Indian Patents. 242723:A PROCESS OF THE MANUFACTURING OF A NOVEL FORM OF FLUVASTATIN SODIUM

Title of Invention	A PROCESS OF THE MANUFACTURING OF A NOVEL FORM OF FLUVASTATIN SODIUM
Abstract	A Novel form of Fluvastain sodium having characteristic peajks on X-ray powder diffractrogram at 20 7.0 = 10.5=0.2 0, 12.7 0, 13.6=0.2 0, 20.5=2.0 0, 22.2 =0.2 0, is disclosed. Said bnovel form of Fluvastain sodium also has characteristic peaks on Ingrared spectorscopic studies at 1572, 1569, 1560 and 1400 cm.

Full Text	Form 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See Section 10 and rule 13) TITLE OF THE INVENTION "A PROCESS FOR THE MANUFACTURING OF A NOVEL FORM OF FLUVASTATIN SODIUM' We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad-380 015, Gujarat, India. The following specification particularly describes the nature of the invention and the manner in which it is to be performed. NOVEL FORM OF FLUVASTATIN SODIUM Field of Invention The present invention relates to a novel form of Fluvastatin sodium. The present invention also relates to a novel process for the crystallization of Fluvastatin sodium from water. More particularly, the present invention relates to a simple and industrially feasible process for the preparation of a novel form of Fluvastatin sodium comprising a technique of crystallization from water. The product thus obtained is free from residual solvents used in manufacturing. Background of the invention Fluvastatin is a member of a class of drugs commonly refer red to as HMG-CoA reductase inhibitors (also called "statins"). The statins are used to reduce blood cholesterol levels in patients in need of such treatment. The compound is represented by following structural formula (I) and is chemically known as (E)-(±)-7-[3-(4-fluorophenyl)-1 -(methylethyl)-1 H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid sodium salt. It is a racemic mixture of (3R, 5S) and (3S, 5R) enantiomers, which is disclosed in EP-0114027. U.S. Patent No. 6,124,340 discloses the use of lyophilization technique to prepare Fluvastatin sodium, which leads to a mixture of crystalline as well as amorphous material. The amorphous form is designated as form A and crystalline form which is a monohydrate, is designated as form B. The inventor has also claimed to convert form A into form B in the various solvent-water systems. The Form A, earlier disclosed in U.S. Patent No. 6,124,340 and WO 02/36563 was obtained by freeze drying of aqueous solution of Fluvastatin sodium. While according to U.S. Patent Application No. 2003/0032666 Al, form A of Fluvastatin sodium can be converted into form C, D, E and F by exposing form A in atmosphere of defined relative humidity. Preparations of Fluvastatin sodium as racemate as well as the single enantiomers are disclosed in U.S. Patent No. 4,739,073. Prior art also teaches a method for the preparation of single enantiomer (3R, 5S) of Fluvastatin sodium in amorphous form by freeze drying that is hygroscopic in nature [Tetrahedron, 5J. 10659 (1997)]. WO 02/36563 teaches that both the single enantiomeric forms have been obtained in crystalline hydrate forms which are less hygroscopic than amorphous form. According to WO 02/36563, Form E of both the enantiomers of Fluvastatin sodium (3R, 5S) and (3S, 5R) are prepared separately by freeze drying of the suspension or of the precipitated product. Form E of Fluvastatin sodium can also be converted into Form A, Bl, B2, C and D by exposing in atmosphere having defined relative humidity. However, these processes are not feasible at commercial production scale The lyophilization technique mentioned in prior art as well as the technique of spray-drying to produce powders from feed stocks is also well known. The spray-drying technique is useful in the applications ranging from powdered milk to bulk chemicals and pharmaceuticals as disclosed in U.S. Patent No. 4,187,617. The formation of different forms of Fluvastatin sodium by technique of crystallization in various solvents leads to the formation of solvated Fluvastatin sodium containing solvents which are higher than the recommended limits as per ICH guidelines. Fluvastatin sodium is very slightly water-soluble. It has been found that the solubility of Fluvastatin sodium in water is 3-4% (w/w) at ambient temperature. Hence, handling of large scale operations for the preparation of Fluvastatin sodium as disclosed in prior-arts by the technique of lyophilization and other techniques such as spray-drying which requires preparation of feedstock, poses great difficulty to handle a huge volume of water, solvent or water -solvent system. However, the technique of lyophilization is time consuming and expensive due to high energy consumption, which reduces the efficiency of production and enhances the production cost. Again the spray-drying