HK1055425B - A crystalline form of perindopril tert-butylamine salt - Google Patents

Description

Alpha crystalline form of perindopril tert-butylamine salt

The present invention relates to a novel alpha crystalline form of tert-butylamine salt of perindopril of formula (I):

a process for the preparation thereof and pharmaceutical compositions comprising the same.

Perindopril and its pharmaceutically acceptable salts, more particularly its tert-butylamine 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 (vasoconstrictor) and on the other hand prevents the degradation of bradykinin (vasodilator) into the inactive peptide.

These two effects contribute to the beneficial effects of perindopril in cardiovascular diseases, more particularly in arterial hypertension and heart failure.

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

In view of the pharmaceutical value of the compound, it is most important to obtain it in excellent purity. It is also important to be able to synthesize it by a process that can be easily converted to an industrial scale, especially in a form that allows rapid filtration and drying. Finally, the form must be completely reproducible, easy to formulate and sufficiently stable to allow long-term storage thereof without particular requirements as to temperature, light, humidity or oxygen content.

Patent specification EP0308341 describes an industrial synthesis process for perindopril. However, this document does not describe the conditions under which perindopril is obtained in a form which reproducibly shows these characteristics.

The applicant of the present application has now found that a specific salt of perindopril, the tert-butylamine salt, can be obtained in a well-defined, fully reproducible crystalline form which exhibits valuable properties in terms of filtration, drying and ease of formulation.

More specifically, the invention relates to the compound of formula (I) in the alpha crystalline form, characterized in that it has the following powder X-ray diffraction pattern, measured using a Siemens D5005 diffractometer (copper on cathode) and expressed in interplanar spacing D, bragg angle 2 θ, intensity and relative intensity (expressed as a percentage of the most intense rays):

2 theta angle (°)	Interplanar spacing d (_)	Strength of	Relative Strength (%)
				7.680	11.50	390	8.8
8.144	10.85	230	5.2
				9.037	9.78	4410	100
10.947	8.08	182	4.1
				13.150	6.73	82	1.9
13.687	6.46	83	1.9
				14.627	6.05	582	13.2
15.412	5.74	770	17.5
				16.573	5.34	1115	25.3
17.357	5.10	340	7.7
				18.109	4.89	193	4.4
19.922	4.45	306	6.9
				20.609	4.31	375	8.5
21.412	4.15	226	5.1
				21.832	4.07	217	4.9
22.158	4.01	483	11
				22.588	3.93	386	8.8
23.323	3.81	107	2.4
				24.200	3.67	448	10.2
24.727	3.60	137	3.1
				25.957	3.43	125	2.8
26.932	3.31	75	1.7
				27.836	3.20	197	4.5
28.966	3.08	129	2.9
				29.213	3.05	117	2.7

The invention also relates to a process for the preparation of the compound of formula (I) in alpha crystalline form, characterized in that a solution of perindopril tert-butylamine salt in ethyl acetate is heated under reflux and the solution is then gradually cooled to completion of crystallization.

In the crystallization process according to the invention, the compounds of formula (I) obtained by any method may be used. It is advantageous to use the compounds of formula (I) obtained by the preparation process described in patent specification EP 0308341.

The concentration of the compound of formula (I) in ethyl acetate is preferably from 70 to 90 g/l.

Advantageously, the solution of the compound of formula (I) in ethyl acetate at reflux is first cooled to a temperature of 55-65 ℃ at a rate of 5-10 ℃/hour, preferably 6-8 ℃/hour, and then cooled to room temperature.

Advantageously, the solution may be seeded during the cooling step at a temperature of from 76 to 65 ℃.

The thus obtained perindopril tert-butylamine salt is in the form of individual needles having a length of about 0.2 mm. The advantage of this homogeneous distribution is that it allows particularly rapid and efficient filtration and drying and allows the preparation of pharmaceutical formulations having a uniform and reproducible composition, which is particularly advantageous when these formulations are intended for oral administration.

The form thus obtained is sufficiently stable to allow long-term storage without special requirements as regards temperature, light, humidity or oxygen content.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) in alpha crystalline form as active ingredient 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, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and the like.

Useful dosages may vary depending on the nature and severity of the disease, the route of administration, and the age and weight of the patient. It varies from 1 to 500 mg/day, in one or more administrations.

The pharmaceutical compositions of the present invention may also comprise a diuretic such as indolinamide.

The following examples illustrate the invention but do not limit it in any way.

