FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF FLUVASTATIN SODIUM IN NOVEL POLYMORPHIC FORM
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for the preparation of Fluvastatin sodium in novel polymorphic form.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention relates to an efficient process for the preparation of Fluvastatin sodium.
Fluvastatin is [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H -indol-2-yl]-3,5-dihydroxy-6-heptenoic acid of Formula I. Fluvastatin, is commercially available as Lescol® Capsules and extended release Tablets in form of its sodium salt. It is indicated for the treatment of hypercholesterolemia (heterozygous familial and non familial), mixed dyslipidemia, secondary prevention of coronary events and atherosclerosis.
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Formula I
US Patent No 5,354,772 discloses the process for synthesis of Fluvastatin, its sodium salt and pharmaceutical compositions thereof.
US Patent No 5,189,164 (the '164 Patent) discloses process for synthesizing syn (E)-3,5-dihydroxy-7-substituted hept-6-enoic acid and heptanoic acid derivatives and intermediates thereof wherein the isolation and purification of fluvastatin and salt thereof is carried out by lyophilization to get a mixture of crystalline and amorphous product. Several processes are known in the art for preparation of fluvastatin or salt thereof, viz. US Patent No 4,870,199; US Patent No 6,743,926; US Patent No 6,875,867 (the '867 Patent).
Several Patents viz. US Patent No 6,124,340, US Patent No 6,696,479, US Patent No 6,858,643, US Application No. 2005/0038114, US Application No. 2005/0119342, US Application No. 2005/0032884 disclose a number of Polymorphic forms of fluvastatin sodium. Most of the polymorphs are prepared by dissolving fluvastatin sodium in a suitable organic solvent followed by addition of anti-solvent to precipitate fluvastatin sodium from the solution to get desired polymorphic form. The anti-solvents include organic solvents such methyl t-butyl ketone, cyclohexane, hexane, diethyl ether, petroleum ether which are either class II solvents or are very difficult to remove during drying.
The present inventors have now surprisingly found an efficient method of removing residual solvents from fluvastatin sodium, by intermittent sieving, sizing and reshuffling of the particle bed. The crude Fluvastatin and salts thereof are
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treated with organic solvents to purify Fluvastatin and salts thereof. The filtered mass is dried at a temperature of 40 °C and above. The partially dried mass is sieved, sifted and reshuffled and the again subjected to drying. The residual solvents are reduced to 0.01-0.3 % w/w i.e. well within ICH acceptable limits.
The inventors also found a new polymorphic form of Fluvastatin and salts thereof. The polymorph W-1 is stable, consistently reproducible and it could be used to make pharmaceutical compositions.
One of the aspects of the present invention provides a process for preparation of Fluvastatin or salt thereof wherein the said process comprises of
a) Drying fluvastatin sodium containing organic solvent or solvents at a temperature of 40 °C and above,
b) Intermittently sieving, sizing and reshuffling the particle bed,
c) Isolating fluvastatin sodium having ICH acceptable residual solvent limits.
Fluvastatin can be prepared by the procedure, which is well known to those skilled in the art. Crude Fluvastatin or salts thereof are purified by treating with solvent-antisolvent.
The organic solvent can be selected from a group comprising of alcohols, ethers, aldehydes, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide (DMSO) or N-methylpyrrolidone.
The solution is filtered and the filtered material is dried at 40 °C and above under vacuum. Intermittently, the partial dried mass is sieved through mesh, reshuffled and again subjected to drying at 40 °C and above, to remove the residual solvents. The residual solvents levels are between 0.01-0.3% w/w.
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In yet another aspect of the present invention there is provided a new polymorphic form W-1 of Fluvastatin sodium, wherein the said polymorph is stable, consistently reproducible and is used to make pharmaceutical compositions. The XRD of the polymorph W-1 showed 26 values of major peak intensity at 3.5, 10.9, 12.0, 147, 15.6, 18.0, 18.7, 21.4, 23.9 and 25.5. The IR peaks are observed at 3208,2937, 1586, 1535, 1498, 1455, 1415, 1386, 1336, 1215, 1156, 1105,1041,1013, 966, 841,739,564 cm'1. The form W-1 has moisture content less than 2% w/w when measured by Karl-Fisher analysis.
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 Polymorphic Form W-1 of fluvastatin sodium and drying
The above Crude fluvastatin sodium (70 g) was suspended in tetrahydrofuran
(1.05 Lit) at ambient temperature and heated to 50-60°C for dissolving and
solution was filtered to remove particulate material. The clear filtrate was
concentrated to minimum (4 volumes) at 38-42°C under vacuum. The resulting
solution was cooled to ambient temperature and 0.7 g of seed was added then
methyl Nbutyl ether (900 ml) was added slowly over a period of 30 minutes. The
precipitated material was stirred for 2 hrs at 20-25°C under nitrogen then filtered
and washed with methyl f-butyl ether (300 ml). Dried the material under vacuum
4 hours at 45-50°C initially. The compound was sieved through 30 mesh again
subjected to drying at 55-60 for 24 hours.
Yield: 62 g (88%)
XRD & IR: As depicted in Figure 1 and 2 respectively.
Purity 99.7%
Residual solvents levels: THF: <0.01% w/w and MTBE: <0.3% w/w.
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WE CLAIMS
1. A process for preparation of Fluvastatin or salt thereof wherein the said
process comprises of
a. drying fluvastatin sodium containing organic solvent or solvents at a
temperature of 40 °C and above,
b. intermittently sieving, sizing and reshuffling the particle bed,
c. isolating fluvastatin sodium having ICH acceptable residual solvent
limits.
2. A stable polymorphic form W-1 of Fluvastatin sodium.
3. A stable polymorphic form W-1 of Fluvastatin sodium as claimed in claim 2 having XRD as depicted in Figure 1.
4. A stable polymorphic form W-1 of Fluvastatin sodium as claimed in claim 2 having IR as depicted in Figure 2.
5. A stable polymorphic form W-1 of Fluvastatin sodium as claimed in claim 2 having moisture content 2% or less.
6. A stable polymorphic form W-1 of Fluvastatin sodium having major XRD peaks at 2 value of 20 values of 3.5, 10.9, 12.0, 14.7, 15.6, 18.0, 18.7, 21.4, 23.9 and 25.5.
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7. A pharmaceutical compositions comprising therapeutically effective amount of polymorphic form W-1 of fluvastatin sodium along with pharmaceutically acceptable excipient.

Dated this 28 th day of March, 2006
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