Title of Invention

"NOVEL POLYMORPHIC FORMS OF FLUVASTATIN SODIUM AND PROCESS FOR PREPARING THE SAME"

Abstract

Disclosed herein are novel polymorphic forms of Fluvastatin sodium, wherein said polymorphic forms are designated as JF, JFI, JF2, JF3 and are characterized by their powder X-ray diffraction patterns, Infrared absorption spectrums, thermo gravimetric analysis and differential scanning calorimetry. The processes for preparing said polymorphic forms are also disclosed. The present invention also relates to process for preparing amorphous form of Fluvastatin sodium.

Full Text

Field of the Invention This invention, in general relates to the field of HMG-CoA Reductase inhibitors, in particular to the field of Fluvastatin sodium More specifically the present invention provides novel crystalline polymorphic forms of Fluvastatin sodium, process for preparing the same Also the present invention provides a process for preparation of amorphous Fluvastatin sodium Background of the Invention Fluvastatin sodium is known by its chemical name (±)-7-(3-(4-fluorophenyi)-l-(l-methylethyl)-lH-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid monosodium salt Fluvastatin sodium is a racemic mixture of the 3R, 5S- and 3S, 5R-dihydroxy enantiomers represented by the Formula I (Formula Removed) Fluvastatin sodium is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles The end result of these biochemical processes is a reduction of the plasma cholesterol concentration Fluvastatin as well as its sodium salt are described in U S Pat No 4,739,073 In this patent Fluvastatin sodium is obtained by lyophilization and discloses the amorphous form, which is unsuitable for large-scale production as disclosed in the further literature US Patent No 6,124,340, describes that lyophilization of Fluvastatin sodium as was performed in examples 6(b) and 8 of '073 patent yields a mixture of a crystalline form, designated as Form A and amorphous matenal The estimated amount of Form A obtained by lyophilization as described by '340 patent is about 50% in the said mixture The '340 patent describes a new crystalline form designated as Form B The crystalline Form B is obtained either by transformation of material containing Form A in a slurry of a mixture of an organic solvent and water, or by crystallization from an organic solvent and water mixture This patent also descnbes that Form B is less hygroscopic than Form A or the amorphous form of the Fluvastatm sodium, which improves handling and storage of the compound US Patent No 6,696,479 descnbes crystalline forms of Fluvastatm sodium hydrates designated as form C, D, E, and F The water content of the forms ranges between 3 to 32% The patent also descnbes a new process for the preparation of highly crystalline form of Fluvastatm sodium Form A The new crystal forms of Fluvastatm sodium were obtained by stonng the sample under atmosphere ranging between 20 and 90% relative humidity International Publication No WO2004/096765A2 descnbes crystalline form of Fluvastatm sodium monohydrate depicted as BA The water content ranges from 3 to 6% Similarly International Publication No WO2005/080332 discloses novel crystalline form of Fluvastatm sodium with charactenstic PXRD peaks The water content ranges from 1 to 8% U S Patent Application No 2005032884, US Patent Application No 20050038114 and US Patent Application No US2005119342 disclose novel crystalline forms of Fluvastatm sodium, some of which are hydrates and solvates Objective of the present invention is to provide novel and stable polymorphic forms of Fluvastam sodium, which can effectively used for different pharmaceutical formulation Further, the process for prepanng said polymorphic forms is cost efficient and the produced polymorph is easy to handle and convenient to operate on commercial scale Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed descnption of examples thereof Summary of the Invention In accordance with principal embodiment of the present invention, there are provided novel crystalline polymorphic forms of Fluvastain sodium, wherein said polymorphic forms are designated as JF, JFI JF2 JF3 and are characterized by using analytical tools selected from infrared absorption spectrum, X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), differential scanning calonmetry (DSC) Further the present invention also provides a process for the preparation of amorphous form of Fluvastatm sodium In accordance with another embodiment, the present invention provides a crystalline polymorphic form of Fluvastatm sodium, wherein