β Crystalline form of the arginine salt of perindopril, a process for its preparation and pharmaceutical compositions containing it

Abstract

β-crystalline form of the compound of formula (I):

Description

The present invention relates to the β crystalline form of the arginine salt of perindopril of formula (I):

to a process for its preparation and to pharmaceutical compositions containing it.

Perindopril and its pharmaceutically acceptable salts, and more especially its arginine salt, have valuable pharmacological properties.

Their principal property is that of inhibiting angiotensin I converting enzyme (or kininase II), which allows, on the one hand, impedance of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, prevention of the degradation of bradykinin (a vasodilator) to an inactive peptide.

Those two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, more especially in arterial hypertension and heart failure.

Perindopril, its preparation and its use in therapeutics have been described in European Patent specification EP 0 049 658.

The arginine salt of perindopril has been described in European Patent specification EP 1 354 873.

In view of the pharmaceutical value of that compound, it has been of prime importance to obtain it with excellent stability, mainly in terms of hygroscopicity, of processability of the powder, of filtrability of the solid, of grindability, and of solvent retention.

Obtaining a well-defined crystalline form allows those requirements to be met.

Patent specification EP 1 354 873 describes the arginine salt of perindopril. That document does not, however, specify the conditions for obtaining that salt in a well-defined crystalline form.

The Applicant has now found that the arginine salt of perindopril can be obtained in a well-defined crystalline form that, as a result, has valuable characteristics for filtration, drying and ease of formulation.

More specifically, the present invention relates to the β crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction peaks, measured using a diffractometer with a copper anti-cathode and expressed in terms of angle 2 theta (°): 4.3, 19.1 and 21.6.

Preferably, the present invention relates to the β crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction peaks, measured using a diffractometer with a copper anti-cathode and expressed in terms of angle 2 theta (°): 4.3, 11.1, 12.2, 16.2, 19.1, 19.6 and 21.6.

Even more preferably, the present invention relates to the β crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction diagram measured using a diffractometer (copper anti-cathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense line):

	Inter-planar		Relative
Angle 2 theta (°)	distance d (Å)	Intensity	intensity (%)
4.29	20.58	2314	100.0
9.73	9.088	257	11.1
11.083	7.977	735	31.8
11.400	7.756	452	19.5
12.237	7.227	762	32.9
13.050	6.778	657	28.4
14.604	6.061	619	26.8
15.039	5.886	436	18.8
16.188	5.471	1025	44.3
19.168	4.627	1820	78.6
19.622	4.521	1016	43.9
21.666	4.098	1352	58.4
22.892	3.882	430	18.6
23.399	3.799	394	17.0
24.197	3.675	232	10.0
26.024	3.421	298	12.9
29.490	3.026	291	12.6

The invention relates also to a process for the preparation of the β crystalline form of the compound of formula (I), wherein the (L)-arginine salt of perindopril is heated with toluene or acetonitrile, at reflux, and then the crystals obtained are filtered off in the hot state and dried.

The invention relates also to pharmaceutical compositions comprising as active ingredient the β crystalline form of the compound of formula (I) together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions.

The dosage used can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. It varies from 1 to 500 mg per day in one or more administrations.

The pharmaceutical compositions according to the invention may also contain a diuretic such as indapamide.

The following Examples illustrate the invention.

The powder X-ray diffraction spectrum was measured under the following experimental conditions:

• Siemens D5005 diffractometer; scintillation detector;
• Copper anti-cathode, voltage 40 KV, intensity 30 mA
• Mounting θ-θ, fixed specimen;
• Temperature: ambient;
• Measurement range: 3° to 30°;
• Increment between each measurement: 0.04°;
• Measurement time per step: 4 s;
• Fixed slits: 1.6 mm;
• Kβ filter (Ni);
• No internal reference;
• Zeroing procedure using Siemens slits;
• Experimental data processed using EVA software (version 9.0).

EXAMPLE 1

β Crystalline Form of Perindopril Arginine Salt

100 g of perindopril (L)-arginine salt and 5 l of acetonitrile are introduced into a reactor with stirring. The mixture is then heated to reflux with stirring. The solid, initially in suspension, dissolves completely, and then precipitates in the hot state after a few minutes. After stirring at reflux for 1 hour, the crystals obtained are filtered off at a temperature of 80° C. The resulting crystals are dried to yield the title product in anhydrous form.

Powder X-Ray Diffraction Diagram

The powder X-ray diffraction profile (diffraction angles) of the β form of perindopril arginine salt is given by the significant lines collated in the following table together with the intensity and relative intensity (expressed as a percentage of the most intense line).

	Inter-planar		Relative
Angle 2 theta (°)	distance d (Å)	Intensity	intensity (%)
4.29	20.58	2314	100.0
9.73	9.088	257	11.1
11.083	7.977	735	31.8
11.400	7.756	452	19.5
12.237	7.227	762	32.9
13.050	6.778	657	28.4
14.604	6.061	619	26.8
15.039	5.886	436	18.8
16.188	5.471	1025	44.3
19.168	4.627	1820	78.6
19.622	4.521	1016	43.9
21.666	4.098	1352	58.4
22.892	3.882	430	18.6
23.399	3.799	394	17.0
24.197	3.675	232	10.0
26.024	3.421	298	12.9
29.490	3.026	291	12.6

EXAMPLE 2

Pharmaceutical Composition

Preparation formula for 1000 tablets each containing 4 mg of active ingredient:

• Compound of Example 1 . . . 4 g
• Hydroxypropylcellulose . . . 2 g
• Wheat starch . . . 10 g
• Lactose . . . 100 g
• Magnesium stearate . . . 3 g
• Talc . . . 3 g

Claims

1. A β-crystalline form of the L-arginine salt of perindopril of formula (I):

2. The β-crystalline form of the compound of formula (I) of claim 1, wherein the crystalline form is characterized by the following X-ray diffraction peaks, measured using a diffractometer with a copper anti-cathode and expressed in terms of Bragg's angle 2 theta (°): 4.3, 11.1, 12.2, 16.2, 19.1, 19.6 and 21.6.

3. The β-crystalline form of the compound of formula (I) of claim 1, wherein the crystalline form is characterized by the following X-ray diffraction diagram, measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense line):

4. A solid pharmaceutical composition comprising as active ingredient the compound of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.

5. The pharmaceutical composition of claim 4, further comprising a diuretic.

6. The pharmaceutical composition of claim 5, wherein the diuretic is indapamide.