The present invention provides a process for preparation of amorphous fluvastatin sodium which comprises of removing solvent from the solution of fluvastatin sodium.
Fluvastatin sodium is chemically monosodium salt of racemic mixture of (3R.5S) and (3S,5R) erythro-7-[3-(4-fluorophenyl)-1 -(1 -methylethyl)-1 H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid of Formula I. Fluvastatin sodium is cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. It is indicated as an adjunct to diet to reduce elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type I la and lib) whose response to dietary restriction of saturated fat and cholesterol and other non-pharmacological measures has not been adequate. It is also indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL cholesterol to target levels.

FORMULA I
Fluvastatin sodium is the first entirely synthetic'HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.
US Patent No. 4,739,073 provides a process for preparation of racemic fluvastatin sodium, which involves lyophilization of aqueous solution of fluvastatin sodium.
PCT Patent Application No. WO 97/49681 and its equivalent US Patent No. 6,124,340 describe that lyophilization of racemic fluvastatin sodium yields a mixture of a crystalline
form, designated as Form A, and amorphous material, and disclose a new crystalline form, designated as Form B. The estimated amount of form A obtained by lyophilization as described in these patents is about 50%. 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. It is also described that form B is less hygroscopic than Form A or the amorphous form of Fluvastatin sodium which improves handling and storage of the compound.
US Patent No. 6,696,479 provides crystalline forms of racemic fluvastatin sodium hydrates, referred to as polymorphic Forms C, D, E and F, processes for the preparation of these crystalline forms and pharmaceutical compositions comprising the crystalline forms. Fluvastatin sodium has estimated water content in range from 3-6% for Form C, 6-12% for Form D, 15-22% for Form E and 24-32% for Form E of Fluvastatin sodium.
US Application No. 20030125569 provides crystalline hydrates of enantiomerically enriched (3R,5S) or (3S.5R) of fluvastatin sodium referred to as Forms A, B1, B2, C, D and E. These forms are characteristically different from the other known crystalline forms as these are forms of either the (3R, 5S) or the (3S.5R) enantiomers of fluvastatin sodium.
Our co-pending Indian Patent Application No 1848/DEL/2004 provides essentially amorphous form of fluvastatin sodium which has more than 15% crystallinity. Additionally another co-pending Indian Patent Application No 428/DEL/2005 provides substantially pure amorphous form of racemic fluvastatin sodium having 15% w/w or less of crystallinity and a process for preparation thereof.
The techniques known in the art presented above involve preparation of amorphous fluvastatin sodium by lyophilization which result in a mixture of amorphous form and crystalline form or by precipitation which gives pure amorphous material. The present inventors have now found that fluvastatin sodium can be obtained in amorphous form having less than 15% of crystallinity by simple spray drying technique.
Although spray drying of a solution of a compound generally results in amorphous product, it is not always true. Certain compound such as efavirenz yield crystalline material upon spray drying. Fluvastatin sodium is also one such compound and the present inventors have observed that when fluvastatin sodium having high moisture content is dissolved in a suitable organic solvent and the resultant solution is spray dried the product obtained has more than 15% of crystallinity.
The present inventors have now found that when fluvastatin sodium having moisture content of 5% w/w or less, is dissolved in suitable solvent and the resultant solution is spray dried, the product obtained is amorphous having 15% or less of crystallinity.
The first aspect of the present invention provides a process for preparation of amorphous Fluvastatin sodium wherein the said process comprises of,
a) dissolving fluvastatin sodium having moisture content 5% w/w or less in a suitable organic solvent
b) removing the organic solvent from the solution thereof.
Fluvastatin sodium having less than 5% of moisture can be prepared by techniques known in the art. After dissolving in a suitable organic solvent, the solution so obtained is concentrated to get amorphous fluvastatin sodium having 15% or less of crystallinity. The suitable organic solvent comprises of C1-4 alcohols; C3-8 ketones; C3-6 esters C4-8 ethers; polar aprotic solvents or mixtures thereof. The solution of fluvastatin sodium can be concentrated by means of spray drying or by vacuum evaporation.
The second aspect of the present invention provides amorphous fluvastatin sodium having 15% or less of crystallinity prepared by a process which comprises of spray drying a solution of fluvastatin sodium wherein the starting fluvastatin sodium has 5% or less of moisture content.
Figure 1 depicts an X-ray diffractogram of amorphous fluvastatin sodium.
Figure 2 depicts an X-ray diffractogram of mixture of crystalline and amorphous fluvastatin sodium.
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE -1
PREPARATION OF AMORPHOUS FLUVASTATIN SODIUM
Crystalline Fluvastatin sodium (10 g; moisture content 4% w/w by Karl Fischer) was dissolved in methanol (100 ml) at 25 to 30°C. The clear solution obtained was spray dried using LAB PLANT mini spray drier (Model SD05). Spray drier was set as to have nozzle diameter 0.5 mm, Inlet temperature: 75°C, Liquid Flow Rate: ~350 ml/hour, Compressor Air Pressure: 1.4 Bar, Air Flow Rate: ~45m3/hour. The product obtained was dried at 40-45°C under vacuum to provide title compound having XRD similar to that depicted in Figure 1. Yield: 3.2 g Moisture content = 2.18% w/w by Karl-Fischer method
EXAMPLE -2
PREPARATION OF AMORPHOUS FLUVASTATIN SODIUM
Crystalline Fluvastatin sodium (300 g; moisture content 4% w/w by Karl Fischer) was
dissolved in methanol (3000 ml) at 25 to 30°C. The clear solution obtained was spray dried
by 0.5 mm pressure nozzle at inlet temperature of 90°C, under nitrogen to get the title
compound having XRD similar to that depicted in Figure 1..
Yield: 220 g
Moisture content = 2.5% w/w by Karl-Fischer method
REFERENCE EXAMPLE
Fluvastatin sodium (25 g; moisture content 14.54% w/w by Karl Fischer) was redissolved in methanol (200 ml) and spray dried using the process provided in Example above at 40-65 °C to get a product which is a mixture of crystalline and amorphous fluvastatin sodium having XRD similar to that depicted in Figure 2. Yield: 11.5 g

WE CLAIM:
1. A process for preparation of amorphous Fluvastatin sodium having 15% or less of
crystallinity wherein the said process comprises of,
a) dissolving fluvastatin sodium having moisture content 5% w/w or less in a one or more organic solvent/solvents
b) removing the organic solvent from the solution thereof.

2. The process according to claim 1 wherein amorphous fluvastatin sodium has 5% or less of crystallinity.
3. The process according to claim 1 wherein the organic solvent in step b) is removed by spray drying.
4. The process according to claim 1 wherein the organic solvent is selected from the group comprising of C1-4 alcohols; C3-8 ketones; C3-6 esters C4-8 ethers; polar aprotic solvents or mixtures thereof.
5. The process according to claim 1 step a) wherein the moisture content of Fluvastatin sodium is less than 4% w/w.
6. The process according to claim 4 wherein the organic solvent is methanol.
7. Amorphous fluvastatin sodium having 15% or less of crystallinity prepared by a process which comprises of spray drying a solution of fluvastatin sodium wherein the starting fluvastatin sodium has 5% or less of moisture content.
8. The process according to claim 7 wherein amorphous fluvastatin sodium has 5% or less of crystallinity.
9. A process according to claims 1 or 7 further comprising drying the product obtained under vacuum.