HK1096388B - βD-CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT - Google Patents

Description

Beta d-crystalline form of ivabradine hydrochloride, process for its preparation and pharmaceutical compositions containing it

The present invention relates to a novel beta d-crystalline form of ivabradine hydrochloride of general formula (I), a process for its preparation and pharmaceutical compositions containing it:

ivabradine and its addition salts with a pharmaceutically acceptable acid, more particularly its hydrochloride, have extremely valuable pharmacological and therapeutic properties, in particular heart rate slowing (bradycardic) properties, making these compounds useful for the treatment or prevention of various clinical conditions of myocardial ischemia, such as angina pectoris, myocardial infarction and related arrhythmias, as well as of various pathological conditions involving arrhythmias, in particular supraventricular arrhythmias, and heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, more particularly the hydrochloride salt thereof, have been described in european patent specification EP 0534859.

In view of the pharmaceutical value of the compound, it is most important to obtain the compound with excellent purity. It is also important to be able to synthesize it by a process which is easy to convert to industrial scale, especially in a form which allows rapid filtration and drying. Finally, the crystalline form must be completely reproducible, easy to formulate and sufficiently stable for its long-term storage without specific requirements as to temperature, light or oxygen level.

A process for the synthesis of ivabradine and its hydrochloride is described in patent specification EP 0534859. However, the conditions for obtaining in a reproducible manner the ivabradine form exhibiting those characteristics are not particularly detailed in this reference.

The applicant has now found that it is possible to obtain a crystalline form of the specific salt of ivabradine, i.e. the hydrochloride salt, which is well defined and exhibits valuable characteristics of stability and processability.

More particularly, the present invention relates to the beta d-form of ivabradine hydrochloride, characterized by a powder X-ray diffraction pattern measured using a PANalytical X 'Pert Pro diffractometer and an X' Celerator detector and according to the line (ray) position (bragg angle 2 θ in degrees), the line height (in counts), the line area (in counts × degrees), the line width at half height ("FWHM", in degrees) and the interplanar spacing d (in counts × degrees)Representation) represents:

the invention also relates to a process for preparing the beta d-crystalline form of ivabradine hydrochloride, characterized in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until complete dissolution and then gradually cooled until complete crystallization, and the crystals thus formed are collected and dehydrated.

In the crystallization process of the invention, ivabradine hydrochloride obtained by any method can be used, for example ivabradine hydrochloride obtained by the preparation process described in patent specification EP 0534859.

The solution can advantageously be seeded in a cooling step.

The invention also relates to a pharmaceutical composition comprising as active ingredient the ss d-crystalline form of ivabradine hydrochloride together with one or more suitable inert non-toxic excipients. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions, suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration.

The useful dosage may vary depending on the nature and severity of the disease, the route of administration and the age and weight of the patient. The dosage varies between 1-500 mg/day and is administered in one or more divided doses.

The following examples illustrate the invention.

The X-ray powder diffraction spectra were determined under the following experimental conditions:

-a PANalytical X 'Pert Pro diffractometer, X' Celerator detector, temperature controlled chamber;

-voltage 45kV and current 40 mA;

-upper machine (motoring) θ - θ;

-a nickel (K β) filter;

-soller slits for incident and diffracted rays: 0.04 rad;

-fixed angle of the diverging slits: 1/8 degrees;

mask (mask): 10 mm;

-an anti-scatter-slit: 1/4 degrees;

-assay format: continuously from 3 degrees to 30 degrees, and gradually increasing according to 0.017 degrees;

-determination time/step: 19.7 s;

-total time: 4min 32s

-determining the speed: 0.108 °/s;

-determination of the temperature: and (4) environment.

Example 1: beta d-crystalline form of ivabradine hydrochloride

720ml of purified water are preheated to 50 ℃ and then 250g of ivabradine hydrochloride obtained according to the method described in patent specification EP 0534859 are added in portions while stirring, and the mixture is heated at 74 ℃ until dissolution is complete. The resulting clear solution was heated at 74 ℃ for an additional 2 hours and then gradually cooled, first to 40 ℃ and then to ambient temperature. The solution was then stored at ambient temperature for 2 days, and the solid suspension was then spread as a thin layer on the crystallization plate. Excess water was driven off in a moderate nitrogen stream.

The product thus obtained was dehydrated by stepwise heating at a rate of 5 ℃/min up to a temperature of 80 ℃.

X-ray powder diffraction pattern:

the X-ray powder diffraction pattern (diffraction angle) of the crystalline form ivabradine β d-hydrochloride is given by the important lines collated in the table below:

example 2: pharmaceutical composition

A formulation was prepared of 1000 tablets each containing 5mg of ivabradine base:

5.39g of the Compound of example 1

Corn starch 20g

0.2g of anhydrous colloidal silica

Mannitol 63.91g

PVP 10g

Magnesium stearate 0.5g

Claims (8)

1. Beta d-crystalline form of ivabradine hydrochloride of general formula (I):

characterized by the following powder X-ray diffractogram, measured using a PANalytical X 'PertPro diffractometer and an X' Celerator detector, and expressed in terms of line position, line height, line area, line width at half height and interplanar spacing d:

wherein the spectral line position is expressed in Bragg angle 2 theta with unit of degree, the spectral line height is expressed in counts, the spectral line area is expressed in counts x degrees, the spectral line width at half height is expressed in degrees, and the interplanar spacing d is expressed in degreesAnd (4) showing.

2. Process for the preparation of the β d-crystalline form of ivabradine hydrochloride according to claim 1, characterized in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until complete dissolution and then cooled stepwise until complete crystallization, and the crystals thus formed are collected and then dehydrated.

3. Process according to claim 2, characterized in that the solution of ivabradine hydrochloride is seeded in a cooling step.

4. Pharmaceutical composition comprising as active ingredient the ss d-crystalline form of ivabradine hydrochloride according to claim 1 together with one or more pharmaceutically acceptable inert non-toxic carriers.

5. Use of the β d-crystalline form of ivabradine hydrochloride according to claim 1 for the preparation of a medicament useful as a medicament for slowing heart rate.

6. Use of the β d-crystalline form of ivabradine hydrochloride according to claim 1 for the preparation of a medicament useful for the treatment or prevention of various clinical conditions of myocardial ischemia and of various pathological conditions involving dysrhythmias and heart failure.

7. The use according to claim 6, wherein the clinical condition of myocardial ischemia is angina pectoris, myocardial infarction or related arrhythmia.

8. Use according to claim 6, wherein said pathological condition involving dysrhythmia is supraventricular dysrhythmia.