said polymorphic form is designated as JF characterized by a PXRD pattern having peaks at 3 3, 3 9, 10 0, 10 9, 17 1, 19 3, 20 6 ± 0 2° 29, essentially as represented in Fig 1 In accordance with another embodiment, the present invention provides a crystalline polymorphic form of Fluvastatm sodium, wherein said polymorphic form is designated as Jp, characterized by having an infrared spectrum in KBr comprising one or more characteristic peaks selected from absorption bands (cm1) at 3399, 1577, 1500, 1217, 1154, 1106, 839, 741, 564 essentially as represented in Fig 2 Further embodiment of the present invention provides a process for preparing said polymorphic form JF wherein the process composes of dissolving Fluvastatm lower alkyl ester in methanol, adding sodium hydroxide to the solution and then isolating Fluvastatm sodium Form Jp from the solution by adding anti-solvent selected from lower alkyl alcohols In accordance with another embodiment, the polymorphic form JF is prepared by dissolving Fluvastatm sodium in methanol, followed by addition of anti-solvent selected from lower alkyl alcohols In accordance with yet another embodiment of present invention there is provided a novel crystalline polymorphic form of Fluvastatm sodium, wherein said polymorphic form is designated as JFI, characterized by a PXRD pattern with peaks at 3 7, 4 9, 5 5, 9 8, 10 2, 11 2, 12 1 ±0 2°20, essentially as represented in FIG 5 In accordance with yet another embodiment of present invention there is provided a novel crystalline polymorphic form of Fluvastatm sodium, wherein said polymorphic form is designated as JFI, characterized by having an infrared spectrum in KBr compnsing one or more characteristic peaks selected from absorption bands (cm-l) at 3392, 1575, 1215, 1155, 839, 813, 740, 564, essentially as represented in Fig 6 Further embodiment of the present invention provides a process for prepanng said polymorphic form JFI, wherein the process compnses of dissolving Fluvastatm lower alkyl ester in methanol, adding sodium hydroxide to the solution and then isolating Fluvastatm sodium Form JFI from the solution by adding anti-solvent selected from nitriles In accordance with another embodiment, the polymorphic form JFI can be prepared by dissolving Fluvastatm sodium in methanol, followed by addition of anti-solvent selected from mtnles In accordance with yet another embodiment of present invention there is provided a novel crystalline polymorphic form of Fluvastatm sodium, wherein said polymorphic form is designated as JF2, charactenzed by a PXRD pattern with peaks at 4 9, 5 2, 5 6, 17 6+0 2°29, essentially as represented in FIG 9 In accordance with yet another embodiment of present invention there is provided a novel crystalline polymorphic form of Fluvastatm sodium, wherein said polymorphic form is designated as JF2, charactenzed by having an infrared spectrum in KBr compnsing one or more charactenstic peaks selected from absorption bands (cml) at 3403, 1722, 1572, 1500, 1457,1402,1219,1104, 969 essentially as represented in Fig 10 Further embodiment of the present invention provides a process for prepanng said polymorphic form JF2, wherein the process compnses of dissolving Fluvastatm lower alkyl ester in methanol, adding sodium hydroxide to the solution and then isolating Fluvastatm sodium Form JF2 from the solution by adding anti-solvent selected from alkyl esters followed by air-drying In accordance with another embodiment, the polymorphic form JF2 is prepared by dissolving Fluvastatin sodium in methanol, followed by addition of anti-solvent selected from alkyl esters followed by air-drying In accordance with yet another embodiment of present invention there is provided a novel crystalline polymorphic form of Fluvastatin sodium, wherein said polymorphic form is designated as JF3 charactenzed by a PXRD pattern with peaks at 5 2, 5 5, 6 0±0 2°20, essentially as represented in FIG 13 In accordance with yet another embodiment of present invention there is provided a novel crystalline polymorphic form of Fluvastatin sodium, wherein said polymorphic form is designated as JF3 charactenzed by having an infrared spectrum in KBr compnsmg one or more charactenstic peaks selected from absorption bands (cm1) at 3411, 1561, 1500, 1457, 1403, 1220, 1104, 837, 742, 565 essentially as represented in Fig 14 Further embodiment of the present invention provides a process for prepanng said polymorphic form JF3 wherein the process compnses of dissolving Fluvastatin lower alkyl ester in methanol, adding sodium hydroxide to the solution and then