Title of Invention	PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALIUM
Abstract	A simple and efficient process for the preparation of amorphous form of Atorvastatin calcium of Formula I The process comprises the conversion of the crystalline Atorvastatin calcium to amorphous Atorvastatin calcium by using pulverization method.

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FIELD OF THE INVENTIONS The present invention relates to a process for the preparation of pure amorphous Atorvastatin calcium from pure crystalline Atorvastatin calcium by purverization method. BACKGROUND OF THE INVENTION Atorvastatin of Formula I is a selective inhibitor of the enzyme 3-hydroxy-3-methyl glutaryl Co A reductase (HMG-CoA reductase) and is chemically known as [R-(R*,R*)-2-(4-fluorophenyl)-p,5-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt. As such Atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypocholesterolemic agent. Atorvastatin was disclosed in US patent 5,273,995 as ring opened dihydroxy acid form. US patents 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792 and 5,342,952, which are herein incorporated by reference, disclose various processes and key intermediates for preparing Atorvastatin calcium. The processes described in the above mentioned US patents do not give amorphous Atorvastatin calcium consistently but give a mixture of its crystalline and amorphous forms, which has unsuitable filtration and drying characteristics. US patent 6,087,511 describes the preparation of amorphous Atorvastatin calcium by dissolving the compound in a non-hydroxylic solvent and removing solvent by vacuum drying. This process suffers from disadvantages such as highly specialized equipment, longer drying time, residual solvents in the product and need to recovery of solvents. US Patent 6,274,740 describes the method for conversion of crystalline form of Atorvastatin calcium to amorphous form which comprises of using two solvents. The process involves complete removal of solvent under high vacuum (5 mm of Hg) at high temperature (90°C) using capital intensive equipment and further vacuum drying at high temperature leads to degradation of the product. US Patent 6,528,660 (75/DEL/99) describes preparation of amorphous Atorvastatin calcium by solvent precipitation. Atorvastatin calcium is dissolved in tetrahydrofuran and an anti solvent is added to obtain amorphous material. However, this process makes use of large quantities of solvents thus requiring efficient solvent recovery. A further drawback of this process is the amount of residual solvents left even after extensive drying. PCT Application WO 01/28999 Al describes an alternate process wherein amorphous Atorvastatin calcium was prepared by crystallization from a lower alkanol containing 2-4 carbon atoms. US application 2002/0183527 also describes the preparation of amorphous Atorvastatin calcium by solvent precipitation. Crystalline Atorvastatin calcium is dissolved in alcohol and ether is added to precipitate the amorphous product. PCT Application WO 02/83637 (333/MUM/2001) discloses the preparation of amorphous Atorvastatin calcium directly from diol protected tert-butyl ester. But disadvantage of this process is that amorphous Atorvastatin calcium prepared is contaminated with unreacted diol compound and needs purifications. PCT Application WO 03/018547 (PCT/INO 1/00152) describes process for the preparation of amorphous Atorvastatin calcium which comprises hydrolyzing the lactone form of Atorvastatin with aqueous base, extracting with organic solvent and adding the same to an anti-solvent to precipitate the product and finally filtering the product to afford amorphous Atorvastatin calcium. Alternatively, amorphous Atorvastatin calcium is prepared from crystalline Atorvastatin calcium, which comprises dissolving the crystalline Atorvastatin calcium in an organic solvent, distilling off half of the solvent and adding the same to an anti solvent to precipitate the amorphous product. Thus, it is evident that most of the methods described in the prior art to prepare amorphous Atorvastatin calcium have some disadvantages such as involving use of large volumes of solvents, thus requiring efficient solvent recovery, low yields and high limits of residual solvents even after sufficient drying which makes these processes industrially unattractive from economical and handling point of view. It is therefore an object of the present invention to provide a process for the preparation of amorphous Atorvastatin calcium which avoids production of mixture of amorphous and crystalline forms and which is economical and capable of being practiced on a commercial scale. According to the present invention amorphous Atorvastatin calcium is prepared by pulverization of crystalline Form I or other crystalline forms of Atorvastatin calcium without the use of organic solvents. BRIEF DESCRIPTION OF ACCOMPANYING DRA WINGS Fig. 1 is a X-ray powder diffractogram