Title of Invention	PROCESS FOR THE PREPARATION OF β CRYSTALLINE FORM OF PERINDOPRIL TERT-BUTYLAMINE SALT
Abstract	NEW P CRYSTALLINE FORM OF PERINDOPRIL TERT-BUTYLAMINE SALT, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT 5 B crystalline form of the compound of formula (I) characterised by its powder X-ray diffraction diagram. Medicaments.

Full Text

FORM 2 THE PATENTS ACT, 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; Rule 13] "PROCESS FOR THE PREPARATION OF B CRYSTALLINE FORM OF PERINDOPRIL TERT-BUTYLAMINE SALT LES LABORATOIRES SERVIER, of 12 Place de la Defense, 92415 Courbevoie, Cedex, France, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- The present invention relates to process for the preparation of p crystalline form of perindopril tert-butylamine salt of formula (I) and more particularly to a new P crystalline form of perindopril tert-butylamine salt 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 tert-butylamine salt, have valuable pharmacological properties. Their principal property is that of inhibiting angiotensin I converting enzyme (or kininase H), which prevents, on the one hand, conversion of the de'capeptide angiotensin I to the octapeptide angiotensin II (a vasoeonstrictor) and, on the other hand, degradation of bradykimin (a vasodilator) to an. inactive peptide. Those two motions -contribute to the benefit effects of oerindopril in cardiavasc.ular 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. In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by T means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without-particular requirements for temperature, light, humidity or oxygen level. The patent specification EP 0 308 341 describes an industrial synthesis process for perindopril. However, that document does not specify the conditions for obtaining perindopril in a form that exhibits those characteristics in a reproducible manner. The Applicant has now found that a particular salt of perindopril, the tert-butylamine salt, can be obtained in a well defined, perfectly reproducible crystalline form that especially exhibits valuable characteristics for formulation. Accordingly, there is provided process for the preparation of B crystalline form of perindopril tert-butylarnine salt of formula (I) characterised in that a solution of perindopril tert-butylarnine salt in dichloromethane is heated at reflux, the solution is then cooled to 0°C and the solid obtained is collected by filtration. More specifically, the present invention relates to the {3 crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 diffiractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage pf the most intense ray): The invention relates also to a process for the preparation of the p crystalline form of the compound of formula (I), which process is characterised in that: - either, according to a first embodiment, a solution of perindopril tert-butylamine salt in dichloromethane is heated at reflux and is then rapdily cooled to 0°C and the solid obtained is collected by filtration, or, according to a second embodiment, a solution of perindopril tert-butylamine salt in ethyl acetate is heated at reflux and is then rapidly cooled to 5°C and the solid obtained is collected by filtration. • In the crystallisation process according to the invention it is possible to use the compound of formula (I) obtained by any process. Advantageously, the compound of formula (I) obtained by the preparation process described in patent specification EP 0 308 341 is used. • In the first embodiment of the process according to the invention, the concentration of the compound of formula (I) in the dichloromethane is preferably from 100 to 200 g/litre. • In the second embodiment of the process according to the invention, the concentration of the compound of formula (I) in the ethyl acetate is preferably from 70 to 90 g/litre. The invention relates also to pharmaceutical compositions comprising as active ingredient the B 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 dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.. The useful dosage 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 comprise a diuretic such as indapamide. The following Examples illustrate the invention but do not limit it in any way. The powder X-ray diffraction spectrum was measured under the following experimental conditions : - Siemens D5005 diffractometer, scintillation detector, - copper anticathode (k=l .5405 A), voltage 40 kV, intensity 40 mA, - mounting 6-6, - measurement range : 5° to 30°, - increment between each measurement: 0.02°, - measurement time per step : 2 s, - variable slits : v6, - filter K/3 (Ni), - no internal reference, - zeroing procedure with the Siemens slits, - experimental data processed using EVA software (version 5.0). EXAMPLE 1 : P crystalline form of perindopril tert-butylamine salt 135 g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP 0 308 341 are dissolved in 1100 ml of dichloromethane heated at reflux. The solution is then cooled to 0°C and the solid obtained is collected by filtration. Powder X-ray diffraction diagram : The powder X-ray diffraction profile (diffraction angles) of the p form of perindopril tert-butylamine salt is given by the significant rays collated in the following table together with the intensity and relative intensity (expressed as a percentage of the most intense ray): EXAMPLE 2 : p crystalline form of perindopril tert-butylamine salt 125 g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP 0 308 341 are dissolved in 1.5 litres of ethyl acetate heated at reflux. The solution is then cooled rapidly to 5°C and the solid obtained is collected by filtration. EXAMPLE 3 : 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 3g WECLAIM:- 1. Process for the preparation of B crystalline form of perindopril tert-butylamine salt of formula (I) characterised in that a solution of perindopril tert-butylamine salt in dichloromethane is heated at reflux, the solution is then cooled to 0°C and the solid obtained is collected by filtration. 2. Process for the preparation of the p crystalline form of the compound of formula (I) as claimed in claim 1, wherein a solution of perindoril tert-butylamine salt in ethyl acetate is heated at reflux, the solution is rapidly cooled to 5°C and the solid obtained is then collected by filtration. 3. Process as claimed in either claim 1 or claim 2, wherein the compound of formula (I) obtained by preparation process described in patent specification EP 0 308 341 is used. 4. Process as claimed in claim 1, wherein the concentration of the compound of formula (I) in the dichloromethane is from 100 to 200 g/litre. 5. Process as claimed in claim 2, wherein the concentration of the compound of formula (I) in the ethyl acetate is from 70 to 90 g/litre. 6. Process for the preparation of p crystalline form of perindopril tert-butylamine salt of formula (I) substantially as hereinbefore described with reference to the foregoing examples. Dated this 3rd day of July, 2002. [SANJAY KUMAR] OP REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