isolating Fluvastatin sodium Form JF3 from the solution by adding anti-solvent selected from alkyl esters In accordance with another embodiment, the polymorphic form JF3 is prepared by dissolving Fluvastatin sodium in methanol, followed by addition of anti-solvent selected from alkyl esters In accordance with another embodiment, there is provided a process for prepanng Fluvastatin sodium in amorphous form, wherein the process compnsmg dissolving Fluvastatin lower alkyl ester in methanol, adding sodium hydroxide to the solution and isolating Fluvastatin sodium in amorphous form from the solution by optionally adding anti-solvent selected from hydrocarbon Further embodiment of the present invention provides a process for prepanng amorphous form of Fluvastatin, wherein said process compnsmg dissolving Fluvastatin sodium in methanol, and then isolating Fluvastatm sodium in amorphous form from the solution by optionally adding anti-solvent selected from hydrocarbon The novel polymorphic forms of Fluvastatm sodium descnbed herein-in the present invention can be effectively used as pharmaceutical agents Bnef Descnption of the Drawing Figures Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the description of preferred embodiments of the present invention which are shown in the accompanying drawing figures FIG 1 depicts a powder X-ray diffractogram of crystalline Fluvastatm sodium, Form JF FIG 2 depicts infrared absorption spectrum of crystalline Fluvastatm sodium Form JF FIG 3 depicts Thermo gravimetric analysis of crystalline Fluvastatm sodium Form JF FIG 4 depicts Differential scanning calonmetry of Fluvastatm sodium Form JF FIG 5 depicts a powder X-ray diffractogram of crystalline Fluvastatm sodium, Form JFI FIG 6 depicts infrared absorption spectrum of crystalline Fluvastatm sodium Form JFI FIG 7 depicts Thermo gravimetric analysis of crystalline Fluvastatm sodium Form JF1 FIG 8 depicts Differential scanning calonmetry of Fluvastatm sodium Form JF1 FIG 9 depicts a powder X-ray diffractogram of crystalline Fluvastatm sodium, Form JF2 FIG 10 depicts infrared absorption spectrum of crystalline Fluvastatm sodium Form JF2 FIG 11 depicts Thermo gravimetnc analysis of crystalline Fluvastatm sodium Form Jp2 FIG 12 depicts Differential scanning calonmetry of Fluvastatm sodium Form JF2 FIG 13 depicts a powder X-ray diffractogram of crystalline Fluvastatm sodium, Form fo FIG 14 depicts infrared absorption spectrum of crystalline Fluvastatm sodium Form JF3 FIG 15depicts Thermo gravimetnc analysis of crystalline Fluvastatm sodium Form JF3 FIG 16 depicts Differential scanning calonmetry of Fluvastatm sodium Form JF3 FIG 17 depicts a powder X-ray diffractogram of amorphous Fluvastatm sodium Descnption of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed descnption of the invention and study of the included drawings The present invention discloses in its aspect novel crystalline polymorphic forms of Fluvastatin sodium designated as Form JF, JFI, JF2 and JF3 that may also exist in solvate forms and are intended to be encompassed within the scope of the present invention The present invention also provides process for the preparation of Fluvastatin sodium in amorphous form Fluvastatin sodium Forms JF, JFI, hi, JF2 and amorphous forms differ from each other in their physical properties, spectral data and process of preparation and are characterized by their X-ray powder diffraction patterns, infra red absorption spectra, differential scanning calonmetry and/or by their thermo gravimetnc analysis (TGA) X-ray powder Diffraction Crystalline Fluvastatin sodium Forms JF, JFI JF2, JF3 and amorphous forms are charactenzed by their X-ray powder diffraction pattern Thus the X-ray diffraction patterns of crystalline Fluvastatin sodium Forms are measured on a PANalytical X' Pert Pro diffractometer with Cu radiation and expressed in terms of 29, d-spacing and relative intensities Methodology Continuous 0/20 coupled scan 2 0° to 50° in 20, scan speed of 0 05°/sec Infrared absorption spectrometer (TR) Methodology All infrared measurement were made on Thermo Nicolet FT IR spectrometer using KBr pellets having the charactenstic absorption bands expressed in reciprocal centimeter Thermo Gravimetnc Analysis (TGA) Methodology TGA thermogram is recorded on TGA Q 50 with a ramp of 10°C/min to 350°C with nitrogen flow rate 60 ml/minute Differential Scanning Calonmetry (DSC) Methodology DSC thermogram is recorded on DSCQ100 equilibrated at 25°C to 350°C at 10°C/minute with nitrogen flow rate 60 ml/minute Crystalline Fluvastatin sodium Form JF IS