of amorphous Atorvastatin calcium. Vertical axis: Intensity (CPS); Horizontal axis: Two theta (degrees) Fig. 2 is a X-ray powder dififractogram of crystalline form 1 of Atorvastatin calcium. Vertical axis: Intensiiy (CPS); Horizontal axis: Two theta (degrees). Fig. 3 is the infi-ared absorption spectrum of amorphous Atorvastatin calcium. Fig. 4 is the infrared absorption spectrum of crystalline form I of Atorvastatin calcium. DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to a simple and efficient process for the preparation of amorphous Atorvastatin calcium, which involves the conversion of crystalline form of Atorvastatin calcium to amorphous form by pulverization. Here, pulverization means crushing or grinding of a substance to fine particles. The crystalline Atorvastatin calcium may be prepared by the methods described in the previously mentioned US Patents, which are incorporated herein by reference. Specifically, the pulverization of crystalline form of Atorvastatin calcium was carried out by using mortar and pestle or mechanical grinding. The said process is conducted in neat without using any solvent. Typically the conversion of crystalline form to amorphous form is completed in 8-10 hrs at ambient temperature and this can be monitored by infrared and X-ray powder diffraction analyses during crushing operation itself Amorphous Atorvastatin calcium, prepared by pulverizing the crystalline form has been characterized by X-ray powder diffraction, which is identical with the reported. The powdered X-ray diffraction of amorphous and crystalline Atorvastatin calcium were determined on Seifert XRD 3003TT system using a copper target X-ray tube, a nickel filter and sample was placed in a Pyrex glass holder. The X-ray powder diffractogram (Fig. 1) of amorphous Atorvastatin calcium shows that peaks characteristic of crystalline form of Atorvastatin calcium (Fig. 2) are entirely absent. The infrared absorption spectra of amorphous and crystalline forms of Atorvastatin calcium were determined on Perkin Elmer-spectrum ONE infrared spectrophotometer. The infrared spectrum of amorphous Atorvastatin calcium also shows difference from the infrared spectrum of crystalline Form-I of Atorvastatin calcium (Refer Fig. 3 and Fig. 4). Thus the major advantages of the present invention as compared to prior art processes are near quantitative yield and high purity, cost effectiveness, absence of residual solvent impurity and hence commercially attractive. No solvent is required to isolate the product and hence no mother liquor is obtained which is difficult to regenerate. Further details of the present invention are to be found in the following examples without limiting it: Example 1 PREPARA TION OF AMORPHOUS A TOR VASTA TIN CALCIUM Crystalline Atorvastatin calcium (Form I, 10 g) was taken in mortar. It was then pulverized using mortar and pestle for about 8-9 hours at room temperature. Atorvastatin calcium (9.9 g) thus obtained was characterized by powdered X-ray diffraction pattern (Fig. 1) showing no peaks, thus demonstrating that the nature of product is amorphous. Example 2 PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM Crystalline Atorvastatin calcium (10 g) was taken. The solid mass was then pulverized using mechanical grinder for about 8-9 hours at room temperature. The powdered X-ray diffraction pattern indicated that the material obtained is amorphous Atorvastatin calcium. WE CLAIM: 1. A process for the preparation of pure amorphous Atorvastatin calcium, which comprises the steps of subjecting the pure crystalline Atorvastatin calcium to pulverization at a temperature of 20-25°C, without using any solvent until the said crystalline Atorvastatin calcium is converted to amorphous form, isolating the amorphous Atorvastatin calcium. 2. The process according to claim 1 wherein pulverization is carried out using mortar and pestle or mechanical grinding or similar equipment to suit scale up. 3. The process according to claim 1 wherein the mortar and pestle is used preferably for carrying out pulverization. 4. The process according to claim 1 wherein the mechanical grinder is used preferably for carrying out pulverization. 5. The process according to claim 1 wherein the process is the solid phase transformation of crystalline Atorvastatin calcium to amorphous Atorvastatin calcium. 6. The process according to claim 1 wherein the process of conversion of crystalline Atorvastatin calcium to amorphous form is completed in 1-10 hours and preferably in 7-9 hours.

Documents:

438-che-2003-abstract.pdf

438-che-2003-claims duplicate.pdf

438-che-2003-claims original.pdf

438-che-2003-correspondnece-others.pdf

438-che-2003-correspondnece-po.pdf

438-che-2003-description(complete) duplicate.pdf

438-che-2003-description(complete) original.pdf

438-che-2003-drawings.pdf

438-che-2003-form 1.pdf

438-che-2003-form 26.pdf

438-che-2003-form 3.pdf

438-che-2003-other documents.pdf

438-che-2003-pct.pdf