MXPA06005679A

MXPA06005679A - Crystalline forms of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride.

Info

Publication number: MXPA06005679A
Application number: MXPA06005679A
Authority: MX
Inventors: Marc-Antoine Perrin
Original assignee: Inflazyme Pharm Ltd
Priority date: 2003-10-20
Filing date: 2004-10-20
Publication date: 2006-08-17
Also published as: WO2005037851A1; CA2542821A1; JP2007509050A; EP1680441A1; KR20070007766A; RU2006117320A; AU2004281998A1

Abstract

The invention relates to novel crystalline forms of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride, referred to as form A, form B and form C, a method for preparing same, the use thereof as a drug, and pharmaceutical compositions containing same.

Description

CRYSTALLINE SHAPES OF 3-BETA-AMINO, CHLORHYDRATE, 17-METHYLENE, ANDROSTAN-6-ALPHA. 7-BETA-DIOL DESCRIPTIVE MEMORY The present invention relates to three crystalline forms of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol (composed of formula I), represented by the structure: The patent application WO0183512 describes the 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol, as well as its pharmaceutically acceptable salts for the treatment of inflammatory diseases, and mainly asthma: The compound 3- Beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol, as described and prepared in said application WO0183512, is mainly in the form of an acetate salt. Said salt in the form of acetate is hygroscopic, which is a major drawback for industrial development.

The object of the invention is to find one or more novel crystalline forms which do not have the drawbacks of the form described above. The solid forms, and mainly the pharmaceuticals, may have more than one crystalline form; what is called polymorphism. Polymorphic form means all unsolvated forms of a crystallized molecule, and by pseudo-polymorph, all solvated forms. The polymorphic and pseudo-polymorphic forms of the same molecule generally show different physical properties, such as solubility, hygroscopic capacity and stability. It should be noted that at the moment there are no methods that allow knowing (experimental screening) or predicting (theoretical screening by molecular modeling), with certainty, the existence of this or that polymorph, of this or that pseudo-polymorph, or of predicting its properties physical The obtaining of novel forms of polymorphs or pseudo-polymorphs of molecules having a therapeutic activity is of great interest for the pharmaceutical industry, mainly from the point of view of their preparation on an industrial scale, their realization within pharmaceutical compositions, and research of better stability. The same demand has revealed three novel crystalline forms of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol (form A, form B and form C). The form A that is anhydrous, the form B that is dehydrated, and the form C that is monohydrated. The crystalline form A, in addition to the advantages already mentioned above, has an absence of hygroscopic capacity. The invention then has, firstly, a novel crystalline form of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol anhydrous, which is designated form A. The crystalline form A of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol, according to the invention, is presented in the form of a crystalline powder, stable from 0 to 90% Relative Humidity (HR ) and begins to chemically degrade towards 240 ° C to decompose completely beyond 280 ° C. Said form has been defined by the indexing of its powder X-ray diagram, which is described hereinafter. The invention also relates to a novel crystalline form of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-aifa, 7-beta-diol hydrate which is designated form B; this form can be used as an intermediary for the preparation of form A. It is a stable dehydrated form beyond 50% RH; likewise, it is defined in the following by the indexing of its X-ray diagram in powders. Another object of the invention is a novel crystalline form of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol hydrated, which is called form C. Form C appears mixed with other forms (anhydrous forms D and E). Form C was obtained pure thanks to a complementary treatment for conservation some days in a humid atmosphere at 97% RH; it is a stable mono-hydrated form of 0 to 90% RH. It is transformed into anhydrous D by heating beyond 60 ° C; likewise, it is defined later by the indexing of its X-ray diagram in powders. The crystalline forms A, B or C of the compound of the formula (I) exhibit similar therapeutic activities as those described for the compound 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol in the application WO0183512. In particular, said forms are useful in the treatment of inflammatory diseases, and of asthma.

