Title of Invention	PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTA
Abstract	An industrially advantageous process for the preperation of pure amorphous atorvastain calcium from crystalline atorvastatin calcium by spray drying using hydroxylic solvents such as methanol, ethanol, isopropanol and thier aqueous mixtures thereof. The pure amorphous Atorvastain calcium, thus obtained is free from resuidal solvents.

Full Text

FIELD OF THE INVENTION The present invention relates to a process for producing pure amorphous Atorvastatin calcium from pure crystalline Atorvastatin calcium. BACKGROUND OF THE INVENTION Atorvastatin of Formula I is a selective inhibitor of the enzyme 3-hydroxy-3-methyi glutaryl CoA reductase (HMG-CoA reductase) and is chemically known as [R-(R*,R*)-2-(4- fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-1-heptanoic acid hemi calcium salt. 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 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 recover the 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 tetrahydrofiiran 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 high 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 Patent 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 rerr-butyl ester. But disadvantage of this process is that amorphous Atorvastatin calcium prepared is contaminated with unreacted diol compound and needs purification. 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. Use of hydroxylic solvents like methanol and ethanol offers advantages such as better solubility of Atorvastatin calcium in such solvents, low toxicity of alcoholic solvents particularly ethanol and low residual solvent content [well within the limits of International Conference on Harmonisation (ICH) guidelines] in the amorphous product. Further, spray drying is known to give consistently amorphous material enabling better control on formulation also. BRIEF DESCRIPTION OF A CCOMPANYING DRA WINGS Fig. 1: X-ray powder diffractogram of amorphous Atorvastatin calcium (Prepared in Example 1) Vertical axis : Intensity (CPS) Horizontal axis: Two theta (degrees) Fig. 2: X-ray powder diffractogram of amorphous Atorvastatin calcium (Prepared in Example 2) Vertical axis: Intensity (CPS) Horizontal axis: Two theta (degrees) Fig. 3; X-ray powder diffractogram of crystalline Atorvastatin calcium Vertical axis: Intensity (CPS) Horizontal axis: Two theta (degrees) Fig. 4: Infrared spectrum of amorphous Atorvastatin calcium (Prepared in Example 1) Fig, 5: Infrared spectrum of amorphous Atorvastatin calcium (Prepared in Example 2) Fig. 6: Infrared spectrum of crystalline Atorvastatin calcium SUMMARY OF THE INVENTION Accordingly, the present invention provides a process for producing pure amorphous Atorvastatin calcium, which comprises the steps of: - dissolving any pure crystalline form of Atorvastatin calcium of Formula I in any hydroxylic solvent such as methanol, ethanol, isopropanol and their aqueous mixtures thereof, - subjecting the resulting clear solution to spray drying at a temperature of 40oC to -90oC to remove the solvent and - isolating the amorphous Atorvastatin calcium in pure form. 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 any crystalline form of Atorvastatin calcium to amorphous Atorvastatin calcium by spray drying using hydroxylic solvents. 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 preparation of amorphous Atorvastatin calcium is carried out easily by spray drying a solution of crystalline Atorvastatin calcium in any suitable hydroxylic solvent. The hydroxylic solvent can be selected from group of solvents such as methanol, ethanol, isopropanol and like and their aqueous mixtures thereof We have found that Atorvastatin calcium is heat stable and withstands spray drying conditions. Spray drying system can be operated in known manner to obtain amorphous Atorvastatin calcium essentially free from crystalline material. This technique is safe and economic due to high recovery of product and use of a single solvent to prepare amorphous Atorvastatin calcium. The product obtained from spray drying has the form of hollow microspheres which can be conveniently compounded into pharmaceutical preparation. Residual solvent may be present in the product, immediately after spray drying which can be reduced by further drying under reduced pressure. Typically the crystalline Atorvastatin calcium is dissolved in any hydroxylic solvent to obtain 5-30% w/v solution, but preferably 10-15% w/v. The solvent may be heated and small quantities of water may be added if required to dissolve the material. The solution is then introduced in mini spray dryer manufactured by Buchi, Switzerland using nitrogen gas as drying gas. The gas inlet temperature is adjusted in the range from 50°C to 90°C and gas outlet temperature is adjusted between 40°C to 80°C. The product is spray dried until white, amorphous powder is obtained. Amorphous Atorvastatin calcium, prepared by the spray drying of the crystalline form has been characterized by powdered X-ray diffraction and infrared spectra. Thus, 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 powdered X-ray diffractograms of amorphous Atorvastatin calcium show no peaks (Fig.l and Fig.2) thereby indicating that product is amorphous, whereas Fig. 3 is a characteristic powdered X-ray diffractogram of crystalline form of Atorvastatin calcium. The infrared absorption spectra of amorphous and crystalline forms of Atorvastatin calcium were determined on Perkin Elmer-spectrum ONE infrared spectrophotometer. The infrared spectra of amorphous Atorvastatin calcium also shows difference with infrared spectrum of crystalline Atorvastatin calcium (Fig.4, Fig.5 and Fig.6). The major advantages realized in the present invention as compared to prior art processes are high purity, cost effectiveness, absence of residual solvent impurity, consistency and hence commercially attractive. Any crystalline form of Atorvastatin calcium that can be dissolved in the said solvents can be spray dried to obtain amorphous Atorvastatin calcium. 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 15 g of crystalline Atorvastatin calcium was dissolved in 100 ml of methanol. The clear solution was then introduced into spray dryer using nitrogen gas as drying gas. The product was then spray dried at a temperature of 58°C to 62°C until a white amorphous powder of Atorvastatin calcium was obtained. The amorphous material, thus obtained was dried under reduced pressure till LOD Example 2 PREPARA TION OF AMORPHOUS A TOR VASTA TIN CALCIUM 10 g of crystalline Atorvastatin calcium was dissolved in 200 ml of ethanol and heated to 60°C to get clear solution. The clear solution was then spray dried at 80°C to 85°C until a white amorphous powder of Atorvastatin calcium was obtained. The amorphous material thus obtained was dried under reduced pressure till moisture content WE CLAIM: 1. A process for producing pure amorphous Atorvastatin calcium, which comprises the steps of: - dissolving any pure crystalline form of Atorvastatin calcium of Formula I in any hydroxylic solvent such as methanol, ethanol, isopropanol and their aqueous mixtures thereof, - subjecting the resulting clear solution to spray drying at a temperature of 40°C to 90°C to remove the solvent and - isolating the amorphous Atorvastatin calcium in pure form. 2. The process as claimed in claim 1, wherein the clear solution of Atorvastatin calcium is prepared at a temperature of 25-60°C. 3. The process as claimed in claim 1, wherein the spray drying is carried out at a temperature of 40-90°Cand preferably at 55-85°C. 4. The process as claimed in claim 1, the pure amorphous Atorvastatin calcium prepared is free from residual solvents. Dated this the 30th day of May 2003

Documents:

439-che-2003-abstract.pdf

439-che-2003-claims duplicate.pdf

439-che-2003-claims original.pdf

439-che-2003-correspondnece-others.pdf

439-che-2003-correspondnece-po.pdf

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

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

439-che-2003-drawings.pdf

439-che-2003-form 1.pdf

439-che-2003-form 19.pdf

439-che-2003-form 26.pdf

439-che-2003-form 3.pdf

439-che-2003-pct.pdf