involves a difficulty in optimizing the recovery of the product and also a chance for the degradation of the product at higher temperature. The above mentioned techniques suffer from disadvantages of critical operations making the process unfeasible on commercial scale. Summary of Invention It has been found that crystalline forms are less readily soluble than amorphous form, which may cause problems in the bioavailibility of Fluvastatin sodium in the body. There is therefore, a need for a form of Fluvastatin sodium having limited crystallinity with improved process and formulation characteristics. It is therefore, desirable to solve the problems associated with the prior arts and to provide an efficient process for the preparation and isolation of the Fluvastatin sodium, with improved and simple process which results in higher recovery with required quality of product in short time. Accordingly, the present invention provides a process for recrystallization of Fluvastatin sodium by dissolving any form of Fluvastatin sodium in pure water through heating to achieve and maintain complete dissolution without any remaining solid. The Fluvastatin sodium recrystallizes from clear solution at cool to ambient temperature. Major advantages of the present invention as compared to the prior arts processes are: (i) the product thus obtained is free from residual solvents; (ii) the operations are less time consuming; (iii) the operations are easy to handle on large scale. Accordingly, the present invention provides a novel form of Fluvastatin sodium having characteristic peaks on X-ray powder diffractogram at 29 7.0 ± 0.2°, 10.5 ± 0.2°, 12.7°, 13.6 ± 0.2°, 20.5 ± 0.2°, 22.2 ± 0.2°. Preferably, said novel form of Fluvastatin sodium has characteristic peaks on Infrared spectroscopic studies at 1572, 1569, 1560, and 1400 cm-1. The present invention also provides a process for the manufacture a novel form of Fluvastatin sodium by the crystallization of known forms of Fluvastatin sodium from pure water comprising : (a) dissolving any form of Fluvastatin sodium in pure water; (b) distilling a part of water under reduced pressure; (c) cooling at 5°C to 50°C; (d) maintaining the temperature between 5°C to 50°C; (e) filtering or centrifuging the precipitated material; (f) drying the wet cake at moderate temperature under vacuum; (g) homogenizing the dried material to uniform free flowing Fluvastatin sodium by multimilling or jetmilling; Preferably, said known form of Fluvastatin sodium is dissolved in 1-10 volumes, preferably 2-5 volumes of pure water as that of Fluvastatin sodium taken for dissolution. Preferably, the dissolution temperature of Fluvastatin sodium in pure water is 35° - 85°C, preferably 47° - 78°C. Preferably, the volume of pure water taken for dissolution is more than five as that of Fluvastatin sodium taken and is reduced to half below 80°C, preferably below 50°C under vacuum. Preferably, clear solution of Fluvastatin sodium in pure water is cooled to 0° -50°C, preferably to 5° - 30°C to crystallize out novel form of Fluvastatin sodium. Preferably, the precipitated material is maintained at 0° - 50°C, preferably to 5° -30°C for 15 min to 240min, preferably 60 min for complete crystallization of Fluvastatin sodium. Preferably, the crystallized material is isolated from its mother liquor by filtration under vacuum or by centrifuging at 600 to 2000 rpm, preferably at 800 rpm. Preferably, the wet cake is dried at 40° - 80°C, preferably 55° - 60°C under vacuum for 6 to 48 hr, preferably 24 hr. Preferably, the water content in final Fluvastatin sodium is 1 - 8 %, preferably 2 - 5 %. Detailed description The present invention will now be described in greater detail with reference to the accompanying drawings wherein: Fig 1 is a X-ray powder diffractogram of Fluvastatin sodium monohydrate; Fig 2 to 8 depict is X-ray powder diffractograms of the material obtained in accordance with the present invention; X-ray powder diffractograms of Fig. 2 to 8 shows very new pattern of peaks at 2° theta 7.0 ± 0.2°, 10.5±0.2°, 12.7°, 13.6±0.2°, 20.5±0.2°, 22.2±0.2°; Fig 9 shows infrared spectroscopy of novel form of Fluvastatin sodium shows characteristic peaks at 1572, 1569, 1560, and 1400 cm-1 It has been found that crystalline forms are less readily soluble than amorphous form, which may cause problems in the bioavailibility of Fluvastatin sodium in the body. It therefore remains a need for a form of Fluvastatin sodium having limited crystallinity with improved process and formulation characteristics. It is the principal object of the present invention to provide an efficient process as well as to obtain a novel form of Fluvastatin sodium that eliminates the problems of prior arts and is convenient to operate on commercial scale that also meets economic demands. A