characterized by powder X-ray diffraction pattern having peaks at 3 3, 3 9, 10 0,10 9,17 1,19 3, 20 6 +0 2° 29 as depicted in Fig 1 Crystalline Fluvastatin sodium Form JF is further characterized by having an infrared spectrum in KBr comprising one or more characteristic peaks selected from absorption bands (cm1) 3399(s), 2973(m), 2934(m), 1577(s), 1536(w), 1500(s), 1455(w), 1418(w), 1370(w), 1342(m), 1217(s), 1154(s), 1106(m), 1068(w), 1019(w), 974(m), 941(w), 839(s), 813(m), 741 (s), 717(w), 688(w), 654(m), 564(s), 522(m), wherein (w)= weak intensity, (m)= medium intensity, (s)= strong intensity as depicted in Fig 2 Crystalline Fluvastatin sodium Form JF IS prepared by hydrolyzing Fluvastatin lower alkyl ester selected from C1-4 alkyl ester in methanol, adding sodium hydroxide solution taken in water and cooled to 0-10°C, preferably 0-5°C The resulting reaction mixture is stirred at room temperature for 1-3 hours Solvent is distilled off The resulting mass is dissolved in an organic solvent such as methanol, heated to about 30-60°C, preferably 40-50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 3-8% by volume preferably between 4-6% by volume Anti-solvent, selected from lower alkyl alcohol such as ethanol, propanol or mixture thereof, is added The resulting solution is seeded with Fluvastatin sodium Form JF and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and dried under vacuum at 50-60°C for 30-60 hours preferably 35-45 hours Crystalline Fluvastatin sodium Form JF can also be prepared by dissolving Fluvastatin sodium in methanol and heating to about 30-60°C, more preferably 40- 50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 3-8% by volume preferably between 4-6% by volume Anti-solvent, selected from lower alkyl alcohol such as ethanol, propanol or mixture thereof, is added The resulting solution is seeded with Fluvastatm sodium Form JF and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and drying under vacuum at 50-60°C for 30-60 hours, preferably 35-45 hours Crystalline Fluvastatm sodium Form JFI IS characterized by powder X-ray diffraction pattern with peaks at 3 7, 4 9, 5 5, 9 8,10 2, 11 2,12 1 ±0 2° 20 as shown in Fig 5 Crystalline Fluvastatm sodium Form JFI is further characterized by having an infrared spectrum in KBr comprising one or more characteristic peaks selected from absorption bands (cm !) 3392(s), 2975(m), 2935(m), 2867(w), 1575(s), 1533(w), 1499(s), 1455(w), 1412(w), 1401(w), 1371(w), 1344(m), 1215(s), 1155(s), 1106(m), 1068(w), 1020(w), 972(m), 941(w), 887(w), 839(s), 813(s), 740(s), 718(w), 690(w), 653(m), 564(s), 522(m), wherein (w)= weak intensity, (m)= medium intensity, (s)= strong intensity as depicted in Fig 6 Crystalline Fluvastatm sodium Form JFI IS prepared by hydrolyzing Fluvastatm lower alkyl ester selected from C1-4 alkyl ester in methanol, adding sodium hydroxide solution taken in water and cooled to 0-10°C, preferably 0-5°C The resulting reaction mixture is stirred at room temperature for 1-3 hours Solvent is distilled off The resulting mass is dissolved in an organic solvent such as methanol, heated to about 30-60°C, preferably about 40-50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 3-8% by volume preferably between 4-6% by volume Anti-solvent, selected from nitnles, preferably acetonitrile, propionitrile or mixture thereof, is added The resulting solution is seeded with Fluvastatm sodium Form JFI and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and dried under vacuum at 50-60°C for 30-60 hours preferably 35-40 hours Crystalline Fluvastatm sodium Form JFI can also be prepared by dissolving Fluvastatm sodium in methanol, heating to about 30-60°C, preferably about 40-50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 3-8% by volume preferably between 4-6% by volume Anti-solvent, selected from nitnles, preferably acetonitrile, propromtnle or mixture thereof, is added The resulting solution is seeded with Fluvastatm sodium Form JFI and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and drying under vacuum at 50-60°C for 30-60 hours, preferably 35-40 hours Crystalline Fluvastatm sodium Form JF2 is characterized by powder X-ray diffraction pattern characterized by a PXRD pattern with peaks at 4 9, 5 2, 5 6, 10 2, 10 8, 11 6, 17 6, 20 9±0 2° 29 as shown in Fig 9 Crystalline Fluvastatm sodium Form JF2 IS further characterized by having an infrared spectrum in KBr comprising one or more characteristic peaks selected from absorption bands (cm1) 3403(s), 2976(m), 2935(m), 2902(w), 1722(m), 1618(w), 1572(s), 1500(s), 1457(s), 1402(s), 