HK1058199B - Novel $g(y) crystalline form of perindopril tert-butylamine salt, preparation method, and pharmaceutical compositions containing same - Google Patents

Description

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

The present invention relates to a novel gamma 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 gamma 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 (%)
				6.298	14.02	630	39.8
7.480	11.81	380	24
				8.700	10.16	1584	100
9.276	9.53	318	20.1
				10.564	8.37	526	33.2
11.801	7.49	54	3.4
				12.699	6.96	86	5.4
13.661	6.48	178	11.2
				14.095	6.28	163	10.3
14.332	6.17	290	18.3
				14.961	5.92	161	10.2
15.793	5.61	128	8.1
				16.212	5.46	179	11.3
16.945	5.23	80	5.1
				17.291	5.12	92	5.8
17.825	4.97	420	26.5
				18.100	4.90	159	10
18.715	4.74	89	5.6
				19.017	4.66	118	7.4
19.362	4.58	134	8.5
				19.837	4.47	133	8.4
20.609	4.31	95	6
				21.232	4.18	257	16.2
21.499	4.13	229	14.5
				21.840	4.07	127	8
22.129	4.01	191	12.1
				22.639	3.92	137	8.6
23.000	3.86	88	5.6

23.798	3.74	147	9.3
				24.170	3.68	70	4.4
25.066	3.55	167	10.5
				25.394	3.50	165	10.4
26.034	3.42	84	5.3
				26.586	3.35	75	4.7
27.541	3.24	74	4.7
				28.330	3.15	85	5.4
29.589	3.02	96	6.1

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

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

or according to a second embodiment, heating a solution of perindopril tert-butylamine salt in ethyl acetate under reflux, then rapidly cooling the solution to 0-5 ℃ and collecting the solid thus obtained by filtration. The solid was suspended in chloroform, the suspension was stirred at room temperature for 5-10 days, and then the solid was collected 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 chloroform is preferably 150-300 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 concentration of the resulting solid in chloroform is preferably 100-150 g/l.

The invention also relates to pharmaceutical compositions comprising the compound of formula (I) in gamma 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: gamma crystalline form of perindopril tert-butylamine salt

100g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP0308341 are dissolved in 500ml of chloroform heated at reflux.

The solution was then cooled to 0 ℃ and stirred at this temperature overnight. The resulting solid was collected by filtration.

Powder X-ray diffraction pattern:

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

2 theta angle (°)	Interplanar spacing d (_)	Strength of	Relative Strength (%)
				6.298	14.02	630	39.8
7.480	11.81	380	24
				8.700	10.16	1584	100
9.276	9.53	318	20.1
				10.564	8.37	526	33.2

11.801	7.49	54	3.4
				12.699	6.96	86	5.4
13.661	6.48	178	11.2
				14.095	6.28	163	10.3
14.332	6.17	290	18.3
				14.961	5.92	161	10.2
15.793	5.61	128	8.1
				16.212	5.46	179	11.3
16.945	5.23	80	5.1
				17.291	5.12	92	5.8
17.825	4.97	420	26.5
				18.100	4.90	159	10
18.715	4.74	89	5.6
				19.017	4.66	118	7.4
19.362	4.58	134	8.5
				19.837	4.47	133	8.4
20.609	4.31	95	6
				21.232	4.18	257	16.2
21.499	4.13	229	14.5
				21.840	4.07	127	8
22.129	4.01	191	12.1
				22.639	3.92	137	8.6
23.000	3.86	88	5.6
				23.798	3.74	147	9.3
24.170	3.68	70	4.4
				25.066	3.55	167	10.5
25.394	3.50	165	10.4
				26.034	3.42	84	5.3
26.586	3.35	75	4.7
				27.541	3.24	74	4.7
28.330	3.15	85	5.4
				29.589	3.02	96	6.1

Example 2: gamma 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 temperature of the solution was then brought rapidly to 0-5 ℃.

The resulting solid was then collected by filtration and suspended in 750g of chloroform. The suspension was stirred at room temperature for 5-10 days, then the solid was collected by filtration.

Example 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. Gamma crystalline form of a compound of formula (I):

characterized in that it has the following powder X-ray diffraction pattern measured using a diffractometer with copper as counter-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 (%) 6.298 14.02 630 39.8 7.480 11.81 380 24 8.700 10.16 1584 100 9.276 9.53 318 20.1 10.564 8.37 526 33.2 11.801 7.49 54 3.4 12.699 6.96 86 5.4 13.661 6.48 178 11.2 14.095 6.28 163 10.3 14.332 6.17 290 18.3 14.961 5.92 161 10.2 15.793 5.61 128 8.1 16.212 5.46 179 11.3 16.945 5.23 80 5.1 17.291 5.12 92 5.8 17.825 4.97 420 26.5 18.100 4.90 159 10 18.715 4.74 89 5.6 19.017 4.66 118 7.4 19.362 4.58 134 8.5 19.837 4.47 133 8.4 20.609 4.31 95 6

21.232 4.18 257 16.2 21.499 4.13 229 14.5 21.840 4.07 127 8 22.129 4.01 191 12.1 22.639 3.92 137 8.6 23.000 3.86 88 5.6 23.798 3.74 147 9.3 24.170 3.68 70 4.4 25.066 3.55 167 10.5 25.394 3.50 165 10.4 26.034 3.42 84 5.3 26.586 3.35 75 4.7 27.541 3.24 74 4.7 28.330 3.15 85 5.4 29.589 3.02 96 6.1

2. Process for the preparation of the compound of formula (I) in gamma crystalline form according to claim 1, characterized in that a solution of perindopril tert-butylamine salt in chloroform is heated at 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 gamma 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, the solid thus obtained is collected by filtration, it is suspended in chloroform, the suspension is stirred at room temperature for 5-10 days, then the solid is collected by filtration.

4. Process according to claim 2, characterized in that the concentration of the compound of the formula (I) in chloroform is 150-300 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.