Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-09-29
1999-10-19
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514423, 514429, C07D207335, A01N 4336
Patent
active
059691565
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to novel crystalline forms of atorvastatin which is known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt useful as pharmaceutical agents, to methods for their production and isolation, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel crystalline compounds of the present invention are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful hypolipidemic and hypocholesterolemic agents.
U.S. Pat. No. 4,681,893, which is herein incorporated by reference, discloses certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (.+-.)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro- 4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
U.S. Pat. No. 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4 -hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; and 5,342,952, which are herein incorporated by reference, disclose various processes and key intermediates for preparing atorvastatin.
Atorvastatin is prepared as its calcium salt, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). The calcium salt is desirable since it enables atorvastatin to be conveniently formulated in, for example, tablets, capsules, lozenges, powders, and the like for oral administration. Additionally, there is a need to produce atorvastatin in a pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications.
Furthermore, the process by which atorvastatin is produced needs to be one which is amenable to large-scale production. Additionally, it is desirable that the product should be in a form that is readily filterable and easily dried. Finally, it is economically desirable that the product be stable for extended periods of time without the need for specialized storage conditions.
The processes in the above United States Patents disclose amorphous atorvastatin which has unsuitable filtration and drying characteristics for large-scale production and must be protected from heat, light, oxygen, and moisture.
We have now surprisingly and unexpectedly found that atorvastatin can be prepared in crystalline form. Thus, the present invention provides atorvastatin in new crystalline forms designated Form I, Form II, and Form IV. Form I atorvastatin consists of smaller particles and a more uniform size distribution than the previous amorphous product and exhibits more favorable filtration and drying characteristics. Additionally, Form I atorvastatin is purer and more stable than the amorphous product.
SUMMARY OF THE INVENTION
Accordingly, the present invention is directed to crystalline Form I atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2.theta., d-spacings, and relative intensities with a relative intensity of >20% measured after 2 minutes of grinding and measured on a Siemens D-500 diffractometer with CuK.sub..alpha. radiation:
______________________________________ Relative
Intensity
(>20%) Ground
2.theta. d 2 Minutes
______________________________________
9.150 9.6565 42.60
9.470 9.3311 41.94
10.266 8.6098 55.67
10.560 8.
REFERENCES:
patent: 5316765 (1994-05-01), Folkers et al.
Bocan, Thomas et al., Antiaherosclerotic activity of inhibitors of 3-hydroxy-3-methylgutaryl coenzyme A reductase, Atherosclerosis, 111, 127-142, Dec. 1994.
Tetrahedron Letters, vol. 33, No. 17, 1992, pp. 2283-2284, Baumann, et al.
Pharmaceutical Research, vol. 10, No. 10, 1993, pp. 1461-1465, Kearney, et al.
Briggs Christopher A.
Harasawa Kikuko
Ichikawa Shigeru
Jennings Rex A.
Minohara Kazuo
Keating Dominic
Ramsuer Robert W.
Tinney Francis J.
Warner-Lambert & Company
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