PROCESS FOR PREPARING POLYMORPHS B AND C OF 1- 2,4-DICHLORO-BETA-[(7-CHLOROBENZO[b]THIEN-3-YL)METHOXY]PHENETYL]IMIDAZOLE MONONITRATE

Abstract: Two novel polymorphs of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl]imidazole mononitrate have been identified. A process for the preparation thereof and the use thereof are described.

Description: The present invention relates to a process for preparing Polymorphs B and C of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl]imidazole mononitrate -compound known as sertaconazole mononitrate (WHO). Brief description of the drawings Figure 1 is an infrared (IR) spectrum of sertaconazole mononitrate Polymorph B. Figure 2 is a differential scanning calorimetry (DSC) thermogram of sertaconazole mononitrate Polymorph B. Figure 3 is an X-ray powder diffractogram of sertaconazole mononitrate Polymorph B. Figure 4 is an infrared (IR) spectrum of sertaconazole mononitrate Polymorph C. Figure 5 is a differential scanning calorimetry (DSC) thermogram of sertaconazole mononitrate of Polymorph C. Figure 6 is an X-ray powder diffractogram of sertaconazole mononitrate Polymorph C. Figure 7 is an infrared (IR) spectrum of sertaconazole mononitrate Polymorph A. Figure 8 is a differential scanning calorimetry (DSC) of sertaconazole mononitrate Polymorph A. Figure 9 is an X-ray diffractogram of sertaconazole mononitrate Polymorph A. Detailed description of the invention 1-[2,4-Dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy] phenethyl]imidazole mononitrate is used in Therapeutics as an antifungal agent. The preparation of this compound with melting point 156-157°C (Polymorph A) was disclosed in European Patent No. 0151477. Sertaconazole mononitrate is known to exhibit two other polymorphs, B and C, which have a melting point in the range of 163-164°C and 164.5-165.5°C respectively (Arz.Forsch. 42, 695-8, 1992). The citation of Chemical Abstracts, 117:137767j discloses the determination of sertaconazole nitrate and its degradation products by HPLC in stock sertaconazole and cream formulations. French Patent No. 2376856 relates to polymorphic forms of ticrinafen, a process for preparing them and the pharmaceutical compositions containing them. The present invention provides a process for obtaining selectively each polymorph B and C of sertaconazole mononitrate. The applicants have found out in the course of different crystallization assays that when polymorph A is recrystallized from absolute ethanol, it yields the new polymorph B, and when polymorph A is recrystallized from chloroform, it yields the new polymorph C. The melting points of the three polymorphs are within a close range, but they are well differentiated by means of the enclosed IR spectra, DSC thermograms and X-ray powder diffractograms. Figures 7, 8 and 9 concerning Polymorph A are enclosed in order to support the differences between the new polymorphs B or C and primary polymorph A. The physical properties of polymorphs B and C of sertaconazole mononitrate are different from those of primary polymorph A. In effect, polymorph B shows higher stability than that of polymorph A versus a moderate supply of external energy (such as sifting and homogenizing processes) and is, therefore, suitable for the preparation of topical dosage solid forms, such as powder. Polymorph C is assumed to be even more stable than polymorph B versus an external energetic supply and can, therefore, be conveniently used in processes requiring a higher energetic supply, such as compression processes, thus being suitable for the preparation of tablets. In case of liquid formulations, either polymolph, B or C, can be used since the proper characteristics of a solid disappear in a solution. In addition to the aforesaid pharmaceutical forms, polymorphs B and C of sertaconazole mononitrate mixed with pharmaceutically acceptable carriers can be administered by the oral route to humans and animals in the form of capsules, syrups, solutions, powder, etc., by injectable route, by rectal route, and by vaginal-intrauterine route in the form of ovulum, ointment, cream, pessary, lotion, etc., at daily doses ranging from 100 to 800 mg; and by topical route in the form of cream, lotion, ointment, emulsion, solution, shampoo, gel, etc., at concentrations ranging from 0.1 to 5%. Also polymorphs B and C of sertaconazole mononitrate in admixture with a diluent or carrier and in suspension with irrigation water can be used against crop diseases; they can also be applied by atomizing, spraying, dusting, or in the form of cream, paste, etc., at the rate of 0.1-15 kg per hectare of soil. The following examples will illustrate the preparation of polymorphs B and C of sertaconazole mononitrate, and pharmaceutical formulations containing them. Example 1 Polymorph B of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl]imidazole mononitrate (Sertaconazole mononitrate polymorph B) 10 g of sertaconazole mononitrate (polymorph A) are dissolved in 100 ml of absolute ethanol at reflux. The hot solution is filtered and allowed to crystallize at room temperature withou stirring. The crystalline solid formed is filtered and dried to give 8.78 g of Polymorph B of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl]imidazole mononitrate (Sertaconazol mononitrate polymorph B). Melting point: 163-164°C IR spectrum (KBr): Figure 1 DSC thermogram: Figure 2 X-ray diffractogram: Figure 3 Example 2 Polymorph C of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl]imidazole mononitrate (Sertaconazol mononitrate polymorph C) 5 g of sertaconazole mononitrate (polymorph A) are dissolved in 150 ml of chloroform at reflux. The hot solution is filtered and allowed to crystallize at room temperature without stirring. The crystalline solid formed is filtered and dried to give 4.2 g of Polymorph C of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl]imidazole mononitrate (Sertaconazol mononitrate polymorph C). Melting point: 164.5-165.5°C IR spectrum (KBr): Figure 4 DSC thermogram: Figure 5 X-ray diffractogram: Figure 6 Example 3 2 % powder for topical application Composition for 100 g: Sertaconazole mononitrate polymorph B 2 g Titanium dioxide 10 g Kaolin 10 g Talc 78 g Example 4 Vaginal tablets Composition for 1 vaginal tablet: Sertaconazole mononitrate polymorph C 500 mg Corn starch 90 mg Aerosil 200 1 mg Primogel 45 mg Compritol 150 mg Magnesium stearate 7.5 mg Avicel PH-101 to volume 1100 mg

Claims: A process for preparing Polymorph B of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl] imidazole mononitrate which has a melting point in the range of 163-164°C, characterized by dissolving Polymorph A in absolute ethanol at reflux, then filtration of the hot solution, crystallization at room temperature and filtration. A process for preparing Polymorph C of 1-[2,4-dichloro-β-[(7-chlorobenzo[ b ]thien-3-yl)methoxy]phenethyl] imidazole mononitrate which has a melting point in the range of 164.5-165.5°C, characterized by dissolving Polymorph A in chloroform at reflux, then filtration of the hot solution, crystallization at room temperature and filtration.

Inventors: ANGLADA BURNIOL LLUIS, CASTELLO BARENYS JOSEP MARIA, FOGUET AMBROS RAFAEL, ORTIZ HERNANDEZ JOSE A, RAGA CARRENO MANUEL MAURICIO, SACRISTAN MUNOZ AURELIO, ANGLADA BURNIOL, LLUIS, CASTELLO BARENYS, JOSEP MARIA, FOGUET AMBROS, RAFAEL, ORTIZ HERNANDEZ, JOSE A., RAGA CARRENO, MANUEL MAURICIO, SACRISTAN MUNOZ, AURELIO, ORTIZ HERNANDEZ, José A.
Applicants: FERRER INT, FERRER INTERNACIONAL, S.A.
Application year: 1995
Main classification: C07D409
IPC codes: C07D233, C07D521