Krystallinsk delta-form af argininsaltet af perindopril, fremgangsmåde til fremstilling heraf og farmaceutiske sammensætninger indeholdende dette

摘要

#CMT# #/CMT# Delta crystalline form of perindopril L-arginine salt (I) having X-ray powder diffraction peaks measured using a diffractometer with a copper anticathode and expressed in terms of Bragg's angle 2 theta values as given in the specification, is new. #CMT# : #/CMT# Independent claims are included for: (1) the preparation of delta crystalline form of (I); and (2) a composition comprising an active agent and the delta crystalline form of (I) in combination with carriers. #CMT#ACTIVITY : #/CMT# Cardiovascular-Gen; Hypotensive; Cardiant; Vasotropic. #CMT#MECHANISM OF ACTION : #/CMT# Angiotensin I converting enzyme inhibitor. #CMT#USE : #/CMT# The delta crystalline form of (I) is useful for the treatment of cardiovascular diseases, preferably arterial hypertension, cardiac failure and the stable coronary disease (all claimed). No biological data given. #CMT#ADVANTAGE : #/CMT# The delta crystalline form of (I) has excellent storage stability and improved pharmacological properties. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of delta crystalline form of (I) comprises crystallization or recrystallization of (I) from a binary mixture of acetonitrile, ethyl acetate or methyl tert-butyl ether and dimethyl sulfoxide, or a ternary mixture of acetonitrile, dimethyl sulfoxide and toluene, at 20[deg] C. Preferred Process: The temperature of the reaction medium is 25-80[deg] C. The reaction mixture is heated to a temperature of 60-80[deg] C, and is seeded with the delta crystalline form. Preferred Components: The delta crystalline form of (I) has X-ray powder diffraction peaks and C-13 NMR spectrum values as given in the specification. The binary mixture of acetonitrile, ethyl acetate or methyl tert-butyl ether and dimethyl sulfoxide has a weight ratio of acetonitrile/dimethyl sulfoxide, ethyl acetate/dimethyl sulfoxide or methyl tert-butyl ether/dimethyl sulfoxide is 90:10-10:90. #CMT#PHARMACEUTICALS : #/CMT# Preferred Composition: The composition further comprises a diuretic, a calcium antagonist or an If current inhibitor. Preferred Components: The diuretic is indapamide. The calcium antagonist is amlodipine. The If current inhibitor is ivabradine. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 1-20 (preferably 2.5-10) mg per day orally, parenterally, intravenously, subcutaneously or nasally. #CMT#EXAMPLE : #/CMT# Perindopril arginine salt (55.32 g), dimethyl sulfoxide (297.50 g) and acetonitrile (94.49 g) were introduced into a reactor. The obtained mixture was heated at 70[deg] C for 7 hours under stirring, and then cooled to 40[deg] C at 1[deg] C/minute. After 30 minutes at 40[deg] C, the mixture was filtered over a glass frit. Then the filter cake was washed with ethyl acetate and dried overnight at 50[deg] C in a fan-circulation oven to yield delta crystalline form of perindopril arginine (54%).