulifloxacin of the present invention.
  • Figure 3 Powder X-ray diffractogram (XRD) of Type I crystals of prulifloxacin prepared by the process of the present invention.
  • Figure 4 Infra-Red (IR) absorption spectra of Type I crystals of prulifloxacin prepared by the process of the present invention.
  • the present invention relates to a novel polymorphic Form A of prulifloxacin which is substantially non-hygroscopic and has good flow characteristics.
  • the present invention provides a process for preparing the novel Form A of prulifloxacin in high yield and purity.
  • the present invention also provides pharmaceutical compositions comprising Form A of prulifloxacin.
  • the process involves isolation of the Form A of prulifloxacin in a solvent-free media, thus producing prulifloxacin free of solvents or having a negligible solvent content.
  • the X-ray powder diffraction pattern of crystalline polymorph Form A of prulifloxacin was measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer using a copper- ⁇ - ⁇ radiation source.
  • the crystalline polymorph Form A of prulifloxacin has an XRD pattern with characteristic peaks at 6.2, 13.7, 16.5, 19.8 and, 26.8 °2 ⁇ ( ⁇ 0.2°2 ⁇ ).
  • the crystalline polymorph Form A of prulifloxacin has an XRD pattern with peaks at 29-values as shown in Table 1.
  • the X-ray powder diffraction spectrum of crystalline polymorphic Form A of prulifloxacin is depicted in Figure 1.
  • Infrared (FT-IR) spectra were obtained in a KBr disk using a Perkin Elmer FT-IR spectrophotometer, paragon 500 at resolution 4 cm “1 .
  • the characteristic absorption bands are expressed in cm "1 .
  • Form A of prulifloxacin of the present invention is characterized by having characteristic IR spectra peaks at about 2940 cm “1 , 2821 cm “1 , 1812 cm '1 , 1739 cm “1 , 1706 cm “1 , 1631 cm “1 , 1598 cm “1 , 1497 cm “1 , 1450 cm “1 , 1380 cm “1 , 1325 cm “1 , 1308 cm “1 , 1288 cm “1 , 1206 cm “1 , 1125 cm “1 , 1102 cm “1 , 1049 cm “1 , 1002 cm “1 , 937 cm “ 892 cm “1 , 862 cm “1 , 822 cm “1 and 804 cm '1 ⁇ 2cm “1 as shown in Figure 2.
  • crystalline polymorph Form A of prulifloxacin of the present invention is characterized by having an IR spectrum as shown in Figure 2.
  • the prulifloxacin used as a starting material can be in any form, e.g. it can be in a reaction solution, suspension, crude or in anhydrous, hyd rated or solvated form
  • Form A prulifloxacin may be prepared by dissolving prulifloxacin in any form or in a mixture of any forms, in a polar aprotic solvent at 80-90°C.
  • the reaction mass may be quenched in water.
  • the solid produced in the reaction solution may be isolated by cooling at 25-30°C and stirring for a prolonged time period.
  • the isolated solid may be further suspended in alcohol or water or mixture thereof for a prolonged time period sufficient to crystallize Form A of prulifloxacin. Examples of prolonged time periods include, but are not limited to, 30 minutes to a few hours such as 2 hours or to a few days such as 2 days.
  • the first prolonged period is from about 30 minutes to about 2 days, typically from about 1 hour to about 2 days, preferably from about 1 hour to about 3 hours, more preferably from about 1 hour to about 2 hours, most preferably from about 1 hour to about 2 hours.
  • the second prolonged period is from about 30 minutes to 2 days, typically from about 1 hour to about 2 days, preferably from about 1 hour to about 3 hours, more preferably from about 1 hour to about 2 hours, most preferably from about 1 hour to about 2 hours.
  • the polar aprotic solvent may be selected from dimethylformamide and dimethylsulfoxide.
  • the solvent is dimethylsulfoxide.
  • the alcoholic solvent may be selected from methanol, ethanol, isopropanol, t-butanol and isobutanol. In a preferred embodiment the solvent is methanol.
  • the precipitated Form A may be isolated by filtration, for example by gravity or suction. The precipitate may be dried at room temperature and/or in vacuum to obtain Form A.
  • the prulifloxacin used to prepare Form A according to the present invention is prepared from Type I crystals of prulifloxacin.
