Crystalline forms of pitavastatin calcium

A technology of crystallization and calcium salts, applied in metabolic diseases, cardiovascular system diseases, organic chemistry, etc., can solve the problem of not giving the precise process and so on

Active Publication Date: 2008-07-16
NISSAN CHEM IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

L.A.Sorbera et al in Drugs of the Future (1998) vol.23, 847-859 pages and M.Suzuki et al in Bioorganic & Medicinal Chemistry Letters (1999) vol.9, 2977-2982 pages described pitava Statin calcium, however, does not give the precise process of its preparation

Method used

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  • Crystalline forms of pitavastatin calcium
  • Crystalline forms of pitavastatin calcium
  • Crystalline forms of pitavastatin calcium

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0057] Example 1: Preparation of Form A

[0058] 4.15gr of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoic acid The tert-butyl ester (pitavastatin tert-butyl ester) was suspended in 52 ml of a mixture of methyl tert-butyl ether and methanol (10:3). To this mixture was added 2.17 ml of 4M aqueous NaOH solution, and the obtained yellow solution was stirred at 50°C for 2.5 hours. The reaction mixture was cooled to room temperature, then 50 ml of water were added and stirred for a further hour. The aqueous phase was separated and extracted once with 20 ml of methyl tert-butyl ether. Add 0.58gr of CaCl to this aqueous solution within 1 hour 2 Solution in 80ml of water. The obtained suspension was stirred at room temperature for about 16 hours. The suspension was filtered and the solid obtained was dried at 40° C. and 50 mbar for about 16 hours. The product obtained was Form A, which was characterized by the X-ray powder diffraction patt...

Embodiment 2

[0059] Example 2: Preparation of Form B

[0060] 100 mg of pitavastatin calcium Form A was suspended in 2 ml of water and stirred at room temperature for 30 min, followed by the addition of 2 ml of ethanol and stirring for an additional 18 hours. The suspension was filtered and air dried to afford 36 mg of Form B. The obtained Form B is characterized by the X-ray powder diffraction pattern shown in FIG. 2 . Further characterization of the obtained Form B by thermogravimetric analysis combined with FT-IR spectroscopy revealed a water content of about 10%.

Embodiment 3

[0061] Example 3: Preparation of Form C

[0062] Suspend 62 mg of pitavastatin calcium Form A in 2 ml of isopropanol containing 5% water. This suspension was heated to 60°C, which resulted in almost complete dissolution of Form A, and cooled to room temperature again. The suspension was stirred at this temperature for 66 hours. The obtained suspension was filtered, washed once with some isopropanol containing 5% water and dried in air. The obtained Form C is characterized by the X-ray powder diffraction pattern shown in FIG. 3 . Further characterization of the obtained Form C by thermogravimetric analysis combined with FT-IR spectroscopy revealed that the sample contained about 6.3% isopropanol and a small amount of water.

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Abstract

The amorphous form of (3R, 5S)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3,5-dihydroxy-6 (E)-heptanoic acid hemicalcium salt.

Description

[0001] This application is a divisional application, and its parent case is an application with an application date of February 2, 2004, an application number of 200480003952.3, and an invention title of "Crystal Form of Pitavastatin Calcium". technical field [0002] The present invention relates to new crystalline and amorphous forms of pitavastatin calcium, processes for their preparation and pharmaceutical compositions comprising these forms. Background technique [0003] The present invention relates to new crystalline and amorphous forms of pitavastatin calcium. Pitavastatin is also known as NK-104, Ivastatin and Nisvastatin. The chemical name of pitavastatin calcium is: (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6( E) - Hemicalcium heptanoate. Pitavastatin calcium has the following formula: [0004] [0005] Pitavastatin calcium was recently developed by Kowa Company Ltd of Japan as a new chemically synthesized and highly potent stat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14A61K31/47A61P9/00
CPCC07D215/14A61P3/06A61P43/00A61P9/00C07B2200/13
Inventor P·A·范德沙夫F·布拉特M·谢拉吉维茨K·-U·舍宁
Owner NISSAN CHEM IND LTD
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