MX2008010266A - αcrystalline form of the arginine salt of perindopril, process for preparing it, and pharmaceutical compositions comprising it - Google Patents

Abstract

αcrystalline form of the compound of formula (I), characterized by its X-ray powder diffraction diagram. Medicaments.

Description

CRYSTALLINE SHAPE OF THE ARGININE SALT OF THE PERINDOPRIL, ITS PROCEDURE OF PREPARATION. AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT The present invention relates to crystalline form a of the L-arginine salt of perindopril of formula (I): to its preparation process as well as to the pharmaceutical compositions containing it. Perindopril, as well as its pharmaceutically acceptable salts and, more particularly its arginine salt, possess interesting pharmacological properties. Its main property is to inhibit the conversion enzyme angiotensin I (or kininase II), which allows, on the one hand, prevent the transformation of decapeptide angiotensima I into octapeptide angiotensin II (vasoconstrictor) and, on the other hand, prevent the degradation of bradykinin (vasodilator) in inactive peptide. These two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, particularly hypertension and heart failure. Perindopril, its preparation and its use in therapy have been described in the European part EPO 049 658. The arginine salt of perindopril has been described in the European part EP 1 354 873. In view of the pharmaceutical interest of this compound, it was essential to obtain it with excellent stability, mainly in terms of hygroscopicity, of powder processability, filterability of the solid, grinding, solvent retention. Obtaining a well-defined crystalline form makes it possible to respond to this specification. Patent EP 1 354 873 describes the arginine salt of perindopril. However, this document does not specify the conditions for obtaining this salt in a well-defined crystalline form. The Applicant has now found that the arginine salt of perindopril could be obtained in a well-defined crystalline form, thereby exhibiting interesting characteristics of filtration, drying and ease of formulation. More specifically, the present invention relates to crystalline form a of the compound of formula (I), characterized by the following powder diffraction peaks RX, measured on a diffractometer with copper antipatho and expressed in terms of 2-theta angle ( °): 4.5, 7.9 and 13.5. Preferably, the invention relates to the crystalline form a of the compound of formula (I), characterized by the following powder diffraction peaks RX, measured on a diffractometer with copper antipatho and expressed in terms of the 2-theta angle (°). : 4.5, 7.9, 13.5, 17.5 and 20.6. Even more preferably, the present invention relates to the crystalline form a of the compound of formula (I), characterized by the diffraction diagram X on the following powder, measured on a diffractometer (copper antipathoid) and expressed in terms of Inter-reticular distance d, Braga 2 theta angle, of intensity and relative intensity (expressed as a percentage of the most intense line): invention also extends to the process Preparation of crystalline form a of the compound of formula (I), in which perindopril is placed in solution in water with L-arginine, an apolar solvent and a polar solvent are added and the obtained crystals are filtered, washed and they dry. Among the apolar solvents, mention may be made, for example, of methylcyclohexane, cyclohexane and toluene. Among the polar solvents, mention may be made, for example, of dimethylsulfoxide, N, N-dimethylformamide, N; N-dimethylacetamide and N-methyl-2-pyrrolidinone. The crystals thus obtained are presented in a compact form, constituted by rods. According to one embodiment of the invention, perindopril is dissolved in water with L-arginine, methylcyclohexane and dimethylsulfoxide are added and the obtained crystals are filtered, washed and dried. The invention also extends to pharmaceutical compositions containing as active ingredient the crystalline form a of the compound of formula (I) with one or more inert excipients, non-toxic and appropriate. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral (intravenous or sub-cutaneous), nasal, plain or dragee tablets, sublingual tablets, capsules, lozenges, suppositories, creams, ointments may be mentioned more particularly. , dermal gels, injectable preparations and drinkable suspensions. The useful dosage can be adapted according to the nature and severity of the condition, the route of administration as well as the age and weight of the patient. This dosage varies from 1 to 500 mg per day in one or more doses.