  • Type I crystals of prulifloxacin may be prepared by dissolving/suspending prulifloxacin in a polar aprotic solvent at 85-90°C, cooling the reaction mass to a temperature ranging from about 25-30°C, stirring for period of time ranging from 1-5 hours, preferably 2-3 hours, chilling the reaction mass further to a temperature ranging from about 0°C to 5°C, stirring for period of time ranging from 1-5 hours, preferably 2-3 hours, and isolating the precipitated Type I crystals of prulifloxacin.
  • the polar aprotic solvent may be selected from tetrahydrofuran, acetone, 1,4-dioxane, dimethylformamide, dimethylsulfoxide and N-methyl-2-pyrolidone.
  • the solvent is DMF.
  • Type I crystals of prulifloxacin were analyzed, characterized and differentiated by X-ray diffractogram, Infrared spectrum and Differential scanning calorimetry thermogram techniques, known per se. The X-ray powder diffraction pattern of Type I crystals of prulifloxacin was measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer using a copper-K-a radiation source.
  • Type I crystals of prulifloxacin has and XRD pattern with peaks at 7.13, 11.81 , 12.3, 12.8,14.3, 15.5,16.28,17.8, 18.8,20.3,21.0, 21.9, 23.1 , 23.7, 24.6, 25.1 , 25.8, and 27.0, 27.7,28.5, 28.8,30.7,32.7 and 32.9 ⁇ 0.2°2 ⁇ .
  • Type I crystals of prulifloxacin has an XRD pattern with peaks at 2 ⁇ - values as shown in Table 2.
  • Type I crystals of prulifloxacin prepared as described above may be characterized by having characteristic IR spectra peaks at about 2922 cm “1 , 2854 cm “1 , 1814 cm “1 , 1709 cm “1 , 1628 cm “1 , 1496 cm “1 , 1467 cm “1 , 1371 cm “1 , 1349 cm “1 , 1332 cm “1 , 1304 cm “1 , 1283 cm '1 , 1250 cm “1 , 1232 cm “1 , 1205 cm “1 , 1133 cm “1 , 1097 cm “1 , 1046 cm “1 , 1007 cm “1 , 930 cm “1 , 894 cm “1 , 862 cm “1 and 847 cm “1 ⁇ 2 cm “1 as shown in Figure 4.
  • a process for preparing prulifloxacin comprises: a) condensation of 5,6-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto-[3,2-a]quinoline-3- carboxylic acid ethyl ester (formula II) with piperazine in aprotic solvent to yield ethyl-6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1 ,3)-thiazeto-[3,2-a]-quinoline-3- carboxylate (formula III) b) hydrolysis of ethyl-6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1 ,3)-thiazeto- [3,2-a]-quinoline-3-carboxylate (formula III) in the presence of a base and a suitable solvent to yield 6-fluoro-1-methyl
  • the reaction in step (a) is carried out in an aprotic solvent selected from N,N- dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), ⁇ , ⁇ -dimethyl acetamide (DMA) and mixtures thereof.
  • the solvent is N,N-dimethyl formamide and the reaction is performed at a temperature ranging from about 25°C to about 70°C, more preferably from about 45°C to about 55°C.
  • the reaction in step (b) is carried out in water or an alcoholic solvent selected from methanol, ethanol, isopropanol, n-butanol and tert-butanol.
  • the reaction is carried out in water and in the presence of a base selected from an alkaline metal hydroxide (for example sodium hydroxide or potassium hydroxide); an alkaline metal carbonate (for example sodium carbonate or potassium carbonate); and an alkaline metal bicarbonate (for example sodium bicarbonate or potassium bicarbonate).
  • a base selected from an alkaline metal hydroxide (for example sodium hydroxide or potassium hydroxide); an alkaline metal carbonate (for example sodium carbonate or potassium carbonate); and an alkaline metal bicarbonate (for example sodium bicarbonate or potassium bicarbonate).
  • a base selected from an alkaline metal hydroxide (for example sodium hydroxide or potassium hydroxide); an alkaline metal carbonate (for example sodium carbonate or potassium carbonate); and an alkaline metal bicarbonate (for example sodium bicarbonate or potassium bicarbonate).
  • the alkaline metal hydroxide is potassium hydroxide.
  • the reaction is carried out at a temperature ranging from about 25°C to the reflux temperature of the
  • step (c) is carried out in a solvent selected from acetonitrile, acetone, THF, methylene chloride, toluene, DMF, DMSO and DMA.
  • a solvent selected from acetonitrile, acetone, THF, methylene chloride, toluene, DMF, DMSO and DMA.
  • the solvent is acetonitrile or acetone.
  • the reaction is carried out in the presence of a base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine.
  • the base is diisopropylethylamine.