1370(w), 1344(m), 1219(s), 1155(s), 1104(s), 969(s), 928(w), 837(s), 814(m), 741(s), 718(w), 695(w), 653(w), 565(s), 522(m), wherein (w)= weak intensity, (m)= medium intensity, (s)= strong intensity as depicted in Fig 10 Crystalline Fluvastatm sodium Form JF2, is prepared by hydrolyzing Fluvastatm lower alkyl ester selected from C1-4 alkyl ester in methanol, adding sodium hydroxide solution taken in water and cooled to 0-10°C preferably 0-5°C The resulting reaction mixture is stirred at room temperature for 1-3 hours Solvent is distilled off The resulting mass is dissolved in an organic solvent such as methanol, heated to about, heated to about 30-60°C, preferably 40-50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 0 5-4% preferably between 1-2 % Anti-solvent selected from alkyl esters preferably ethyl acetate, butyl acetate or mixture thereof, is added The resulting solution is seeded with Fluvastatm sodium Form JF2 and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and air-dned for 30-60 minutes Crystalline Fluvastatm sodium Form JF2 can also be prepared by dissolving Fluvastatm sodium in methanol, heating to about heated to about 30-60°C, preferably 40-50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 0 5-4% preferably between 1-2 % Anti-solvent selected from alkyl esters preferably ethyl acetate, butyl acetate or mixture thereof, is added The resulting solution is seeded with Fluvastatin sodium Form JF2 and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and then air-dried for 30-60 minutes Crystalline Fluvastatin sodium Form JF3 is characterized by powder X-ray diffraction pattern characterized by a PXRD pattern with peaks at 5 2, 5 5, 6 0, 10 2 ± 0 2° 29 as shown in Fig 13 Crystalline Fluvastatin sodium Form JF3 is further characterized by having an infrared spectrum in KBr comprising one or more characteristic peaks selected from absorption bands (cm"1) 341 l(s), 2974(m), 2935(w), 1673(w), 1617(w), 1561(s), 1500(s), 1457(s), 1403(s), 1369(w), 1343(m), 1220(s), 1155(m), 1104(s), 1063(w), 1014(w), 974(m), 837(s), 815(m), 742(s), 715(w), 696(w), 654(w), 565(s), 519(m), wherein (w)= weak intensity, (m)= medium intensity, (s)= strong intensity as depicted in Fig 14 Crystalline Fluvastatin sodium Form JF3, IS prepared by hydrolyzing Fluvastatin lower alkyl ester selected from C1-4alkyl ester in methanol, adding sodium hydroxide solution taken in water and cooled to 0-10°C preferably 0-5°C The resulting reaction mixture is stirred at room temperature for 1-3 hours Solvent is distilled off The resulting mass is dissolved in methanol, heated to about heated to about 30-60°C, preferably 40-50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 0 5-4% preferably between 1-2 % Anti-solvent, selected from alkyl esters preferably ethyl acetate, butyl acetate or mixture thereof, is added The resulting solution is seeded with Fluvastatin sodium Form JF3 and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and dned under vacuum at 50-60°C for 30-60 hours, preferably 35-40 hours Crystalline Fluvastatm sodium Form JF3 can also be prepared by dissolving Fluvastatm sodium in methanol, heated to about heated to about 30-60°C, preferably 40-50°C to obtain clear solution Water can be added optionally The moisture content of the resulting solution is maintained between 0 5-4% preferably between 1-2 % Anti-solvent, selected from alkyl esters preferably ethyl acetate, butyl acetate or mixture thereof, is added The resulting solution is seeded with Fluvastatm sodium Form JF3 and stirred at room temperature for 15-20 hours, preferably 16-18 hours The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and dried under vacuum at 50-60°C for 30-60 hours preferably 35-40 hours Disclosed herein according to the present invention, Fluvastatm sodium in amorphous form, is prepared by dissolving Fluvastatm lower alkyl ester selected from C1-4 alkyl ester in methanol, adding sodium hydroxide solution taken in water and cooled to 0-10°C preferably 0-5°C The resulting reaction mixture is stirred at room temperature for 1-3 hours Solvent was distilled off The resulting mass is dissolved in methanol, heated to about 45-60°C to obtain clear solution Methanol was distilled off Anti-solvent, selected from hydrocarbon preferably n-hexane, n- heptane, n-octane or mixture thereof, is added and was stirred for 1-2 hours preferably 30-50 minutes The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and dried under vacuum at 65-75°C for 30-60 hours preferably 35-40 hours Fluvastatm sodium in amorphous form can also be prepared