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POLYMORPHIC FORM OF RAMIPRIL

IP.com Disclosure Number: IPCOM000222858D
Publication Date: 2012-Oct-25

Publishing Venue

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Abstract

The present disclosure relates to a polymorphic form of ramipril and its preparation. The polymorphic form of the present disclosure is designated as Form A of ramipril.

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POLYMORPHIC FORM OF RAMIPRIL

Abstract

The present disclosure relates to a polymorphic form of ramipril and its preparation.  The polymorphic form of the present disclosure is designated as Form A of ramipril.

Ramipril is chemically described as (2S,3aS,6aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid as represented by Formula I.

FORMULA I

Ramipril is indicated for the treatment of hypertension.  It may be used alone or in combination with thiazide diuretics.

U.S. Patent No. 5,061,722 describes the process for the preparation of ramipril using crystallization from ether, gives a ramipril which has a melting point of 110ºC to 112ºC. 

U.S. Patent Application No 2007/0232680 describes a process for the purification of ramipril using solvents selected from ether, a ketone, water, or a mixture thereof.

WO 2005/068422 describes monohydrate of ramipril and its conversion to anhydrous ramipril.  This monohydrate is further characterized by XRD and DSC data and having a water content between 4% to 4.5%.  It also describes a process of preparation of optically pure ramipril having optical purity of at least 99.9% by crystallization of optically impure ramipril from a solvent or a mixture of solvents selected from a group consisting of methyl formate, nitroalkanes, acetate, and ethers.

WO 2009/122433 describes the process for the crystallization of ramipril using acetonitrile and ethyl acetate.

The present authors have found that ramipril can be crystallized in polymorphic Form A.  The present disclosure also provides a simple, efficient and industrially preferable process for the preparation of polymorphic Form A of ramipril.  The polymorphic Form A of ramipril is stable and suitable for developing pharmaceutical dosage forms.

One aspect of the present disclosure provides a polymorphic Form A of ramipril.  The polymorphic Form A of ramipril is characterized by an XRPD (X-ray powder diffraction) pattern having interplanar spacing (d) values substantially at 11.72, 10.96, 6.95, 6.58, 6.30, 5.87, 5.49, 5.04, 4.96, 4.90, 4.32, 4.28, 4.19, 3.74, 3.66, 3.47 and 3.24 ± 0.2 (Å).  The polymorphic Form A of ramipril is further characterized by an XRPD (X-ray powder diffraction) pattern having interplanar spacing (d) values substantially at 11.72, 10.96, 8.61, 6.95, 6.58, 6.48, 6.30, 6.18, 5.87, 5.65, 5.49, 5.24, 5.04, 4.96, 4.90, 4.62, 4.43, 4.32, 4.28, 4.19, 3.92, 3.74, 3.71, 3.66, 3.55, 3.47, 3.44, 3.33, 3.24, 3.21, 3.15, 3.03, 2.90, 2.84, 2.73, 2.68, 2.60, 2.53, 2.46, 2.41, 2.33 and 2.29 ± 0.2 (Å).  The polymorphic Form A of ramipril exhibits an endotherm between about 110ºC to about 130ºC in differential scanning calorimetery (DSC).

Another aspect of present disclosure provides a process for the preparation of polymorphic Form A of ramipril wherein the process comprises:

a)            treating ramipril with a first organic solvent; and

b)            treating the mixture obtained in step a) wit...