Diffraction of X-rays in powders The analyzes are carried out in a Philips X'pert Pro diffractometer that has a copper antipathous tube, equipped with a monochromator in front (wavelength of the copper Kai ray: 1.54060 Á). The assembly is of the Bragg-Brentano type, with a Philips X'celerator detector. The angular sweep margin extends from 2 to 40 degrees in 2T with a step of 0.02 degrees in 2T. The counting time is 300 seconds per step.

Form A Form A is crystallized in a monoclinic network (space group P2- ?, Z = 2) whose mesh parameters are the following at T = 295 K: a = 16.058 (2) A, ß = 90.24 (2) ° 5 = 6.995 (1) A, V = 1012.2 A3 c = 9.011 (2) A density = 1.168 The asymmetric unit is composed of a molecule of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol. Since all the stripes present on the diffraction pattern are indexed, form A, as obtained according to the crystallization process described in Example 1 or Example 2 described below, is a pure physical form. The indexing of the first 30 lines of the powder X-ray diffraction diagram of Form A of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol in T = 295 K, in interreticular distances, as well as in positions 2T «? Cu« amedio », give the following result: Form B Form B can be used as an intermediate for the preparation of Form A. Form B is a dehydrated form that is crystallized in a triclinic network (space group P?, Z = 1) whose mesh parameters are the following in T = 295 K: a = 8856 (2) A, a - 100.76 (1) ° fc = 18.482 (1) A, ß = 90.06 (1) ° C = 6.904 (2) A? = 78.35 (1) ° V = 1086.5 A3 density = 1.198 The asymmetric unit consists of two hydrochloride molecules of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol and 4 molecules of water.

Since all the stripes present in the diffraction diagram are indexed, form B, as obtained according to the crystallization process described in Example 3 described below, is a pure physical form. Indexing of the first 30 lines of the powder X-ray diffraction diagram of form B of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol at T = 295 K, in interreticular distance, as well as in positions 2T «? cu Kamedio» give the following result: Form C Form C is a monohydrated form that is crystallized in a triclinic network (space group P "\, Z = 1) whose mesh parameters are the following at T = 295 K: a = 7.2328 (5) A, a = 97.135 (6) ° d = 21.063 (2) A, ß = 102.653 (5) ° c = 7.1563 (5) A? = 91.177 (6) ° V = 1054.2 A3 density = 1.178 The asymmetric unit is composed of two molecules of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol and 2 water molecules, as all the lines present in the diffraction diagram are indexed, the C form, such and as obtained according to the crystallization process described in Example 4 described below, it is a pure physical form The indexing of the first 30 stripes of the powder X-ray diffraction diagram of the form C of the 3-beta-hydrochloride amino, 17-methylene, androstan-6-alpha, 7-beta-diol in T = 295 K, in interreticular distance, as well as in positions 2T «? Cu Kamedio» give the following result: The object of the invention is therefore the crystalline forms A, B or C, as described above as medicaments.

The crystalline forms A, B or C of the 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol can be used orally, parenterally, topically by inhalation, or via implants. They can be prescribed in the form of simple tablets or dragees, capsules, granules, suppositories, ovules, injectable preparations, ointments, creams, gels, microspheres, implants, patches, which are prepared according to common methods. The crystalline forms A, B or C of the 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol can be mixed with the excipients, diluents and any vehicle known to the person skilled in the art for the manufacture of compositions Pharmaceutical As examples of excipients commonly used in said pharmaceutical compositions, there may be mentioned talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various agents for humidification, dispersants or emulsifiers, and preservatives. The invention also encompasses pharmaceutical compositions comprising as active ingredient at least one of the crystalline forms A, B or C of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol, such and as already defined herein, and one or more pharmaceutically acceptable excipients, diluents or carriers. Additionally, the invention has for its object the application of the crystalline forms A, B or C of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol, as already defined in the present for the preparation of a medicament intended to treat inflammatory diseases, such as asthma. The following examples illustrate the invention without limiting it at all.