594-MUM-2002-ABSTRACT(3-7-2002).pdf

594-mum-2002-abstract(6-7-2005).doc

594-mum-2002-abstract(6-7-2005).pdf

594-MUM-2002-ABSTRACT(GRANTED)-(16-4-2008).pdf

594-mum-2002-cancelled pages(6-7-2005).pdf

594-MUM-2002-CLAIMS(COMPLETE)-(3-7-2002).pdf

594-MUM-2002-CLAIMS(GRANTED)-(16-4-2008).pdf

594-mum-2002-claims(granted)-(6-7-2005).doc

594-mum-2002-claims(granted)-(6-7-2005).pdf

594-MUM-2002-CORRESPONDENCE(6-7-2005).pdf

594-mum-2002-correspondence(7-7-2005).pdf

594-MUM-2002-CORRESPONDENCE(IPO)-(22-5-2008).pdf

594-mum-2002-correspondence(ipo)-(7-7-2005).pdf

594-MUM-2002-DESCRIPTION(COMPLETE)-(3-7-2002).pdf

594-MUM-2002-DESCRIPTION(GRANTED)-(16-4-2008).pdf

594-mum-2002-form 1(10-8-2002).pdf

594-MUM-2002-FORM 1(16-8-2002).pdf

594-mum-2002-form 1(3-7-2002).pdf

594-mum-2002-form 1(6-7-2005).pdf

594-mum-2002-form 19(1-4-2004).pdf

594-MUM-2002-FORM 2(COMPLETE)-(3-7-2002).pdf

594-MUM-2002-FORM 2(GRANTED)-(16-4-2008).pdf

594-mum-2002-form 2(granted)-(6-7-2005).doc

594-mum-2002-form 2(granted)-(6-7-2005).pdf

594-MUM-2002-FORM 2(TITLE PAGE)-(COMPLETE)-(3-7-2002).pdf

594-MUM-2002-FORM 2(TITLE PAGE)-(GRANTED)-(16-4-2008).pdf

594-mum-2002-form 3(10-3-2005).pdf

594-mum-2002-form 3(10-8-2002).pdf

594-MUM-2002-FORM 3(16-8-2002).pdf

594-mum-2002-form 3(3-7-2002).pdf

594-MUM-2002-FORM 3(3-9-2002).pdf

594-mum-2002-petition under rule 137(10-3-2005).pdf

594-MUM-2002-PETITION UNDER RULE 138(10-3-2005).pdf

594-MUM-2002-POWER OF AUTHORITY(4-9-2002).pdf

594-MUM-2002-SPECIFICATION(AMENDED)-(10-3-2005).pdf

594-MUM-2002-SPECIFICATION(AMENDED)-(6-7-2005).pdf

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