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Novel crystalline form of atorvastatin hemi-calcium salt, hydrate thereof, and method of producing the same

a technology of hemicalcium salt and atorvastatin, which is applied in the field of new crystal form of atorvastatin hemicalcium salt, a hydrate thereof, can solve the problems of limited storage conditions and unsuitable amorphous forms for the filtration and drying of products, and achieves the effect of improving the stability and stability of the produ

Inactive Publication Date: 2012-05-17
KYONGBO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a novel crystalline form of high-purity atorvastatin hemi-calcium salt that is more stable, easy to produce in large amounts, and show no difference between batches according to the preparation method. This crystalline form is obtained by a method that involves adding a seed crystal and carrying out filtration at reduced temperature. The impurities in the crude atorvastatin hemi-calcium salt are managed by controlling the impurity levels during the preparation process. The present invention also provides a pharmaceutical composition containing this new crystalline form of atorvastatin hemi-calcium salt hydrate."

Problems solved by technology

Such amorphous forms are unstable to heat, light, oxygen and moisture, and thus the storage conditions thereof are limited.
Also, such amorphous forms are unsuitable for the filtration and drying of products in mass production.

Method used

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  • Novel crystalline form of atorvastatin hemi-calcium salt, hydrate thereof, and method of producing the same
  • Novel crystalline form of atorvastatin hemi-calcium salt, hydrate thereof, and method of producing the same
  • Novel crystalline form of atorvastatin hemi-calcium salt, hydrate thereof, and method of producing the same

Examples

Experimental program
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Effect test

example 1

[0045]As crude atorvastatin, an amorphous atorvastatin hemi-calcium salt prepared according to the method of Example 10 of U.S. Pat. No. 5,273,995 was used. The HPLC graph and peak results of the amorphous atorvastatin hemi-calcium salt are shown in FIG. 1 and Table 1 below.

TABLE 1ClassificationRTArea% area1Peak 115.2962.488580.0062Peak 216.3331.717200.0043des-fluoro23.61621.173570.0554trans-isomer24.14330.460730.0795Atorvastatin25.72338294.599.4576di-fluoro27.2937.377440.0197Peak 732.6450.000000.0008Lactone34.20963.308010.1649Peak 939.35812.007710.03110Pak 1040.69726.278360.06811Peak 1147.80321.324550.05512Peak 1249.50618.769460.04913Peak 1351.2664.142770.011

[0046]Subsequently, 10 g of the prepared amorphous atorvastatin hemi-calcium salt was added to a mixture of 50 ml of methanol and 600 ml of water and stirred at room temperature for 1 hour. The stirred mixture was filtrated, and the resulting solid was washed with water. The washed solid was dried under reduced pressure at 40° ...

example 2

[0057]10 g of a mixture of amorphous and crystalline forms of atorvastatin hemi-calcium salt was added to a mixture of 50 ml of methanol and 500 ml of water and stirred at 5˜15° C. for 5 hours. The stirred mixture was filtered and the resulting solid was washed with water. The washed solid was dried under reduced pressure at 40° C. for 5 hours, thus obtaining 9.8 g of a crystalline Form α atorvastatin hemi-calcium salt.

[0058]The X-ray powder diffraction spectrum of the obtained crystalline Form a atorvastatin hemi-calcium salt is shown in FIG. 8, and the numerical values of the X-ray powder diffraction spectrum are shown in Table 8 below.

[0059]The 13C NMR (nuclear magnetic resonance) of the obtained crystalline Form a atorvastatin hemi-calcium salt are shown in FIG. 9, and the numerical values thereof are shown in Table 9 below.

TABLE 82θdRelative intensity (>10%)8.9609.861134.09.4999.302919.511.9397.406516.216.8995.2422100.019.3224.590021.421.7014.092049.023.3393.808322.429.2583.050...

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Abstract

The present invention provides a novel crystalline form of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-mthylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptanoic acid hemi-calcium salt (atorvastatin hemi-calcium salt) of the following formula 1, which is known to be useful as a drug, a hydrate thereof and a preparation method thereof:

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application is a non-provisional application, which claims priority to Korean Application No. 10-2010-0072991, filed Jul. 28, 2010. The entire content of the prior application is hereby incorporated by reference.TECHNICAL FIELD[0002]The present invention relates to a novel crystal form of atorvastatin hemi-calcium salt, a hydrate thereof, a preparation method thereof, and a pharmaceutical composition containing the same.BACKGROUND ART[0003]Atorvastatin having the following structural formula is an inhibitor of HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase) and is known as an effective therapeutic agent for hyperlipidemia, hypercholesterolemia, arteriosclerosis, osteoporosis, benign prostatic hyperplasia and Alzheimer's disease:[0004]U.S. Pat. Nos. 4,681,893 and 5,273,995 discloses, as atorvastatin, lactone forms of trans (±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyra...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D207/335
CPCC07D207/34A61P3/06A61P9/10A61P13/08A61P19/10A61P25/28A61P43/00A61K31/409C07D207/36C07D207/42
Inventor LEE, KYUNG JUSON, HOE JOOCHOI, DOO SEONGCHANG, SUN HOOH, DO YEON
Owner KYONGBO PHARMA