preferred embodiment of the invention is the crystallization of Fluvastatin sodium from aqueous solution to obtain a novel form. The objective of present invention is also to determine the solubility of Fluvastatin sodium in water at various temperatures for optimum recovery of novel form of Fluvastatin Sodium. While warming the suspension of Fluvastatin sodium in pure water, it was found that solubility of Fluvastatin sodium increases. Hence, it was thought to optimize the solubility of the Fluvastatin sodium in pure water. To emphasize the process of crystallization, more amount of Fluvastatin sodium in pure water is stirred and is heated to get a clear solution at the temperature range 50-80°C. The clear solution so obtained is allowed to approach at cool to ambient temperature affording novel form of Fluvastatin sodium. Different experiments were performed employing Fluvastatin sodium (form-B) varying the volume of water (2 to 5 volumes as that of Fluvastatin sodium monohydrate form-B) to dissolve Fluvastatin sodium monohydrate form-B at various temperature (45 - 80°C). It was observed that with more volumes of water taken for dissolution, the temperature for dissolution is lesser and the recovery of product is also less. Fluvastatin sodium monohydrate form-B is dissolved completely in two volumes of water as that of form-B at 78°C, cooled to 25 - 30°C, filtered at 25 - 30°C, dried at 55 - 60°C under vacuum for 24 hours to provide a free flowing material with 80% recovery. X-ray powder diffractogram (Figure - 2) of the material thus obtained is completely different from that of Fluvastatin sodium monohydrate (Figure - 1), demonstrating the change in crystalline structure. Likewise the volume of water was increased from 2-5 volumes as that of form-B to observe dissolution temperature and percentage recovery. Alternatively, Fluvastatin sodium monohydrate form-B is dissolved in 5 volumes of water, 50% of water is removed under vacuum below 50°C, the precipitated material is filtered at 25 - 30°C and under similar conditions of experiments as described above. The precipitated material is filtered at 5 - 10°C. Wet cake is dried at 55 - 60°C under vacuum for 24 hours to provide Fluvastatin sodium as a free flowing material after homogenization. The dissolution temperature and percentage of recovery are summarized in table-1 Table-1 Volume of water . taken for dissolution Temperature for dissolution % recoveryat 25 - 30°C(Filtrationtemperature) % recoveryat 5 - 10°C (Filtrationtemperature) 2 78°C 80% — 3 75°C 65% — 4 53°C 70% — 5 48°C 68% 85% 5* 47°C 82% ■ *After dissolution 50% water is removed under vacuum. Under various experimental conditions as described in table 1, X-ray powder diffractograms of the above experiments are in close resemblance with each other but are entirely different when compared with the X-ray powder diffractogram of Fluvastatin sodium form-B (i.e. hitherto known forms of fluvastatin). Likewise lyophilized Fluvastatin sodium and spray dried Fluvastatin sodium or any other form of Fluvastatin sodium can be converted into same novel form as described above. The X-ray powder diffractogram of Fluvastatin sodium prepared by crystallization technique described above does not correlate with the other forms as disclosed in prior-arts. X-ray powder diffractogram [Fig. 2 to 8] shows very new pattern of peaks at 2° theta 7.0 ± 0.2°, 10.5±0.2°, 12.7°, 13.6±0.2°, 20.5±0.2°, 22.2±0.2° and the peaks disclosed in US 6,124,340 at 29 4.0°, 11.0°, 11.3°, 12.9°,15.9°, 16.3°, 18.7°, 19.3°, 19.6°, for form B as well as the peaks at 26 3.9°, 7.9°, 11.9°, for form A are absent in the novel form of Fluvastatin sodium recrystallized from water as described above. Moreover, Infrared spectroscopy [Figure 9] of novel form of Fluvastatin sodium shows characteristic peaks at 1572, 1569, 1560, and 1400 cm-1 which are not present in monohydrate form B disclosed in US 6,124,340. Furthermore, characteristic peaks at 1587, 1534, 1387, 1041, 1042, 842, 692 and 532 cm-ldiscribed in US 6,124,340 for form B are absent in form of Fluvastatin sodium recrystallized from water as described above. The crystallization of Fluvastatin sodium from water is most useful and simple preparation of a substantially pure novel form of Fluvastatin sodium. The invention is further described in the following examples, which are in no way intended to limit the scope of invention. Example: 1 10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 20 ml of pure water at 78°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 8.0 gm product with 3.9% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 2) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure. Example: 2 10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 30 ml of pure water at 75°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 