by dissolving Fluvastatm sodium in methanol, heated to about 45-60°C to obtain clear solution Solvent was distilled off Anti-solvent, selected from hydrocarbon preferably n-hexane, n-heptane, n-octane or mixture thereof, is added and was stirred for 1-2 hours preferably 30-50 minutes The solid is then separated out from the solvent by, for example, filtering or decanting under an inert atmosphere and dried under vacuum at 65-75°C for 30-60 hours preferably 35-40 hours The following non-hmitmg examples illustrate specific embodiments of the present invention They are, however, not intended to be limiting the scope of present invention in anyway Example 1 Preparation of Crystalline Fluvastatin sodium Form JF Fluvastatin ethyl ester (30 gm) was taken in methanol (180 ml) and cooled to 2-5°C Sodium hydroxide taken in water was added at above temperature The reaction mixture was stirred at 25-30°C for 90-120 minutes The resulting mixture was treated with activated carbon and filtered Solvent was distilled off To the resulting residue, methanol (60 ml) was added and stirred at 45-50°C to obtain clear solution Water was added optionally Absolute alcohol (180 ml) was added The resulting solution was seeded with Fluvastatin sodium Form JF and stirred at 25-30°C for 15-20 hours The resulting solid was filtered off under inert atmosphere, washed with chilled absolute alcohol and dried under vacuum at 50-60°C for 30-50 hours Example 2 Preparation of Crystalline Fluvastatin sodium Form JF Fluvastatin sodium (30 gm) was taken in methanol (60 ml) and stirred at 45-50°C to obtain clear solution Water was added optionally Absolute alcohol (180 ml) was added The resulting solution was seeded with Fluvastatin sodium Form JF and stirred at 25-30°C for 15-20 hours The resulting solid was filtered off under inert atmosphere, washed with chilled absolute alcohol and dried under vacuum at 50-60°C for 30-45 hours Example 3 Preparation of Crystalline Fluvastatm sodium Form JFI Fluvastatin ethyl ester (30 gm) was taken in methanol (180 ml) and cooled to 2-5°C Sodium hydroxide solution was added at above temperature The reaction mixture was stirred at 25-30°C for 90-120 minutes The resulting mixture was treated with activated carbon and filtered Solvent was distilled off To the resulting residue, methanol (60 ml) was added and stirred at 45-50°C to obtain clear solution Water was added optionally Acetomtnle (180 ml) was added and the resulting solution was seeded with Fluvastatin sodium Form JF1 and stirred at 25-30°C for 15-18 hours The resulting solid was filtered off under inert atmosphere, washed with chilled acetomtnle and dried under vacuum at 50-60°C for 30-40 hours Example 4 Preparation of Crystalline Fluvastatin sodium Form JFI Fluvastatin sodium (30 gm) was taken in methanol (60 ml) and stirred at 45-50°C to obtain clear solution Water was added optionally Acetomtnle (180 ml) was added and the resulting solution was seeded with Fluvastatin sodium Form JFI and stirred at 25-30°C for 15-18 hours The resulting solid was filtered off under inert atmosphere, washed with chilled acetomtnle and dried under vacuum at 50-60°C for 30-45 hours Example 5 Preparation of Crystalline Fluvastatin sodium Form JF2 Fluvastatin ethyl ester (30 gm) was taken in methanol (180 ml) and cooled to 2-5°C Sodium hydroxide solution was added at 2-5°C The reaction mixture was stirred at 25-30°C for 90-120 minutes The resulting mixture was treated with activated carbon and filtered Solvent was distilled off To the resulting residue, methanol (60 ml) was added and stirred at 45-50°C to obtain clear solution Water was added optionally Ethyl acetate (160 ml) was added and the resulting solution was seeded with Fluvastatin sodium Form JF2 and stirred at 25-30°C for 15-18 hours The resulting solid was filtered off under inert atmosphere, washed with chilled ethyl acetate and air-dned for 30-60 minutes Example 6 Preparation of Crystalline Fluvastatin sodium Form JF2 Fluvastatin sodium (30 gm) was taken in methanol (60 ml) and stirred at 45-50°C to obtain clear solution Water was added optionally Ethyl acetate (160 ml) was added and the resulting solution was seeded with Fluvastatin sodium Form JF2 and stirred at 25-30°C for 15-18 hours The resulting solid was filtered off under inert atmosphere, washed with chilled ethyl acetate and air-dned for 30-60 minutes Example 7 Preparation of Crystalline Fluvastatin sodium Form JF3 Fluvastatin ethyl ester (30 gm) was taken in methanol (180 ml) and cooled to 5°C Sodium hydroxide solution was added at 2-5°C The reaction