EXAMPLE 1 3-Beta-amino hydrochloride, 17-methylene, andtostan-6-alpha, 7-beta-diol, Form A 250 mg of product of the formula I are dissolved at room temperature in the minimum of methanol; isopropyl ether is added until the start of precipitation. After centrifuging, 195 mg of product I, form A are obtained.

EXAMPLE 2 3-Beta-amino hydrochloride, 17-methylene, androstan-6-alpha-beta-diol, Form A 250 mg of product of formula I are dissolved at room temperature in the minimum ethanol, water is added until the beginning of crystallization, and the product of formula I, polymorph B, is obtained.

Then, after evaporation under a stream of nitrogen at room temperature, the product of formula I, form A, is obtained.

EXAMPLE 3 3-Beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-dioi, Form B The product of formula I, form A, preserved for 3 days under relative humidity greater than 95%, is transformed to form B.

EXAMPLE 4 3-Beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol, Form C 250 mg of product of the formula I are dissolved at room temperature in the minimum of methyl ethyl ketone. After transferring to the water for azeotropic distillation in constant volume, and equilibrating under a relative humidity higher than 97%, the product of the formula I, form C is obtained.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A crystalline form A of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol which responds to the structure: said form being characterized in that the indexing of stripes of the powder X-ray diffraction diagram at 295 K gives the following result for the first 30 stripes: 2. - A crystalline form A of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol, characterized in that it crystallizes in a monoclinic network (space group P2- ?, Z = 2) whose mesh parameters T = 295 K are: a = 16.058 (2) A,? = 90.24 (2) ° 0 = 6.995 (1) A, V = 1012.2 A3 c = 9.011 (2) A density = 1.168 3.- A dehydrated crystalline form B of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol, characterized in that the indexing of the X-ray diffraction pattern in powders at 295 K gives the following result: 4. - A dehydrated crystalline form B of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol, characterized in that it crystallizes in a triclinic network (space group P1, Z = 1) whose Mesh parameters are as follows at T = 295 K are: a = 8856 (2) A, a = 100.76 (1) ° b = 18.482 (1) A, ß = 90.06 (1) ° c = 6.904 (2) A ? = 78.35 (1) ° V = 1086.5 A3 density = 1198 5.- A mono-hydrated C-crystalline form of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-dioI, characterized because the indexing of the stripes of the X-ray diffraction pattern in powders at 295 K give the following result for the first 30 stripes: 6. - A mono-hydrated crystalline form C of 3-beta-amino hydrochloride, 17-methylene, androstan-6-alpha, 7-beta-diol, characterized in that it crystallizes in a triclinic network (space group P1, Z = 1 ) whose mesh parameters at T = 295 K are: a = 7.2328 (5) A, a = 97.135 (6) ° b = 21.063 (2) A, ß = 102.653 (5) ° c = 7.1563 (5) A? = 91.177 (6) ° V = 1054.2 A3 density = 1.178 7.- A method of preparing form A, defined in claim 1 or 2, said process being characterized in that the crystallization is carried out in a mixture of alcohol and of ether, and mainly in the mixture of methanol / isopropyl ether. 8. A method of preparing form C, which is defined in claim 5 or 6, characterized in that 250 mg of product of the formula I are dissolved at room temperature in a solvent, such as methyl ethyl ketone, then transferred in water by azeotropic distillation at constant volume and equilibrated under a relative humidity greater than 97%. 9. The crystalline forms A, B or C, as defined in claims 1 to 8, for use as a medicine. 10. A pharmaceutical composition characterized in that it comprises the form A of the hydrochloride of 3-beta-amino, 17-methylene, androstan-6-alpha, 7-beta-diol in the pure state or optionally in combination with one and / or another of the crystalline forms B or C and / or in the form of a combination with any inert, compatible and pharmaceutically acceptable adjuvant or diluent. 11. The use of crystalline forms as defined in any of claims 1 to 8, for the preparation of a medicament for treating inflammatory diseases.