6.5 gm product with 2.5% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 3) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure. Example: 3 10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 40 ml of pure water at 53°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 7.0 gm product with 2.8% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 4) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure. Example: 4 25 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 125 ml of pure water at 48°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 17.0 gm product with 3.3% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 5) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure. Example: 5 10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 50 ml of pure water at 47°C, the solution is cooled to 25 - 30°C which is further cooled to 5 - 10°C and is maintained at 5 - 10°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 8.5 gm product with 5.0% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 6) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure - 1) demonstrating the change in crystalline structure. Example: 6 50 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 250 ml of pure water at 47°C. 125 ml of water is distilled under vacuum (10 mm of mercury) below 50°C the resultant mass is cooled to 25 - 30°C and is further maintained at 25 - 30°C for 1 hour, The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 41.0 gm product with 2.8% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure-7) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure - 1) demonstrating the change in crystalline structure. Example: 7 100 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 500 ml of pure water at 47°C. 250 ml of water is distilled under vacuum (10 mm of mercury) below 50°C. The resultant mass is cooled to 25 - 30°C which is further cooled to 5 - 10°C and is maintained at 5 - 10°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 78.0 gm product with 2% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 8) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure - 1) demonstrating the change in crystalline structure. We Claim: 1. A novel form of Fluvastatin sodium having characteristic peaks on X-ray powder diffractogram at 26 7.0 ± 0.2°, 10.5 ± 0.2°, 12.7°, 13.6 ± 0.2°, 20.5 ± 0.2°, 22.2 ± 0.2°. 2. A novel form of Fluvastatin sodium having characteristic peaks on Infrared spectroscopic studies at 1572, 1569, 1560, and 1400 cm-1. 3. A process for the manufacture a novel form of Fluvastatin sodium by the crystallization of known forms of Fluvastatin sodium from pure water comprisin (h) dissolving any form of Fluvastatin sodium in pure water; (i) distilling a part of water under reduced pressure; (j) cooling at 5°C to 50°C; (j) maintaining the temperature between 5°C to 50°C; (I) filtering or centrifuging the precipitated material; (m) drying the wet cake at moderate temperature under vacuum; (n) homogenizing the dried material to uniform free flowing Fluvastatin sodium by multimilling or jetmilling; 4. A process as claimed in claim 3 wherein said known form of Fluvastatin sodium is dissolved in 1-10 volumes, preferably 2-5 volumes of pure water as that of Fluvastatin sodium taken for dissolution. 5. A process as claimed in claim 3 or 4 wherein the dissolution temperature of Fluvastatin sodium in pure water is 35° - 85°C, preferably 47° - 78°C. 6. A process as claimed in any one of claims 3 to 5 wherein the volume of pure water taken for dissolution is more than five as that of Fluvastatin sodium taken and is reduced to half below 80°C, preferably below 50°C under vacuum. 7. A process as claimed in any one of claims 3 to 6 wherein clear solution of Fluvastatin sodium in pure water is cooled to 0° - 50°C, preferably to 5° - 30°C to crystallize out novel form of Fluvastatin sodium. 8. A process as claimed in any one of claims 3 to 7 wherein the precipitated material is maintained at 0° - 50°C, preferably to 5° - 30°C for 15 min to 240min, preferably 60 min for complete crystallization of Fluvastatin sodium. 9. A process as claimed in any one of claims 3 to 8 wherein crystallized material is isolated from its mother liquor by filtration under vacuum or by centrifuging at 600 to 2000 rpm, preferably at 800 rpm. 10. A process as claimed in any one of claims 3 to 9 wherein the wet cake is dried at 40° - 80°C, preferably 55° - 60°C under vacuum for 6 to 48 hr, preferably 24 hr. Abstract A novel form of Fluvastatin sodium having characteristic peaks on X-ray powder diffractogram at 2q 7.0 ± 0.2°, 10.5 ± 0.2°, 12.7°, 13.6 ± 0.2°, 20.5 ± 0.2°, 22.2 ± 0.2° is disclsoed. Said novel form of Fluvastatin sodium also has characteristic peaks on Infrared spectroscopic studies at 1572, 1569, 1560, and 1400 cm-1.