mixture was stirred at 25-30°C for 90-120 minutes The resulting mixture was treated with activated carbon and filtered Solvent was distilled off To the resulting residue, methanol (60 ml) was added and stirred at 45-50°C to obtain clear solution Water was added optionally Ethyl acetate (160 ml) was added and the resulting solution was seeded with Fluvastatin sodium Form JF3 and stirred at 25-30°C for 15-18 hours The resulting solid was filtered off under inert atmosphere, washed with chilled ethyl acetate and dried under vacuum at 50-60°C for 30-40 hours Example 8 Preparation of Crystalline Fluvastatm sodium Form JF3 Fluvastatm sodium (30 gm) was taken in methanol (60 ml) and stirred at 45-50°C to obtain clear solution Water was added optionally Ethyl acetate (160 ml) was added and the resulting solution was seeded with Fluvastatm sodium Form JF3 and stirred at 25-30°C for 15-18 hours The resulting solid was filtered off under inert atmosphere, washed with chilled ethyl acetate and dried under vacuum at 50-60°C for 30-40 hours Example 9 Preparation of Amorphous Fluvastatm sodium Fluvastatm ethyl ester (30gm) was taken in methanol (180 ml) and cooled to 5°C Sodium hydroxide solution was added at 5-10°C The reaction mixture was stirred at 25-30°C for 90-120 minutes The resulting mixture was treated with activated carbon and filtered Solvent was distilled off To the resulting residue, methanol (150 ml) was added and stirs at 45-50°C to obtain clear solution Methanol was distilled off completely and n-heptane (150 ml) was added, stir for 30-40 minutes The resulting solid was filtered off under inert atmosphere, washed with n-heptane and dried under vacuum at 65-75°C for 30-40 hours Example 10 Preparation of Amorphous Fluvastatm sodium Fluvastatm sodium (30 gm) was taken in methanol (150 ml) and stir at 45-50°C to obtain clear solution Methanol was distilled off completely, n-heptane (150 ml) was added and stir for 30-40 minutes The resulting solid was filtered off under inert atmosphere, washed with n-heptane and dried under vacuum at 65-75°C for 30-40 hours While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments Rather, in view of the present disclosure, which descnbes the current best mode for practicing the invention, many modifications and vanations would present themselves to those skilled in the art without departing from the scope and spirit of this invention We Claim: 1. A process for the preparation of amorphous form of (*)-7-(3-(4-fluoropheny1)- 1- (1 -methylethyl)- 1H -indol-2-yl)-3,5-dihydroxy-6-heptenoiacc id sodium salt comprising: (a) hydrolyzing a lower alkyl ester of (*)-7-(3-(4-fluoropheny1)- 1 -(Imethylethyl)- lH-indol-2-yl)-3,5-dihydroxy-6-heptenoica cid in a solution containing sodium hydroxide in a mixture consisting of methanol, (b) evaporating the methanol from the mixture to obtain residue, (c) dissolving the residue in methanol, (d) removing the methanol to obtain the solid, (e) optionally adding anti-solvent to isolate amorphous (*)-7-(3-(4- fluoropheny1)- 1 -(1 -methylethyl)- 1 H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid sodium salt. 2. The process as claimed in claim 1, wherein the anti-solvent is selected from nhexane, n-heptane or n-octane or mixture thereof. 3. A process for the preparation of amorphous form of (*)-7-(3-(4-fluoropheny1)- 1- (1 -methylethyl)- 1H -indol-2-yl)-3,5-dihydroxy-6-heptenoiacc id sodium salt comprising: (a) dissolving (*)-7-(3-(4-fluoropheny1)- 1 -( 1 -methylethyl)- 1 H-indol-2-y1)- 3,5-dihydroxy-6-heptenoica cid sodium salt in methanol, (b) removing the methanol to obtain the solid, and (c) optionally adding anti-solvent to isolate amorphous(*)-7-(3-(4- fluoropheny1)- 1 -(1 -methylethyl)- 1 H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid sodium salt. 4. The process as claimed in claim 3, wherein the anti-solvent is selected from nhexane, n-heptane or n-octane or mixture thereof. 5. A process for the preparation of amorphous form of (*)-7-(3-(4-fluoropheny1)- 1- (1- methylethyl)- 1H -indol-2-yl)-3,5-dihydroxy-6-heptenoiacc id sodium salt comprising: (a) dissolving (*)-7-(3-(4-fluoropheny1)- 1 -(1 -methylethyl)- 1 H-indol-2-y1)-3,5- dihydroxy-6-heptenoic acid sodium salt in methanol, (b) removing the methanol to obtain the solid, and (c) isolating amorphous (*)-7-(3-(4-fluoropheny1)- 1 -(1 -methylethyl)- 1 Hindol- 2-yl)-3,5-dihydroxy-6-heptenoiacc id sodium salt. 6. The process as claimed in claim 5, wherein the methanol is removed under vacuum. 7. The process as claimed in claim 5, wherein the methanol is removed by spray drying.