  • the reaction is preferably performed at a temperature ranging from about 0°C to about 50°C. Preferably, the reaction is performed at a temperature ranging from about 20°C to about 40°C to obtain prulifloxacin.
  • the prulifloxacin is crystallized in step (d), suitably from acetonitrile.
  • the -crystallization may be carried out in accordance with a process disclosed in the prior art or in accordance with a process as disclosed herein.
  • the crystallized prulifloxacin may be in the form of Type I, II, III or a mixture of forms.
  • the crystallized prulifloxacin may be further used as the starting material for the preparation of any form of prulifloxacin, as well as for the preparation of the new polymorphic Form A. This further process is a recrystallization process.
  • the prulifloxacin may be recrystallized using DMF or DMSO.
  • the reaction is performed in DMF at a temperature ranging from about 30°C to about 100°C, more preferably from about 80°C to about 85°C to yield prulifloxacin.
  • the prulifloxacin is in the form of Type I crystals.
  • the Type I crystals are stable and reproducible.
  • the prulifloxacin may be recrystallized using the process described above for the preparation of Form A.
  • the prulifloxacin crystallized from acetonitrile may be used as the starting material in the process for preparing Form A as described above.
  • the process of the present invention may be used as a method for purifiying any form of prulifloxacin, as well as for the preparation of the new polymorphic Form A.
  • the novel polymorph of prulifloxacin obtained according to the present invention is substantially free from other forms of prulifloxacin.
  • substantially free from other forms of prulifloxacin shall be understood to mean that the polymorphs of prulifloxacin contain less than 10%, preferably less than 5%, of any other forms of prulifloxacin and less than 1% of other impurities, water or solvates.
  • Prulifloxacin obtained according to the present invention has been found to be effective for treating infectious diarrhea, including travelers' diarrhea, which can be caused by a broad range of bacteria.
  • Pharmaceutical compositions according to the present invention comprise Form A prulifloxacin as an active ingredient together with one or more pharmaceutically acceptable carriers, excipients or diluents. Any conventional technique may be used for the preparation of pharmaceutical compositions according to the invention.
  • the precipitated solid was filtered, washed of chilled DMF (2 x 50 ml). The solid was slurry washed with water (300 ml), filtered, washed with water ( 2 x 100 ml) and dried under vacuum at 70-75°C to yield the title compound [90 gms, 74 % yield, 95% HPLC purity].
  • Prulifloxacin (65 gms) was added to 200 ml of DMF at 25-30°C and heated to 80-85°C for 1 hour. The mixture was then slowly cooled to 25-30°C, stirred for 2 hours, chilled to 0-5°C for 2 hours. The precipitated solid was filtered and dried under vacuum at 70- 75°C to yield Type I crystals of prulifloxacin (55 gms, 99.5 % HPLC purity).
  • Type I crystals of prulifloxacin Prulifloxacin (65 gms) was added to 200 ml of DMF at 25-30°C and heated to 80-85°C for 1 hour. The mixture was then slowly cooled to 25-30°C, stirred for 2 hours, chilled to 0-5°C for 2 hours. The precipitated solid was filtered and dried under vacuum at 70- 75°C to yield Type I crystals of prulifloxacin (52.5 gms, 99.5 % HPLC purity).
  • Type I crystals of prulifloxacin (25 gms) were dissolved in 150 ml of DMSO at 80-85°C, and quenched into 375 ml of water at 25-30°C. The contents were stirred at 25-30°C, filtered, and washed with 25 ml of water. The solid was slurried in 125 ml of water at 25-30°C for 1 hour, filtered, washed with 50 ml of water and dried at 25-30°C for 6 hours (22.5 gms, 90 % Yield, 99.5 % HPLC purity).
  • Type I crystals of prulifloxacin (25 gms) were dissolved in 150 ml of DMSO at 80-85°C, clarified and quenched into 375 ml of water at 25-30°C. The contents were stirred at 25-30°C, filtered, and washed with 25 ml of water. The solid was slurried in 125 ml of 25% aqueous methanol at 25-30°C for 1 hour, filtered, washed with 50 ml 25% aqueous methanol and dried at 25-30°C for 6 hours (22 gms, 88 % Yield, 99.5% HPLC purity). It will be appreciated that the invention may be modified within the scope of the appended claims.