Full Text

Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 and rule 13)
TITLE OF THE INVENTION
"A PROCESS FOR THE MANUFACTURING OF A NOVEL FORM OF FLUVASTATIN SODIUM'
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad-380 015, Gujarat, India.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

NOVEL FORM OF FLUVASTATIN SODIUM
Field of Invention
The present invention relates to a novel form of Fluvastatin sodium. The present invention also relates to a novel process for the crystallization of Fluvastatin sodium from water. More particularly, the present invention relates to a simple and industrially feasible process for the preparation of a novel form of Fluvastatin sodium comprising a technique of crystallization from water. The product thus obtained is free from residual solvents used in manufacturing.
Background of the invention
Fluvastatin is a member of a class of drugs commonly refer red to as HMG-CoA reductase inhibitors (also called "statins"). The statins are used to reduce blood cholesterol levels in patients in need of such treatment. The compound is represented by following structural formula (I) and is chemically known as (E)-(±)-7-[3-(4-fluorophenyl)-1 -(methylethyl)-1 H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid sodium salt. It is a racemic mixture of (3R, 5S) and (3S, 5R) enantiomers, which is disclosed in EP-0114027.

U.S. Patent No. 6,124,340 discloses the use of lyophilization technique to prepare Fluvastatin sodium, which leads to a mixture of crystalline as well as amorphous material. The amorphous form is designated as form A and crystalline form

which is a monohydrate, is designated as form B. The inventor has also claimed to convert form A into form B in the various solvent-water systems.
The Form A, earlier disclosed in U.S. Patent No. 6,124,340 and WO 02/36563 was obtained by freeze drying of aqueous solution of Fluvastatin sodium. While according to U.S. Patent Application No. 2003/0032666 Al, form A of Fluvastatin sodium can be converted into form C, D, E and F by exposing form A in atmosphere of defined relative humidity.
Preparations of Fluvastatin sodium as racemate as well as the single enantiomers are disclosed in U.S. Patent No. 4,739,073. Prior art also teaches a method for the preparation of single enantiomer (3R, 5S) of Fluvastatin sodium in amorphous form by freeze drying that is hygroscopic in nature [Tetrahedron, 5J. 10659 (1997)]. WO 02/36563 teaches that both the single enantiomeric forms have been obtained in crystalline hydrate forms which are less hygroscopic than amorphous form.
According to WO 02/36563, Form E of both the enantiomers of Fluvastatin sodium (3R, 5S) and (3S, 5R) are prepared separately by freeze drying of the suspension or of the precipitated product. Form E of Fluvastatin sodium can also be converted into Form A, Bl, B2, C and D by exposing in atmosphere having defined relative humidity. However, these processes are not feasible at commercial production scale
The lyophilization technique mentioned in prior art as well as the technique of spray-drying to produce powders from feed stocks is also well known. The spray-drying technique is useful in the applications ranging from powdered milk to bulk chemicals and pharmaceuticals as disclosed in U.S. Patent No. 4,187,617.
The formation of different forms of Fluvastatin sodium by technique of crystallization in various solvents leads to the formation of solvated Fluvastatin sodium containing solvents which are higher than the recommended limits as per ICH guidelines.
Fluvastatin sodium is very slightly water-soluble. It has been found that the solubility of Fluvastatin sodium in water is 3-4% (w/w) at ambient temperature. Hence, handling of large scale operations for the preparation of Fluvastatin sodium as disclosed in prior-arts by the technique of lyophilization and other techniques such as spray-drying which requires preparation of feedstock, poses great difficulty to handle a huge volume of water, solvent or water -solvent system. However, the technique of

lyophilization is time consuming and expensive due to high energy consumption, which reduces the efficiency of production and enhances the production cost.
Again the spray-drying involves a difficulty in optimizing the recovery of the product and also a chance for the degradation of the product at higher temperature. The above mentioned techniques suffer from disadvantages of critical operations making the process unfeasible on commercial scale.
Summary of Invention
It has been found that crystalline forms are less readily soluble than amorphous form, which may cause problems in the bioavailibility of Fluvastatin sodium in the body. There is therefore, a need for a form of Fluvastatin sodium having limited crystallinity with improved process and formulation characteristics.
It is therefore, desirable to solve the problems associated with the prior arts and to provide an efficient process for the preparation and isolation of the Fluvastatin sodium, with improved and simple process which results in higher recovery with required quality of product in short time.
Accordingly, the present invention provides a process for recrystallization of Fluvastatin sodium by dissolving any form of Fluvastatin sodium in pure water through heating to achieve and maintain complete dissolution without any remaining solid. The Fluvastatin sodium recrystallizes from clear solution at cool to ambient temperature.
Major advantages of the present invention as compared to the prior arts processes are:
(i) the product thus obtained is free from residual solvents; (ii) the operations are less time consuming;
(iii) the operations are easy to handle on large scale.
Accordingly, the present invention provides a novel form of Fluvastatin sodium having characteristic peaks on X-ray powder diffractogram at 29 7.0 ± 0.2°, 10.5 ± 0.2°, 12.7°, 13.6 ± 0.2°, 20.5 ± 0.2°, 22.2 ± 0.2°.
Preferably, said novel form of Fluvastatin sodium has characteristic peaks on Infrared spectroscopic studies at 1572, 1569, 1560, and 1400 cm-1.