Documents:

302-DEL-2005-Abstract-(07-06-2012).pdf

302-del-2005-abstract.pdf

302-del-2005-Claims-(02-05-2011).pdf

302-DEL-2005-Claims-(07-06-2012).pdf

302-del-2005-Claims-(22-02-2013).pdf

302-del-2005-claims.pdf

302-DEL-2005-Correspondence Others-(07-06-2012).pdf

302-del-2005-Correspondence-Others-(02-05-2011).pdf

302-del-2005-Correspondence-Others-(14-02-2013).pdf

302-DEL-2005-Correspondence-Others-(16-12-2011).pdf

302-del-2005-Correspondence-Others-(22-02-2013).pdf

302-del-2005-correspondence-others.pdf

302-del-2005-description (complete).pdf

302-del-2005-description (provisional).pdf

302-del-2005-drawings.pdf

302-del-2005-form-1.pdf

302-del-2005-Form-13-(02-05-2011).pdf

302-del-2005-form-18.pdf

302-del-2005-form-2.pdf

302-del-2005-form-26.pdf

302-DEL-2005-Form-3-(16-12-2011).pdf

302-del-2005-Form-3-(22-02-2013).pdf

302-del-2005-form-3.pdf

302-del-2005-form-5.pdf

302-del-2005-GPA-(14-02-2013).pdf

302-DEL-2005-Petition-137-(07-06-2012).pdf