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention porte sur une forme cristalline polymorphe de l'acide 6-fluoro-1-méthyl-7-{4-[(5-méthyl-2-oxo-1,3-dioxol-4-yl)méthyl]pipérazin-1-yl}-4-oxo-4H-[1,3]-thiazéto-[3,2-a]-quinoléine-3-carboxylique (prulifloxacine). De façon plus spécifique, l'invention porte sur une forme cristalline de la prulifloxacine (appelée ici forme A) et sur un procédé pour la préparation de la forme cristalline A. La présente invention porte en outre sur une formulation pharmaceutique comprenant la nouvelle forme de la prulifloxacine.
PCT/GB2011/000982 2010-06-30 2011-06-30 Forme cristalline de la prulifloxacine et procédés pour sa préparation Ceased WO2012001357A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB1301307.3A GB2498107A (en) 2010-06-30 2011-06-30 Crystalline form of prulifloxacin and processes for its preparation
IN2925MUN2012 IN2012MN02925A (fr) 2010-06-30 2011-06-30

Applications Claiming Priority (2)

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IN1920/MUM/2010 2010-06-30
IN1920MU2010 2010-06-30

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WO2012001357A1 true WO2012001357A1 (fr) 2012-01-05

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PCT/GB2011/000982 Ceased WO2012001357A1 (fr) 2010-06-30 2011-06-30 Forme cristalline de la prulifloxacine et procédés pour sa préparation

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GB (1) GB2498107A (fr)
IN (1) IN2012MN02925A (fr)
WO (1) WO2012001357A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102718781A (zh) * 2012-05-08 2012-10-10 四川科伦药物研究有限公司 一种普卢利沙星的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315828A1 (fr) * 1987-11-07 1989-05-17 Nippon Shinyaku Company, Limited Dérivés de l'acide quinolinecarboxylique
EP1626051A1 (fr) 2003-04-30 2006-02-15 Nippon Shinyaku Co., Ltd. Cristaux d'un solvate de derive d'acide quinolinecarboxylique
WO2008059512A1 (fr) 2006-11-17 2008-05-22 Hetero Drugs Limited Procédé de préparation de prulifloxacine utilisant de nouveaux intermédiaires
WO2008111016A1 (fr) 2007-03-14 2008-09-18 Ranbaxy Laboratories Limited Procédé de préparation de prulifloxacine pure
WO2008111018A2 (fr) 2007-03-14 2008-09-18 Ranbaxy Laboratories Limited Procédé de préparation de cristaux de prulifloxacine
WO2010084508A2 (fr) 2009-01-14 2010-07-29 Elder Pharmaceuticals Ltd. Procédé pour la préparation de prulifloxacine cristalline de type i, de type ii et de type iii

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315828A1 (fr) * 1987-11-07 1989-05-17 Nippon Shinyaku Company, Limited Dérivés de l'acide quinolinecarboxylique
US5086049A (en) 1987-11-07 1992-02-04 Nipponshinyaku Co., Ltd. 7[4-(5 methyl-2-oxo-1,3-dioxalen-4-yl)methyl 1-piperzinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids
EP1626051A1 (fr) 2003-04-30 2006-02-15 Nippon Shinyaku Co., Ltd. Cristaux d'un solvate de derive d'acide quinolinecarboxylique
US20070149540A1 (en) 2003-04-30 2007-06-28 Nippon Shinyaky Co., Ltd. Crystals of quinolinecarboxylic acid derivative solvate
WO2008059512A1 (fr) 2006-11-17 2008-05-22 Hetero Drugs Limited Procédé de préparation de prulifloxacine utilisant de nouveaux intermédiaires
WO2008111016A1 (fr) 2007-03-14 2008-09-18 Ranbaxy Laboratories Limited Procédé de préparation de prulifloxacine pure
WO2008111018A2 (fr) 2007-03-14 2008-09-18 Ranbaxy Laboratories Limited Procédé de préparation de cristaux de prulifloxacine
WO2010084508A2 (fr) 2009-01-14 2010-07-29 Elder Pharmaceuticals Ltd. Procédé pour la préparation de prulifloxacine cristalline de type i, de type ii et de type iii

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LYAKUHIN KENKYU, vol. 28, no. 1, 1997, pages 1 - 11

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102718781A (zh) * 2012-05-08 2012-10-10 四川科伦药物研究有限公司 一种普卢利沙星的制备方法

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GB201301307D0 (en) 2013-03-06
IN2012MN02925A (fr) 2015-05-22
GB2498107A (en) 2013-07-03

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