The present invention also provides a process for the manufacture a novel form of Fluvastatin sodium by the crystallization of known forms of Fluvastatin sodium from pure water comprising :
(a) dissolving any form of Fluvastatin sodium in pure water;
(b) distilling a part of water under reduced pressure;
(c) cooling at 5°C to 50°C;
(d) maintaining the temperature between 5°C to 50°C;
(e) filtering or centrifuging the precipitated material;
(f) drying the wet cake at moderate temperature under vacuum;
(g) homogenizing the dried material to uniform free flowing Fluvastatin sodium by multimilling or jetmilling;
Preferably, said known form of Fluvastatin sodium is dissolved in 1-10 volumes, preferably 2-5 volumes of pure water as that of Fluvastatin sodium taken for dissolution.
Preferably, the dissolution temperature of Fluvastatin sodium in pure water is 35° - 85°C, preferably 47° - 78°C.
Preferably, the volume of pure water taken for dissolution is more than five as that of Fluvastatin sodium taken and is reduced to half below 80°C, preferably below 50°C under vacuum.
Preferably, clear solution of Fluvastatin sodium in pure water is cooled to 0° -50°C, preferably to 5° - 30°C to crystallize out novel form of Fluvastatin sodium.
Preferably, the precipitated material is maintained at 0° - 50°C, preferably to 5° -30°C for 15 min to 240min, preferably 60 min for complete crystallization of Fluvastatin sodium.
Preferably, the crystallized material is isolated from its mother liquor by filtration under vacuum or by centrifuging at 600 to 2000 rpm, preferably at 800 rpm.
Preferably, the wet cake is dried at 40° - 80°C, preferably 55° - 60°C under vacuum for 6 to 48 hr, preferably 24 hr.
Preferably, the water content in final Fluvastatin sodium is 1 - 8 %, preferably 2 - 5 %.
Detailed description
The present invention will now be described in greater detail with reference to the accompanying drawings wherein: Fig 1 is a X-ray powder diffractogram of Fluvastatin sodium monohydrate;

Fig 2 to 8 depict is X-ray powder diffractograms of the material obtained in accordance
with the present invention; X-ray powder diffractograms of Fig. 2 to 8 shows very new
pattern of peaks at 2° theta 7.0 ± 0.2°, 10.5±0.2°, 12.7°, 13.6±0.2°, 20.5±0.2°,
22.2±0.2°;
Fig 9 shows infrared spectroscopy of novel form of Fluvastatin sodium shows
characteristic peaks at 1572, 1569, 1560, and 1400 cm-1
It has been found that crystalline forms are less readily soluble than amorphous form, which may cause problems in the bioavailibility of Fluvastatin sodium in the body. It therefore remains a need for a form of Fluvastatin sodium having limited crystallinity with improved process and formulation characteristics.
It is the principal object of the present invention to provide an efficient process as well as to obtain a novel form of Fluvastatin sodium that eliminates the problems of prior arts and is convenient to operate on commercial scale that also meets economic demands.
A preferred embodiment of the invention is the crystallization of Fluvastatin sodium from aqueous solution to obtain a novel form. The objective of present invention is also to determine the solubility of Fluvastatin sodium in water at various temperatures for optimum recovery of novel form of Fluvastatin Sodium. While warming the suspension of Fluvastatin sodium in pure water, it was found that solubility of Fluvastatin sodium increases.
Hence, it was thought to optimize the solubility of the Fluvastatin sodium in pure water. To emphasize the process of crystallization, more amount of Fluvastatin sodium in pure water is stirred and is heated to get a clear solution at the temperature range 50-80°C. The clear solution so obtained is allowed to approach at cool to ambient temperature affording novel form of Fluvastatin sodium.
Different experiments were performed employing Fluvastatin sodium (form-B) varying the volume of water (2 to 5 volumes as that of Fluvastatin sodium monohydrate form-B) to dissolve Fluvastatin sodium monohydrate form-B at various temperature (45 - 80°C). It was observed that with more volumes of water taken for dissolution, the temperature for dissolution is lesser and the recovery of product is also less.
Fluvastatin sodium monohydrate form-B is dissolved completely in two volumes of water as that of form-B at 78°C, cooled to 25 - 30°C, filtered at 25 - 30°C, dried at 55 - 60°C under vacuum for 24 hours to provide a free flowing material with 80% recovery. X-ray powder diffractogram (Figure - 2) of the material thus obtained is

