FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of atorvastatin sodium. BACKGROUND OF THE INVENTION
Atorvastatin, chemically known as [R-(R*, R*)]-2-(4-fluorophenyl)-P, 8-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid is an HMG-CoA reductase inhibitor and is used as an antihypercholesterolemic agent. Atorvastatin is marketed as the hemi-calcium salt trihydrate under the brand name LIPITOR.
Atorvastatin was first disclosed and claimed in US Patent No. 4,681,893, as the racemic lactone, i.e., trans-5- (4-fluorophenyl)-2-(l-methylethyl)-N, 4-diphenyl-l- [2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-lH-pyrrole-carboxamide. The patent teaches a method of synthesizing the racemic atorvastatin lactone and sodium salt of (R*, R*)-2-(4-fluorophenyl)-P,8-dihydroxy-5- (1 -methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-1-heptanoic acid ("racemic atorvastatin sodium") by treating the racemic lactone with sodium hydroxide in mixture of THF and water.
Atorvastatin, the pure [R(R*,R*)] enantiomer of 2-(4-fiuorophenyl)-p, 5-dihydroxy-5-(l~methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid and its hemi-calcium salt were first disclosed in US patent No. 5,273,995.
The US Patent 5,273,995 teaches a method of making the calcium salt of atorvastatin by first treating the atorvastatin lactone with sodium hydroxide in a mixture of methanol and water to get the sodium salt and treating the sodium salt with slight excess of CaCl2.2H2O. Atorvastatin hemi-calcium salt was further purified by recrystallization from a 5:3 mixture of ethyl acetate and hexane.
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Thus, atorvastatin sodium is the useful precursor in the manufacture of atorvastatin hemi-calcium salt. However, there is no disclosure in the prior art on crystalline form(s) of the sodium salt of atorvastatin first disclosed in US Patent No. 5,273,995.
Processes for preparing atorvastatin salts, atorvastatin lactone, and key intermediates are disclosed in US Patent Nos. 6,777,552; 6,528,661; 5,298,627; 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5245,047; 5,280,126; and Baumann, K.I, et al. Tetrahedron Letters, 33, 2283-2284, (1992).
The process to manufacture atorvastatin and its salts disclosed in US Patent Nos. 5,298,627, and 5,273,995 teaches to convert the sodium salt to calcium salt by treating with calcium chloride or calcium acetate without isolation and purification of the sodium salt obtained by hydrolyzing the lactone/ester/amide intermediate with methanolic sodium hydroxide.
The prior art conversions of the t-butyl ester or the lactone intermediate to hemi-calcium salt goes via in situ formation of sodium salt and conversion to calcium salt without isolation. This affects the purity of the calcium salt and also decreases its solubility.
There are no reports of isolating and utilizing the crystalline sodium salt. The inventors have now found that it is advantageous to isolate the crystalline sodium salt as it reduces the impurities in the atorvastatin hemi calcium salt which is the ultimate product
OBJECT OF THE INVENTION
Thus it is an object of the present invention to provide a novel crystalline form of atorvastatin sodium that has advantageous physical properties useful in the manufacture of atorvastatin hemi-calcium salt.
SUMMARY OF THE INVENTION
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The present inventors have found that isolation of the sodium salt of atorvastatin and its subsequent conversion to hemi-calcium salt significantly improved the purity of atorvastatin hemi-calcium salt.
The inventors found that the isolation of the atorvastatin sodium salt get rid of the inorganic impurities that reduce the solubility of the atorvastatin hemicalcium salt.
Accordingly, the present invention provides a novel crystalline form of atorvastatin sodium, having high storage stability, high purity of greater than 99.5%,
Description of the accompanying drawings
Figure 1: powder X-ray diffraction pattern of the crystalline atorvastatiun sodium of present invention
Figure 2: DSC of the crystalline atorvastatin sodium of present invention
The crystalline atorvastatin sodium of present invention is characterized by a powder X-ray diffraction pattern given in the Figure-1 and DSC given in Figure-2.
The crystalline atorvastatin sodium was stable for 3 months when stored at 40 °C under relative humidity of 75%.
The crystalline atorvastatin sodium salt of the present invention is prepared as depicted in the following process Scheme-1.
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The invention is further illustrated by the following non-limiting examples.
EXAMPLE
To a stirred mixture of t-butyl ester intermediate (III) (100 gm, 0.153 moles) and isopropanol (1500 ml) kept at about 25-30 °C, dilute HC1 (15 ml, 0.15 w/v) was added and warmed to 40-45 °C till the ester intermediate (III) disappeared as indicated by HPLC. After the ester was completely hydrolyzed sodium hydroxide (14.67 gm, 0.367 moles) in water (110 ml) was added and refluxed to 78-82 °C till the diol ester (II) was completely converted to sodium salt. The reaction mixture was cooled to 25-30 °C and stirred for about 3 hours. The crude sodium salt was washed with isopropanol (2 x 100 ml). The wet sodium salt was then charged into 1000 ml of isopropanol containing 5% water and heated to 78-82 °C for about an hour, cooled to 25-30 °C, and then stirred for 1-2 hours, filtered under N2 atmosphere and dried under vacuum to obtain crystalline atorvastatin sodium of purity 99.6%. Melting point: 136.7-139.2 °C.
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The purification of the crude atorvastatin sodium may be repeated one or more time to get crystalline form with purity above 99.6%.
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WE CLAIM:
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1. Crystalline atorvastatin sodium.
2. Crystalline atorvastatin sodium as claimed in claim 1 having characteristic X-ray
powder diffraction pattern given in Figure-1.
3. Crystalline atorvastatin sodium as claimed in claim 1 or 2 with a purity of above
99.5%