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

a Siemens D5005 diffractometer, a scintillation detector,

copper anticathode (λ 1.5405 — min.), voltage 40kV, intensity 40mA,

-installing a device of theta-theta,

-measuring the angle: 5 to 30 degrees are included,

-the increment between measurements: 0.02 degree,

-measurement time per step: the time of the reaction is 2 seconds,

-a variable slit: the voltage of the voltage v6 is adjusted,

-a filter K beta (Ni),

-the absence of an internal standard,

zero-setting procedure using Siemens slits,

the experimental data were processed using EVA software (version 5.0).

Example 1: alpha crystalline form of perindopril tert-butylamine salt

125g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP0308341 are dissolved in 1.68 l of ethyl acetate heated at reflux.

The solution temperature was then allowed to reach 60 ℃ over 2 hours and 30 minutes, after which it was cooled to room temperature. The resulting solid was collected by filtration.

Powder X-ray diffraction pattern:

the powder X-ray diffraction pattern (diffraction angle) of the alpha form of perindopril tert-butylamine salt is given by the effective rays and the intensities and relative intensities (expressed as a percentage of the strongest rays) classified in the following table:

2 theta angle (°)	Interplanar spacing d (_)	Strength of	Relative strength(％)
				7.680	11.50	390	8.8
8.144	10.85	230	5.2
				9.037	9.78	4410	100
10.947	8.08	182	4.1
				13.150	6.73	82	1.9
13.687	6.46	83	1.9
				14.627	6.05	582	13.2
15.412	5.74	770	17.5
				16.573	5.34	1115	25.3
17.357	5.10	340	7.7
				18.109	4.89	193	4.4
19.922	4.45	306	6.9
				20.609	4.31	375	8.5
21.412	4.15	226	5.1
				21.832	4.07	217	4.9
22.158	4.01	483	11
				22.588	3.93	386	8.8

23.323	3.81	107	2.4
				24.200	3.67	448	10.2
24.727	3.60	137	3.1
				25.957	3.43	125	2.8
26.932	3.31	75	1.7
				27.836	3.20	197	4.5
28.966	3.08	129	2.9
				29.213	3.05	117	2.7

Example 2: pharmaceutical composition

A formulation for preparing 1000 tablets each containing 4mg of active ingredient was prepared:

… … … … … … … … … … … … … … … … 4g of the Compound from example 1

Hydroxypropyl cellulose … … … … … … … … … … … … … … … … … … 2g

… … … … … … … … … … … … … … … … … … … … 10g of wheat starch

Lactose … … … … … … … … … … … … … … … … … … … … … … 100g

… … … … … … … … … … … … … … … … … … … … 3g of magnesium stearate

Talc … … … … … … … … … … … … … … … … … … … … … … 3g

Claims (9)

1.α crystalline form of a compound of formula (I):

characterized in that it has the following powder X-ray diffraction pattern measured using a diffractometer (copper vs. cathode) and expressed in interplanar spacing d, bragg angle 2 θ, intensity and relative intensity (expressed in percentage with respect to the most intense ray):

2 theta angle (°) Interplanar spacing d (_) Strength of Relative Strength (%) 7.680 11.50 390 8.8 8.144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17.357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21.832 4.07 217 4.9 22.158 4.01 483 11 22.588 3.93 386 8.8 23.323 3.81 107 2.4 24.200 3.67 448 10.2 24.727 3.60 137 3.1 25.957 3.43 125 2.8 26.932 3.31 75 1.7

27.836 3.20 197 4.5 28.966 3.08 129 2.9 29.213 3.05 117 2.7

2. Process for the preparation of the compound of formula (I) in the alpha crystalline form according to claim 1, characterized in that a solution of perindopril tert-butylamine salt in ethyl acetate is heated under reflux and then the solution is gradually cooled until crystallization is complete.

3. Process according to claim 2, characterized in that the concentration of the compound of formula (I) in ethyl acetate is between 70 and 90 g/litre.

4. A process according to claim 2, characterized in that the solution of the compound of formula (I) in ethyl acetate at reflux is first cooled to a temperature of 55-65 ℃ at a rate of 5-10 ℃/hour and then to room temperature.

5. Process according to claim 2, characterized in that the solution of the compound of formula (I) in ethyl acetate is seeded during the cooling step at a temperature of 76-65 ℃.

6. A process according to claim 4, characterized in that the solution of the compound of formula (I) in ethyl acetate at reflux is first cooled to a temperature of 55-65 ℃ at a rate of 6-8 ℃/h and then to room temperature.

7. A pharmaceutical composition comprising a compound according to claim 1 as active ingredient in combination with one or more pharmaceutically acceptable inert, non-toxic carriers.

8. The pharmaceutical composition according to claim 7 for the manufacture of a medicament for use as an inhibitor of angiotensin I converting enzyme.

9. The pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment of cardiovascular diseases.