completely different from that of Fluvastatin sodium monohydrate (Figure - 1), demonstrating the change in crystalline structure. Likewise the volume of water was increased from 2-5 volumes as that of form-B to observe dissolution temperature and percentage recovery.
Alternatively, Fluvastatin sodium monohydrate form-B is dissolved in 5 volumes of water, 50% of water is removed under vacuum below 50°C, the precipitated material is filtered at 25 - 30°C and under similar conditions of experiments as described above. The precipitated material is filtered at 5 - 10°C. Wet cake is dried at 55 - 60°C under vacuum for 24 hours to provide Fluvastatin sodium as a free flowing material after homogenization. The dissolution temperature and percentage of recovery are summarized in table-1
Table-1

Volume of water . taken for dissolution Temperature for dissolution % recoveryat 25 - 30°C(Filtrationtemperature) % recoveryat 5 - 10°C (Filtrationtemperature)
2 78°C 80% —
3 75°C 65% —
4 53°C 70% —
5 48°C 68% 85%
5* 47°C 82% ■
*After dissolution 50% water is removed under vacuum.
Under various experimental conditions as described in table 1, X-ray powder diffractograms of the above experiments are in close resemblance with each other but are entirely different when compared with the X-ray powder diffractogram of Fluvastatin sodium form-B (i.e. hitherto known forms of fluvastatin). Likewise lyophilized Fluvastatin sodium and spray dried Fluvastatin sodium or any other form of Fluvastatin sodium can be converted into same novel form as described above.
The X-ray powder diffractogram of Fluvastatin sodium prepared by crystallization technique described above does not correlate with the other forms as disclosed in prior-arts. X-ray powder diffractogram [Fig. 2 to 8] shows very new pattern of peaks at 2° theta 7.0 ± 0.2°, 10.5±0.2°, 12.7°, 13.6±0.2°, 20.5±0.2°, 22.2±0.2° and the peaks disclosed in US 6,124,340 at 29 4.0°, 11.0°, 11.3°, 12.9°,15.9°,

16.3°, 18.7°, 19.3°, 19.6°, for form B as well as the peaks at 26 3.9°, 7.9°, 11.9°, for form A are absent in the novel form of Fluvastatin sodium recrystallized from water as described above.
Moreover, Infrared spectroscopy [Figure 9] of novel form of Fluvastatin sodium shows characteristic peaks at 1572, 1569, 1560, and 1400 cm-1 which are not present in monohydrate form B disclosed in US 6,124,340.
Furthermore, characteristic peaks at 1587, 1534, 1387, 1041, 1042, 842, 692 and 532 cm-ldiscribed in US 6,124,340 for form B are absent in form of Fluvastatin sodium recrystallized from water as described above. The crystallization of Fluvastatin sodium from water is most useful and simple preparation of a substantially pure novel form of Fluvastatin sodium.
The invention is further described in the following examples, which are in no way intended to limit the scope of invention.
Example: 1
10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 20 ml of pure water at 78°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 8.0 gm product with 3.9% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 2) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure.
Example: 2
10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 30 ml of pure water at 75°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 6.5 gm product with 2.5% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 3) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure.
Example: 3

