"Novel Crystalline Forms Of Nateglinide"
Abstract:
This invention provides novel crystalline forms of N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine and process for the preparation of N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine which may be produced by crystallization of N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine with solvents and forming crystals in the antisolvents. The crystal forms produced in this process have different melting point, infrared spectra and X-ray diffraction patterns from earUer known polymorphs of Nateglinide. The present invention also provides process for the preparation of Netaglinide form B.
Specification
NOVEL CRYSTALLINE FORMS OF NATEGLINIDE
FIELD OF THE INVENTION:
The present invention relates to novel crystalline forms of N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine (i.e. Nateglinide), denominated forms DR and GP and method for manufacturing thereof The present invention also provides the process for the preparation of crystalline From B of N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine.
BACKGROUND OF THE INVENTION:
N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine (Nateglinide) of Formula (I) is known substance having therapeutic utility in depressing blood glucose levels.
N-(Trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine is disclosed in Japanese Patent AppUcation No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484). The Japanese patent describes that N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine may be crystallized from aqueous methanol to yield crystals having a melting point of 129*^ to 130°C and these crystals are labeled as "B-type" crystals. An infra red spectrum, DSC and powder X-ray diffraction pattern are mentioned in the US PatentNo.5463116.
us patent No.5463116 describes that N-(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine may be crystallized from aqueous ethanol, isopropanol and acetone to yield the "H-type" crystals of Nateglinide having the melting point 136° to 142°C.
Journal of Medicinal Chemistry, 32,1436 described the process for the preparation of N- (trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (Nateglinide) and its related compounds generically. The said journal also described the pharmaceutical composition and method of treatment using Nateglinide and its related compounds.
WO 02/34713 a PCT publication in Japanese, provides in its abstract:"A processes for preparing the B form of nateglinide crystals containing substantially no H form crystals, which comprises wet crystals of nateglinide solvate at low temperature until the solvate disappear and causing them xmdergoes a crystal transition. PCT application WO 03/022251 discloses novel stable AL type crystal form of Netaglinide and the
process for the preparation of novel stable AL type crystal form of Netaglinide.The said form is
obtained form the solution of acetonitrile under a specific temperature range.
PCT application WO 03/087039 discloses the crystalline M and P type crystals form of Nateglinide and process for the preparation thereof The M and P forms are charectersirized by XRPD having peak 6.0,14.2,15.2,18.8(2 Theta) and 4.8,5.3,14.3,15.2 (2 Theta).
PCT application WO 03/087038 discloses the Form R of nateglinide having a melting point of about 108 °C or solvate thereof The form R is obtained by dissolving nateglinide in ethanol toluene mixture and treating the solution with water containg hydroxypropylmethylcellulose.
Recently PCT application WO 04/009532 discloses the 26 polymorph of nateglinide. The forms are A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, alpha, beta, gamma, delta, epsilon, sigma, theta and omega. Some of these crystalline forms are hydrates, anhydrate and solvates. The said patent also discloses process for the preparation of these forms and also preparation of form B from these forms. Therefore there is need for new soUd forms of nateglinide and method of manufacturing thereof
SUMMARY OF INVENTION:
The present invention relates to the two crystalline forms of N(trans-4-isopropylcyclohexyl carbonyl) D-phenylalanine i.e. Nateglinide, denominated forms DR and GP . The crystalline forms DR and GP are substantially stable to the physical grinding and milUng. Such types of crystals are therefore more suitable for formulation.
An objective of the present invention is to provide a novel stable crystalline DR and GP form of N-[[trans-4-(l-methylethyl)cyclohexyl]-D-phenylalanine-
Further objective of the present invention is to provide method for manufacturing the novel stable crystalline DR and GP forms of N-[[^ra«5'"4-(l-methylethyl)cyclohexyl]-D"phenylalanine.
Further objective of the present invention is to provide process for the manufacturing the crystalline "Form-B" of N-[[/ran5-4-(l-methylethyl)cyclohexyl]-D-phenylalanine.
BRIEF DESCMPTION OF THE ANNEXURES WITH DRAWINGS
Fig-1:- Differential scanning calorimetry (DSC) of crystalline DR form of N-[[^ra«5-4-(l -
methylethyl)cyclohexyl]-D-phenylalanine in accordance with the present invention.
Fig-2:- Powder X-ray diffraction pattern of crystalline DR form of N-[[^raw5-4-(l-methylethyl)cyclohexyl]-D-phenylalanine as per the present invention.
Fig-3:- An infra red absorption spectrum of crystalline DR form of l
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