HK1129669B - α CRYSTALLINE FORM OF THE ARGININE SALT OF PERINDOPRIL, PROCESS FOR PREPARING IT, AND PHARMACEUTICAL COMPOSITIONS COMPRISING IT - Google Patents

Description

Alpha crystalline form of perindopril arginine salt, process for its preparation and pharmaceutical compositions containing it

The present invention relates to the alpha crystalline form of the L-arginine salt of perindopril of formula (I), processes for the preparation thereof and pharmaceutical compositions containing the same,

perindopril and its pharmaceutically acceptable salts, more particularly its arginine salt, have valuable pharmacological properties. Their main properties are the inhibition of angiotensin I converting enzyme (or kininase II), which on the one hand prevents the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and on the other hand prevents the degradation of bradykinin (a vasodilator) to an inactive peptide. These two effects make perindopril have a beneficial effect in cardiovascular diseases, more particularly in arterial hypertension and heart failure.

Perindopril, its preparation and its therapeutic use have been described in european patent specification EP 0049658.

The arginine salt of perindopril is already described in european patent specification EP 1354873.

In view of the pharmaceutical value of the compound, it is most important to obtain the compound excellent in stability mainly in terms of hygroscopicity, powder processability, solid filterability, grindability and solvent retention.

Obtaining a well-defined crystalline form can meet those requirements.

Patent specification EP 1354873 describes the arginine salt of perindopril. However, this document does not describe the conditions for obtaining a well-defined crystalline form of the salt.

The applicant has now found that the arginine salt of perindopril can be obtained in a well-defined crystalline form, as a result of which it has valuable properties with respect to filterability, drying and ease of formulation.

More particularly, the present invention relates to the alpha crystalline form of the compound of formula (I) characterized by the following powder X-ray diffraction peaks measured with a diffractometer having a copper anticathode and expressed in 2 theta angles (°): 4.5, 7.9 and 13.5.

The present invention preferably relates to the alpha crystalline form of the compound of formula (I) characterized by the following powder X-ray diffraction peaks measured with a diffractometer having a copper anticathode and expressed in 2 theta angles (°): 4.5, 7.9, 13.5, 17.5 and 20.6.

Even more preferably, the present invention relates to the alpha crystalline form of the compound of formula (I), characterized by the following powder X-ray diffraction diagram, determined with a diffractometer (copper vs. cathode) and expressed in interplanar spacing d, bragg angle 2 θ, intensity and relative intensity (expressed as a percentage of the most intense line):

the invention also relates to a process for the preparation of the alpha crystalline form of the compound of formula (I), wherein perindopril is dissolved in water containing L-arginine, then a non-polar solvent and a polar solvent are added, and the resulting crystals are filtered off, washed and then dried.

As the nonpolar solvent, methylcyclohexane, cyclohexane and toluene may be mentioned by way of example. As polar solvents, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methyl-2-pyrrolidone may be mentioned by way of example.

The compound thus obtained is in a compact form consisting of a cuboid.

According to one embodiment of the invention perindopril is dissolved in water containing L-arginine, then methylcyclohexane and dimethyl sulfoxide are added, and the resulting crystals are filtered off, washed and then dried.

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

The dosage used may be adjusted according to the nature and severity of the disorder, the route of administration and the age and weight of the patient. The dose varies between 1 and 500mg per day, administered one or more times.

The pharmaceutical compositions of the present invention may also contain a diuretic such as indapamide.

The following examples illustrate the invention.

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

siemens D5005 diffractometer; a flicker detector;

copper to cathode, 40KV voltage, 30mA current intensity;

installing theta-theta and fixing a sample;

temperature: ambient temperature;

measurement range: 3 ° to 30 °;

increment between each assay: 0.04 degree;

measuring time at each step: 4 seconds;

fixing the slit: 1.6 mm;

a K β filter (Ni);

no internal standard;

carrying out zero setting operation by using a Siemens slit;

the experimental data were processed using EVA software (version 9.0).

Example 1: alpha crystalline form of perindopril arginine salt

1.5kg of water, 328g of perindopril and 155g L-arginine were added to the reactor with stirring at ambient temperature. When a clear solution was obtained, 630g of methylcyclohexane was added, followed by slow addition of 4.7kg of dimethyl sulfoxide. The mixture is then stirred until the temperature of the heterogeneous mixture stabilizes at around 20.0 ℃, after which the mixture is filtered off and the solid obtained is washed and dried.

The compound thus obtained is in a compact form consisting of a cuboid.

The water content of the product obtained is around 3.2%, which corresponds to the monohydrate.

Powder X-ray diffraction pattern

The powder X-ray diffraction pattern (diffraction angles) of the alpha crystalline form of perindopril arginine salt is given by the significant lines and intensities and relative intensities (expressed as a percentage of the most intense line) summarized in the table below:

example 2: pharmaceutical composition

A formulation for making 1000 tablets, each tablet containing 4mg of active ingredient:

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Claims (7)

1. Alpha crystalline form of the L-arginine salt of perindopril of formula (I),

characterized in that it is obtained by means of a powder X-ray diffraction diagram measured with a diffractometer having a copper anticathode and expressed in interplanar spacing d, Bragg angle 2 theta, intensity and relative intensity, wherein the relative intensity is expressed as a percentage of the most intense line:

2. a process for the preparation of the alpha crystalline form of the compound of formula (I) according to claim 1, wherein perindopril is dissolved in water containing L-arginine, followed by the addition of a non-polar solvent selected from methylcyclohexane and a polar solvent selected from dimethyl sulfoxide, and the resulting crystals are filtered off, washed and then dried.

3. A pharmaceutical composition comprising as active ingredient the alpha crystalline form of the L-arginine salt of perindopril of formula (I) according to claim 1 and one or more pharmaceutically acceptable inert non-toxic carriers.

4. Pharmaceutical composition according to claim 3, characterized in that it also contains a diuretic.

5. A pharmaceutical composition according to claim 4, characterized in that said diuretic is indapamide.

6. Use of the alpha crystalline form of the L-arginine salt of perindopril of formula (I) according to claim 1 for the preparation of a medicament for use as angiotensin I converting enzyme inhibitor.

7. Use of the alpha crystalline form of the L-arginine salt of perindopril of formula (I) according to claim 1 for the preparation of a medicament for the treatment of cardiovascular diseases.