POLYMORPHS A AND B OF 1-(DIPHENYLMETHYL)-4-[3-(2-PHENYL-1,3-DIOXOLAN-2-YL) PROPYL]PIPERAZINE

Abstract: Polymorphs A and B of (1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propyl]piperazine have been identified. A process for preparation thereof and the use thereof are described.

Description: The present invention relates to novel Polymorph B of 1-(Diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl) propyl]piperazine -compound known as dotarizine (WHO). Brief description of the drawings Figure 1 is an infrared (IR) spectrum of dotarizine Polymorph A at the range from 4000 to 400 cm -1 . Figure 2 is an infrared (IR) spectrum of dotarizine Polymorph A at the range from 2000 to 400 cm -1 . Figure 3 is a differential scanning calorimetry (DSC) thermogram of dotarizine Polymorph A. Figure 4 is an X-ray powder diffractogram of dotarizine Polymorph A. Figure 5 is an infrared (IR) spectrum of dotarizine Polymorph B at the range from 4000 to 400 cm -1 . Figure 6 is an infrared (IR) spectrum of dotarizine Polymorph B at the range from 2000 to 400 cm -1 . Figure 7 is a differential scanning calorimetry (DSC) thermogram of dotarizine Polymorph B. Figure 8 is an X-ray powder diffractogram of dotarizine Polymorph B. Detailed description of the invention 1-(Diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl) propyl]piperazine is an antiserotonergic agent (5HT 1C and 5HT 2 ) and calcium antagonist. This compound is effective in the prophylaxis of migraine and in the treatment of vertigo. The preparation of this compound was disclosed in European Patent No. 0097340 showing a melting point of 93-97°C. The article Gubert et al. Arzneimittel Forschung. Drug Research, Vol.37, no. 10, 1987, pages 1103-1107 describes the preparation of Polymorph A by crystallisation from methanol showing a melting point of 100-101°C (Table 1, example 17). The applicants have found out that dotarizine exhibits a novel polymorph B, which has a melting point in the range between 100 and 103°C. The differential scanning calorimetry (DSC) thermograms of both polymorphs do not show significant differences as illustrated in Figures 3 and 7. Nevertheless, the applicants have found out that their IR spectra do show significant differences especially in the range 1100-900 cm -1 in accordance with the enlarged IR spectra in Figures 2 and 6. Dotarizine polymorph A is characterized by showing bands at 2962, 2949, 2808, 2767, 1446, 1040, 1025, 1002, 993, 970, 960, 761 and 707 cm -1 and dotarizine polymorph B is characterized by showing bands at 2961, 2883, 2812, 2777, 2760, 1448, 1283, 1058, 1042, 1029, 1006, 978, 951, 758 and 703 cm -1 (Figures 1 and 5). The present invention provides a process for obtaining polymorph B of dotarizine; polymorph A is obtained by crystallization in methanol, while polymorph B is obtained by crystallization in n-hexane. The use of polymorph A for preparing pharmaceutical formulations in the form of drops (suspensions) is recommended, while the use of polymorph B for preparing capsules or other solid forms is preferred. Polymorphs A and B of dotarizine mixed with pharmaceutically acceptable carriers can be administered at daily doses ranging from 50 and 150 mg. The following examples will illustrate the preparation of polymorphs A and B of dotarizine and pharmaceutical formulations containing them. The examples are not intended to limit the scope of the invention as defined hereinabove or as claimed hereinafter. Example 1 (reference example) Polymorph A of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propyl)piperazine 11.2 g of dotarizine are dissolved in 56 ml of methanol at reflux. The solution is filtered and allowed to crystallize at a temperature of between 20 and 25°C with gentle stirring. A crystalline solid is formed, which weighs 9.9 g (yield 88.5%) after dried. IR spectrum (KBr), range from 4000 to 400 cm -1 : Fig. 1. IR spectrum (KBr), range from 2000 to 400 cm -1 : Fig. 2. Differential scanning calorimetry (DSC) thermogram: Fig. 3. X-ray powder diffractogram: Fig. 4. Example 2 Polymorph B of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propyl)piperazine 10 g of dotarizine are dissolved in 100 ml of n-hexane at reflux. The solution is filtered and allowed to crystallize at a temperature of between 20 and 25°C with stirring. A crystalline solid is formed, which weighs 7.6 g (yield 76%) after dried. IR spectrum (KBr), range from 4000 to 400 cm -1 : Fig. 5. IR spectrum (KBr), range from 2000 to 400 cm -1 : Fig. 6. Differential scanning calorimetry (DSC) thermogram: Fig. 7. X-ray powder diffractogram: Fig. 8. Example 3 (Reference example) Drops Composition for 100 ml: Dotarizine polymorph A 7.50 g Sucrose 30.00 g Microcrystalline cellulose RC-581 1.00 g Carboxymethylcellulose sodium 0.10 g Saccharin sodium 3.50 g Methyl- p -hydroxybenzoate 0.15 g Propyl- p -hydroxybenzoate 0.03 g Polysorbate 80 0.20 g Distilled water q.s. 100.00 ml Example 3 Capsules Composition for 1 capsule Dotarizine polymorph B 50.0 mg Silicon dioxide 2.0 mg Croscarmellose sodium 8.0 mg Corn starch 50.0 mg Talc 8.0 mg Magnesium stearate 1.5 mg Microcrystalline cellulose q.s. 210.0 mg

Claims: Polymorph B of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propyl]piperazine characterized in that it shows IR bands at 2961, 2883, 2812, 2777, 2760, 1448, 1283, 1058, 1042, 1029, 1006, 978, 951, 758 and 703 cm -1 as presented in Figures 5 and 6. A process for the preparation of Polymorph B of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propyl] piperazine by crystallization in n-hexane. A pharmaceutical composition containing the polymorph and pharmaceutically acceptable carriers according to claims 1 and 2, which is useful in the prophylaxis of migraine and in the treatment of vertigo.

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: C07D405
IPC codes: A61K31, C07D317, A61P25