The pharmaceutical compositions according to the invention may also contain a diuretic such as indapamide. The following examples illustrate the invention. The diffraction aspect X on powder was determined with the following experimental conditions: Siemens D5005 diffractometer; scintillation detector, copper anticytode, voltage 40KV, current 30mA, TT assembly, fixed sample, temperature: ambient, field of measurements: 3rd to 30 °, increment between each measurement: 0.04 °, measurement time per step: 4s, slits Fixed: 1.6 mm, Filter? ß (Ni), Without internal reference, Zero procedure with Siemens slots, Experimental data treated with the EVA software (version 9.0). EXAMPLE 1: Crystal form a of the arginine salt of perindopril In a reactor, 1.5 kg of water, 328 g of perindopril and 155 g of L-arginine are introduced at room temperature and with stirring. When a clean solution is obtained, 630 g of methylcyanohexane are added and then 4.7 kg of dimethyl sulfoxide are added slowly. The medium is left with stirring until the temperature of the heterogeneous mixture stabilizes around 20.0 ° C, the mixture is filtered and the solid obtained is washed and dried. The crystals thus obtained are presented in a compact form, constituted by rods. The amount of water of the product obtained is approximately 3.2%, which corresponds to a monohydrate. Diffraction X diagram on powder: The powder X-ray diffraction profile (diffraction angles) of the a-form of the arginine salt of perindopril is given by the significant lines gathered in the following table, with intensity and intensity relative (expressed as a percentage with respect to the most intense line).

EXAMPLE 2: Pharmaceutical composition Formula of preparation for 1,000 tablets at a dose of 4 mg: Compound of example 1 Hydroxypropylcellulose Wheat starch Lactose Magnesium stearate ... Talc

Claims (12)

1. CLAIMS 1.- Crystal form a of the L-arginine salt of perindopril, of formula (I): characterized by the following powder diffraction peaks RX, measured on a diffractometer with copper anticoat and expressed in terms of the 2-theta angle (°): 4.5, 7.9 and 13.5.
2. 2. - Crystal form a of the compound of formula (I) according to claim 1, characterized by the following powder diffraction peaks RX measured on a diffractometer with copper antipatho and expressed in terms of Braga 2-theta angle (°) : 4.5, 7.9, 13.5, 17.5 and 20.6.
3. 3. - Crystalline form a of the compound of formula (I) according to claim 1, characterized by the diffraction diagram X on following powder, measured on a diffractometer (copper antipatho) and expressed in terms of interreticular distances d, angle of Braga 2 theta, of intensity and relative intensity (expressed as a percentage of the most intense line):
4. 4. - Process for preparing the crystalline form a of the compound of formula (I) according to any one of claims 1 to 3, wherein the perindopril is placed in solution in water with the L-arginine, an apolar solvent and an The polar solvent and the obtd crystals are filtered, washed and dried.
5. 5. Process according to claim 4, wherein the apolar solvent is selected from methylcyclohexane, cyclohexane and toluene.
6. 6. - Method according to any one of claims 4 or 5, wherein the polar solvent is selected from dimethylsulfoxide, N, N-dimethylformamide,?,? -dimethylacetamide and N-methyl-2-pyrrolidinone.
7. 7. The process according to claim 4, wherein the apolar solvent is methylcyclohexane and the polar solvent is dimethyl sulfoxide.
8. 8. - Pharmaceutical composition contng as active ingredient the compound according to any one of claims 1 to 3, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles.
9. 9. - Pharmaceutical composition according to claim 8, characterized in that it also cont a diuretic.
10. 10. - Pharmaceutical composition according to claim 9, characterized in that the diuretic is indapamide.
11. 11. - Use of the compound according to any one of claims 1 to 3 for the manufacture of medicaments useful as inhibitors of the angiotensin I conversion enzyme.
12. 12. Use of the compound according to any one of claims 1 to 3 for the manufacture of medicines useful in the treatment of cardiovascular diseases.