Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-06
2003-09-02
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06613916
ABSTRACT:
The present invention relates to a novel process for the preparation of atorvastatin in an amorphous form.
Atorvastatin, the substance known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt is known as HMG-CoA reductase inhibitor and is used as an antihypercholesterolemic agent. Processes for the preparation of atorvastatin and key intermediates are disclosed in the 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; 5,342,952; and 5,397,792. Atorvastatin is usually prepared as its calcium salt since it enables atorvastatin to be conveniently formulated in the pharmaceutical formulations, for example, in tablets, capsules, powders and the like for oral administration.
Atorvastatin can exist in an amorphous form or in one of the crystalline forms (Form I, Form II, Form III and Form IV), which are disclosed in the PCT patent applications WO-A-97/3958 and WO-A-97/3959. It is known that the amorphous forms in a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to the crystalline forms (Konno T.,
Chem Pharm Bull.,
1990,38: 2003-2007). For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation. Since processes for the crystallization and the preparation, respectively, of the amorphous substance are sometimes difficult to be performed, and as a product afford amorphous-crystalline mixtures, that is, a crystalline form instead of an amorphous form, there is a constant need for processes which enable the preparing of atorvastatin in an amorphous form without simultaneous formation of crystalline forms, or which will enable the conversion of the crystalline forms into the amorphous form.
Atorvastatin is the substance which is very slightly water-soluble, and it has been found that the crystalline forms are less readily soluble than the amorphous form which may cause problems in the bioavailability of atorvastatin in the body. It has been found that the production of amorphous atorvastatin according to the previously disclosed processes was not consistently reproducible, therefore the process has been developed for converting the crystalline forms of atorvastatin (formed in the synthesis of atorvastatin) to the amorphous form. The process is described in the PCT patent application WO-A-97/3960 and comprises dissolving the crystalline form of atorvastatin in a non-hydroxylic solvent and after removal of the solvent affords amorphous atorvastatin. The preferred non-hydroxylic solvent is selected from the group consisting of tetrahydrofuran, and mixtures of tetrahydrofuran and toluene. The disadvantage of the above process is primarily the use of non-nature-friendly solvents. Furthermore, even after extensive and strict drying measures, the amorphous atorvastatin product still contains amounts of the non-hydroxylic solvent.
It is an object of the present invention to provide an improved process for the preparation of atorvastatin in a more amorphous state compared to the above-mentioned processes of the prior art.
This and further objects are accomplished by the present invention.
The object of the present invention is achieved by a process for the preparation of atorvastatin in an amorphous form, which comprises:
a) providing a solution of atorvastatin in one or more solvents of a first type such that atorvastatin is freely soluble;
b) providing a mixture of said atorvastatin solution with one or more solvents of a second type, in which atorvastatin is insoluble or very slightly soluble, such that atorvastatin precipitates;
c) separating the precipitate formed in step (b) from the mixture of solvents.
Further objects can be achieved by preferred embodiments as set forth in the claims being dependent from claim
1
.
In the following, the drawings will be briefly described.
REFERENCES:
patent: 5385929 (1995-01-01), Bjorge et al.
patent: 6528660 (2003-03-01), Kumar et al.
patent: WO 97/03958 (1996-07-01), None
patent: WO 97/03959 (1996-07-01), None
patent: WO 97/03960 (1996-07-01), None
patent: WO 0071116 (2000-11-01), None
patent: WO 00/71116 (2000-11-01), None
Baumann et al.; The Convergent Synthesis of CI-981, an Optically Active, Highly Potent, Tissue Selective Inhibitor of HMG-CoA Reductase, Apr. 21, 1992.
Database Chemabs; Patent Abstracts, 1998.
Bromberg & Sunstein LLP
Isang Rei
LEK Pharmaceuticals d.d.
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