HK1058200B - Novel $g(b) crystalline form of perindopril tert-butylamine salt, preparation method, and pharmaceutical compositions containing same - Google Patents

Description

Novel beta crystalline form of perindopril tert-butylamine salt, process for its preparation and pharmaceutical compositions containing it

The present invention relates to a novel beta 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, is obtainable in a well-defined, fully reproducible crystalline form, which shows particularly valuable properties for formulation.

More specifically, the invention relates to a compound of formula (I) in β 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 (%)
				5.169	17.08	523	16.5
8.379	10.54	1001	31.5
				9.350	9.45	3175	100
14.746	6.00	236	7.4
				15.411	5.74	753	23.7
15.931	5.56	279	8.8
				16.711	5.30	113	3.6
18.161	4.88	122	3.8
				20.564	4.32	1198	37.7
21.285	4.17	330	10.4
				21.781	4.08	317	10
22.632	3.93	190	6
				23.308	3.81	133	4.2
23.797	3.74	427	13.4
				24.276	3.66	118	3.7
25.190	3.53	92	2.9
				25.924	3.43	251	7.9
26.646	3.34	250	7.9
				27.620	3.23	96	3
28.306	3.15	133	4.2

The invention also relates to a process for the preparation of a compound of formula (I) in beta crystalline form, characterized in that:

-according to a first embodiment, a solution of perindopril tert-butylamine salt in dichloromethane is heated at reflux, then the solution is rapidly cooled to 0 ℃ and the resulting solid is collected by filtration;

or according to a second embodiment, heating a solution of perindopril tert-butylamine salt in ethyl acetate at reflux, then rapidly cooling the solution to 5 ℃ and collecting the resulting solid by filtration.

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.

In the first embodiment of the process of the invention, the concentration of the compound of formula (I) in dichloromethane is preferably 100-200 g/l.

In a second embodiment of the process according to the invention, the concentration of the compound of formula (I) in ethyl acetate is preferably from 70 to 90 g/l.

The invention also relates to pharmaceutical compositions comprising as active ingredient a compound of formula (I) in beta crystalline form 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: beta crystalline form of perindopril tert-butylamine salt

135g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP0308341 are dissolved in 1100ml of dichloromethane heated at reflux.

The solution was then cooled to 0 ℃ and the resulting solid was collected by filtration.

Powder X-ray diffraction pattern:

the powder X-ray diffraction pattern (diffraction angle) of the β 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 (%)
				5.169	17.08	523	16.5
8.379	10.54	1001	31.5
				9.350	9.45	3175	100
14.746	6.00	236	7.4
				15.411	5.74	753	23.7
15.931	5.56	279	8.8
				16.711	5.30	113	3.6
18.161	4.88	122	3.8
				20.564	4.32	1198	37.7
21.285	4.17	330	10.4
				21.781	4.08	317	10
22.632	3.93	190	6
				23.308	3.81	133	4.2
23.797	3.74	427	13.4
				24.276	3.66	118	3.7
25.190	3.53	92	2.9
				25.924	3.43	251	7.9
26.646	3.34	250	7.9
				27.620	3.23	96	3
28.306	3.15	133	4.2

Example 2: beta 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 1.5 l of ethyl acetate heated at reflux.

The solution was then rapidly cooled to 5 ℃ and the resulting solid was collected by filtration.

Practice ofExample 3: 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 (8)

1. A compound of formula (I) in β crystalline form:

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 (%) 5.169 17.08 523 16.5 8.379 10.54 1001 31.5 9.350 9.45 3175 100 14.746 6.00 236 7.4 15.411 5.74 753 23.7 15.931 5.56 279 8.8 16.711 5.30 113 3.6 18.161 4.88 122 3.8 20.564 4.32 1198 37.7 21.285 4.17 330 10.4 21.781 4.08 317 10 22.632 3.93 190 6 23.308 3.81 133 4.2 23.797 3.74 427 13.4 24.276 3.66 118 3.7 25.190 3.53 92 2.9 25.924 3.43 251 7.9 26.646 3.34 250 7.9 27.620 3.23 96 3 28.306 3.15 133 4.2

2. Process for the preparation of the compound of formula (I) in beta crystalline form according to claim 1, characterized in that a solution of perindopril tert-butylamine salt in dichloromethane is heated under reflux, then the solution is cooled to 0 ℃ and the resulting solid is collected by filtration.

3. Process for the preparation of the compound of formula (I) in beta crystalline form according to claim 1, characterized in that a solution of perindopril tert-butylamine salt in ethyl acetate is heated under reflux, then the solution is rapidly cooled to 5 ℃ and the resulting solid is collected by filtration.

4. Process according to claim 2, characterized in that the concentration of the compound of the formula (I) in dichloromethane is 100-200 g/l.

5. A process according to claim 3, characterized in that the concentration of the compound of formula (I) in ethyl acetate is from 70 to 90 g/l.

6. 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.

7. The pharmaceutical composition according to claim 6 for the manufacture of a medicament for use as an inhibitor of angiotensin I converting enzyme.

8. The pharmaceutical composition according to claim 7 for the manufacture of a medicament for the treatment of cardiovascular diseases.