MXPA06002274A - Beta-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it - Google Patents

Abstract

A beta-Crysta11ine form of ivabradine of formula (I):characterised by its powder X-ray diffraction data. Medicinal products containing the same which are useful as bradycardics.

Description

FORM ß-CRYSTALINE OF IVABRADINE CHLORHYDRATE, A PROCESS FOR ITS PREPARATION AND COMPACTION PHARMACEUTICALS THAT CONTAIN IT The present invention relates to the new ß-crystalline form of ivabradine hydrochloride of formula (I), to a process for its preparation and to pharmaceutical compositions containing it: Ivabradine and the addition salts thereof with a pharmaceutically acceptable acid and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making these compounds useful in the treatment or prevention of various clinical ischemic situations myocardial diseases such as angina pectoris, myocardial infarction and associated rhythm disturbances, and also of various pathologies involving rhythm disturbances, especially alterations of supraventricular rhythm, and in heart failure, The preparation and therapeutic use of ivabradine and salts of addition of the same with a pharmaceutically acceptable acid, and more especially its hydrochloride have been described in the Specification of. European Patent EP 0 634 859. In view of the pharmaceutical value of this compound, it has been of paramount importance to obtain it with excellent purity. It has also been important to be able to synthesize it by means of a process that can be easily converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form would have to be perfectly reproducible, formulated easily and sufficiently stable to allow its storage for prolonged periods without particular requirements of temperature, light or concentration of oxygen. Patent specification EP 0 534 859 describes a synthesis process for ivabradine and its hydrochloride. However, the document does not specify the conditions for obtaining ivabradine in a form that exhibits these characteristics in a reproducible manner. The Applicant has now found that a particular salt of ivabrádine, the hydrochloride, can be obtained * in a crystalline form that is well defined and exhibits valuable stability and processability characteristics. More specifically, the present invention relates to the ß-crystalline form of ivabradine hydrochloride, which is characterized by the following powder X-ray diffraction diagram, edidp using a PANaiytical X'Pert Pro diffractometer together with a detector X ' Celerator and expressed in terms of beam position (Bragg angle 2 theta, expressed in degrees), beam height (expressed in beads), beam area (expressed in x-degree beads), ray width at mid-height ("FWHM") ", expressed in degrees) and interplane distance d (expressed in Á): The invention also relates to a process for the preparation of the ß-crystalline form of ivabradine hydrochloride, the process is characterized in that a mixture of ivabradine hydrochloride and water, or a mixture of ivabradine hydrochloride, isopropanol and water is heated to that the solution is complete and then progressively cooled until the crystallization is complete and the crystals formed are collected. • In the crystallization process according to the invention it is possible to use ivabradine hydrochloride obtained by any process, for example ivabradine hydrochloride obtained by the preparation process described in the patent specification EP 0 534 859. • The solution can advantageously be sown during the cooling stage. The invention also relates to pharmaceutical compositions comprising as active ingredient the ß-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert and non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those which are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or lozenges, sublingual tablets, gelatin capsules, diamond-shaped tablets, suppositories, creams, ointments, dermal gels, injectable preparations and ingestible suspensions. The useful dosage can be varied according to the nature and severity c} the disorder, the route of administration and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations. The following Examples illustrate the invention. The powder X-ray diffraction spectrum was measured under the following experimental conditions: - PANatytical X'Pert Pro dífractometer, X'Celerator detector, chamber with regulated temperature - voltage 45 kV, current 40 mA, - assembly? -? - nickel filter (Kß), - slot Soller of incident beam and diffracted beam: 0.04 rads, - fixed angle of divergence slots: 1/8 °, - filter: 10 mm, - anti-scatter slot: 1/4 °, - measurement mode: continuous from 3o to 30 °, in increments of 0.017 °, - measurement time per stage: 19.7 sec., - total time: 4 minutes 32 sec., - measurement speed: O.108 ° / ség. , - measurement temperature: ambient.

EXAMPLE 1: ß-crystalline form of ivabradine hydrochloride 720 ml of purified water were preheated to 50 ° C and then 250 g of ivabradine hydrochloride, obtained according to the process described in EP 0 534 patent specification, were added in portions. 859, with stirring, and the mixture was heated to 74 ° C until the solution was complete. The resulting clear solution was cured for 2 more hours at 74 ° C and then cooled progressively, first at 40 ° C and then at room temperature. The solution was subsequently stored at room temperature for 2 days, and then the solid suspension was spread on a thin layer on a crystallization plate. The excess water was removed under a gentle stream of nitrogen. The water content of the resulting product, determined by coulometry, is 12.4%, which corresponds to a tetrahydrate.

X-ray powder diffraction diagram: The X-ray powder diffraction profile (diffraction angles) of the ß-form of ivabradine hydrochloride is given by the significant rays compared in the following Table: EXAMPLE 2: Pharmaceutical composition Formula for the preparation of 1, 000 tablets, each containing 5 mg of ivabradine base: Compound of Example 1, 5.39 g Corn starch 20 g Colloidal anhydrous silica, 0.2 g Mannitol 63.91 g PVP t 10 g Magnesium stearate 0.5 g

Claims (6)

1. CLAIMS 1. ß-crystalline form of ivabradine hydrochloride of formula (I): characterized by the following X-ray powder diffraction diagram, measured using a PANalyticai X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of beam position (Bragg angle 2 theta, expressed in degrees), height of the beam (expressed in beads), area of the beam (expressed in x-degree beads), width of the beam at half height ("FWHM", expressed in
2. 2. Process for the preparation of the ß-crystalline form of ivabradine hydrochloride, where a mixture of ivabradine hydrochloride and water, or a mixture of ivabradipa hydrochloride, isOpropanol and water is heated until the solution is complete and then progressively cooled until the crystallization is complete, and the crystals formed are collected.
3. 3. Process according to claim 2, wherein the ivábradjna hydrate solution is seeded during the cooling step.
4. 4. A pharmaceutical composition comprising as an active ingredient the β-crystalline form of the ivabradine hydrochloride according to claim 1, in combination with one or more pharmaceutically acceptable, inert and non-toxic carriers.
5. 5. Use of the ß-crystalline form of the ivabradine hydrochloride according to claim 1, in the manufacture of medicaments that are useful as bradycardic.
6. 6. Use of the β-crystalline form of. ivabradine hydrochloride according to claim 1, in the manufacture of drugs that are useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarction and associated rhythm disturbances, and also of various pathologies that involve alterations , of rhythm, especially subrotentricular rhythm changes, and in heart failure.