Title of Invention	" y CRYSTALLINE FORM OF PERINDOPRIL TERT-BUTYLAMINE COMPOUND OF FORMULA ( I )
Abstract	γ crystalline form of perindopril tert-butylamine compound of formula (I): characterized by the following powder X-ray diffraction diagram, measured using a diffract meter (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage with respect to the most intense ray):

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FORM 2 THE PATENTS ACT, 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; Rule 13] "γ CRYSTALLINE FORM OF PERINDOPRIL TERT-BUTYLAMINE COMPOUND OF FORMULA (I)" LES LABORATOIRES SERVIER, of 12, Place de La Defense, F-92415 Courbevoie Cedex, France, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- GRANTED 28-12-2006 ORIGINAL The present invention relates to a γ crystalline form of perindopril tert-butylamine compound 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 II), which prevents, on the one hand, conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, 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. 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 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. More specifically, the present invention relates to the y crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 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 ray): The invention relates also to a process for the preparation of the y 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 chloroform is heated at reflux, the solution is then rapdily cooled to 0°C and, after stirring, 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, the solution is rapidly cooled to between 0 and 5°C and the solid thereby obtained is then collected by filtration. The solid is suspended in chloroform, the suspension is stirred at ambient temperature for from 5 to 10 days, and the solid is then collected by filtration. • In the crystallsation 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 chloroform is preferably from 150 to 300 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 concentration, in chloroform, of the solid obtained is preferably from 100 to 150 g/litre. The invention relates also to pharmaceutical compositions comprising as active ingredient the y 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 adminisfration, 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 : Sieniens D5005 diffractometer, scintillation detector, - copper anticathode (A,=1.5405 A), voltage 40 kV, intensity 40 mA, mounting d-d, measurement range : 5° to 30°, - increment between each measurement; 0.02°, - measurement time per step : 2 s, - variable slits : v6, - filter KB (Ni), - no internal reference, zeroing procedure with the Siemens slits, experimental data processed using EVA software (version 5.0). EXAMPLE 1 : y crystalline form of perindopril tert-butylamine salt 100 g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP 0 308 341 are dissolved in 500 ml of chloroform heated at reflux. The solution is then cooled to 0°C and stirred overnight at that temperature. The solid obtained is collected by filtration. Powder X-ray diffraction diagram : The powder X-ray diffi-action profile (diffraction angles) of the y 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 : y 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 temperature of the solution is then rapidly brought to between 0 and 5°C. The solid obtained is then collected by filtration and is then suspended in 750 g of chloroform. The suspension is stirred at ambient temperature for from 5 to 10 days and the solid is then 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 3 g We Claim: 1. γ crystalline form of perindopril tert-butylamine compound of formula (I): characterized by the following powder X-ray diffraction diagram, measured using a diffract meter (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage with respect to the most intense ray): 2. Process for the preparation of the γ crystalline form of perindopril tert-butylamine compound as claimed in claim 1, wherein a solution of prerindopril tert-butylamine salt in ethyl acetate is heated at reflux, the solution is rapidly cooled and the solid thereby obtained is then collected by filtration, it is suspended in chloroform, the suspension is stirred at ambient temperature for from 5 to 10 days, and the solid is then collected by filtration. 3. 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. 4. Pharmaceutical composition comprising active ingredient as y crystalline form of perindopril tert-butylamine compound of formula (I) as claimed in claim 1, in combination with one or more pharmaceutically acceptable inert nontoxic carriers. 5. Pharmaceutical composition as claimed in any one of claim 4, wherein said composition optionally comprises a diuretic. 6. Pharmaceutical composition as claimed in claim 10, wherein said diuretic is indapamide. Dated this 02nd day of May, 2005. [DEEPAK KUMAR) OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

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362-mumnp-2005-claim(granted)-(28-12-2006).doc

362-mumnp-2005-form 2(granted)-(28-12-2006).doc

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362-mumnp2005-form 1(2-5-2005).pdf

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362-mumnp2005-form 2(granted)-(28-12-2006).pdf

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362-mumnp2005-form 3(21-8-2006).pdf

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362-mumnp2005-form-pct-isa-210(2-5-2004).pdf

362-mumnp2005-petition under rule 137(22-8-2006).pdf

362-mumnp2005-power of authority(2-5-2005).pdf

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