10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 40 ml of pure water at 53°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 7.0 gm product with 2.8% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 4) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure.
Example: 4
25 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 125 ml of pure water at 48°C, the solution is cooled to 25 - 30°C with concurrent precipitation of Fluvastatin sodium. The solution is maintained at 25 - 30°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 17.0 gm product with 3.3% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 5) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure -1) demonstrating the change in crystalline structure.
Example: 5
10 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 50 ml of pure water at 47°C, the solution is cooled to 25 - 30°C which is further cooled to 5 - 10°C and is maintained at 5 - 10°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 8.5 gm product with 5.0% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 6) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure - 1) demonstrating the change in crystalline structure.
Example: 6
50 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 250 ml of pure water at 47°C. 125 ml of water is distilled under vacuum (10 mm of mercury) below 50°C the resultant mass is cooled to 25 - 30°C and is further maintained at 25 - 30°C for 1 hour, The precipitated material is filtered and is sucked

dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 41.0 gm product with 2.8% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure-7) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure - 1) demonstrating the change in crystalline structure. Example: 7
100 gm of Fluvastatin sodium monohydrate (Form-B) is dissolved completely in 500 ml of pure water at 47°C. 250 ml of water is distilled under vacuum (10 mm of mercury) below 50°C. The resultant mass is cooled to 25 - 30°C which is further cooled to 5 - 10°C and is maintained at 5 - 10°C for 1 hour. The precipitated material is filtered and is sucked dry. Finally the wet cake is dried at 55 - 60°C under vacuum (60 mm of mercury) for 24 hours to provide 78.0 gm product with 2% water content. Finally the product is homogenized to give free flowing Fluvastatin sodium. X-ray powder diffractogram (Figure - 8) of the material thus obtained is completely different with that of Fluvastatin sodium monohydrate (Figure - 1) demonstrating the change in crystalline structure.

We Claim:
1. A novel form of Fluvastatin sodium having characteristic peaks on X-ray powder diffractogram at 26 7.0 ± 0.2°, 10.5 ± 0.2°, 12.7°, 13.6 ± 0.2°, 20.5 ± 0.2°, 22.2 ± 0.2°.
2. A novel form of Fluvastatin sodium having characteristic peaks on Infrared spectroscopic studies at 1572, 1569, 1560, and 1400 cm-1.
3. A process for the manufacture a novel form of Fluvastatin sodium by the crystallization of known forms of Fluvastatin sodium from pure water comprisin
(h) dissolving any form of Fluvastatin sodium in pure water;
(i) distilling a part of water under reduced pressure;
(j) cooling at 5°C to 50°C;
(j) maintaining the temperature between 5°C to 50°C;
(I) filtering or centrifuging the precipitated material;
(m) drying the wet cake at moderate temperature under vacuum;
(n) homogenizing the dried material to uniform free flowing Fluvastatin sodium by multimilling or jetmilling;
4. A process as claimed in claim 3 wherein said known form of Fluvastatin sodium is dissolved in 1-10 volumes, preferably 2-5 volumes of pure water as that of Fluvastatin sodium taken for dissolution.
5. A process as claimed in claim 3 or 4 wherein the dissolution temperature of Fluvastatin sodium in pure water is 35° - 85°C, preferably 47° - 78°C.
6. A process as claimed in any one of claims 3 to 5 wherein the volume of pure water taken for dissolution is more than five as that of Fluvastatin sodium taken and is reduced to half below 80°C, preferably below 50°C under vacuum.
7. A process as claimed in any one of claims 3 to 6 wherein clear solution of Fluvastatin sodium in pure water is cooled to 0° - 50°C, preferably to 5° - 30°C to crystallize out novel form of Fluvastatin sodium.
8. A process as claimed in any one of claims 3 to 7 wherein the precipitated material is maintained at 0° - 50°C, preferably to 5° - 30°C for 15 min to 240min, preferably 60 min for complete crystallization of Fluvastatin sodium.

9. A process as claimed in any one of claims 3 to 8 wherein crystallized material is isolated from its mother liquor by filtration under vacuum or by centrifuging at 600 to 2000 rpm, preferably at 800 rpm.
10. A process as claimed in any one of claims 3 to 9 wherein the wet cake is dried at 40° - 80°C, preferably 55° - 60°C under vacuum for 6 to 48 hr, preferably 24 hr.

Abstract
A novel form of Fluvastatin sodium having characteristic peaks on X-ray powder diffractogram at 2q 7.0 ± 0.2°, 10.5 ± 0.2°, 12.7°, 13.6 ± 0.2°, 20.5 ± 0.2°, 22.2 ± 0.2° is disclsoed. Said novel form of Fluvastatin sodium also has characteristic peaks on Infrared spectroscopic studies at 1572, 1569, 1560, and 1400 cm-1.

A PROCESS OF THE MANUFACTURING OF A NOVEL FORM OF FLUVASTATIN SODIUM

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