Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-17
2001-05-01
Reamer, James H. (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06225474
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a technique for controlling polymorphs, which is important in the case where a pharmaceutical composition comprising a useful compound as a drug is supplied in a qualitatively stable manner. More particularly, it relates to a method of producing a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid. This compound has an activity to regulate biosynthesis of uric acid in vivo and can be used as a therapeutic agent for hyperuricemia.
BACKGROUND ART
When a certain compound forms two or more crystalline states, these different crystalline states are referred to as polymorphism. It is generally known that the stability varies with each polymorph (crystal form) of polymorphism. For example, Japanese Unexamined Patent Publication (KOKAI) No. 62-226980 describes that two polymorphs of prazosin hydrochloride each having a different stability, thus exerting an influence on the results of the long-term storage stability. Also, Japanese Unexamined Patent Publication (KOKAI) No. 64-71816 describes that a specific one among different polymorphs of buspirone hydrochloride is advantageous in view of retention of specific physical properties under storage or manufacturing conditions.
As described above, a specific polymorph is superior in stability, sometimes. Accordingly, in case where a plurality of polymorphs are present, it is important to develop a technique of preferentially producing each polymorph. Particularly, in case where a pharmaceutical composition comprising a useful compound as a drug is produced, it is suitable to control polymorphism so as to formulate a pharmaceutical composition containing only a superior specific polymorph.
As described in International Publication WO92/09279, it is known that 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid represented by the following formula has an activity for inhibiting xanthine oxidase.
However, the above-mentioned publication does not describe polymorphism, and therefore, the crystal form of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid studied in the publication is not clear. It is only assumed from the experimental operation described therein that it is an ethanolate. The evaluation of the activity described in that publication is not conducted in a solid state and, therefore, there is not any description about characteristics of the polymorph.
Polymorphism is meaningless unless solid physical properties exert an influence on biological activity, physiochemical properties or an industrial manufacturing method of the substance. For example, when using as a solid preparation in animals, it is important that the presence or absence of polymorphism is confirmed in advance and a technique of selectively producing a desired polymorph is developed. In case where the substance is stored for a long period of time, a question is how the crystal form can be retained in a stable manner. It is also an important object to develop a technique of producing the crystal form in an industrially easy and reproducible manner.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to solve the above-described problems about 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid. That is, the present invention provides a technique of selectively producing desired various polymorphs if polymorphism is present after confirming the presence or absence of polymorphism.
The present inventors have intensively studied, and found that at least six polymorphs including an amorphous compound and a solvate are present for 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid. It has been found that the solvate includes two members (methanolate and hydrate). It has also been found that all polymorphs other than the amorphous compound exhibit characteristic X-ray powder diffraction (XRD) patterns. Each polymorph has a specific 2&thgr; value. Even in case where two or more polymorphs are present simultaneously, the content of about 0.5% can be detected by X-ray powder diffraction analysis.
Each of all polymorphs including the amorphous compound exhibits a characteristic absorption pattern in infrared (IR) spectroscopic analysis. Furthermore, sometimes, each polymorph exhibits a different melting point. In this case, the polymorphism can also be analyzed by differential scanning calorimetry (DSC).
Also the present inventors have studied a method for producing those polymorphs and found a technique for obtaining 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in the desired crystal form.
Thus, the present invention provides a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (hereinafter also referred to as crystal A), which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2&thgr; of about 6.62, 7.18, 12.80, 13.26, 16.48, 19.58, 21.92, 22.68, 25.84, 26.70, 29.16 and 36.70°;
a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (hereinafter also referred to as crystal B), which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2&thgr; of about 6.76, 8.08, 9.74, 11.50, 12.22, 13.56, 15.76, 16.20, 17.32, 19.38, 21.14, 21.56, 23.16, 24.78, 25.14, 25.72, 26.12, 26.68, 27.68 and 29.36°;
a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (hereinafter also referred to as crystal C), which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2&thgr; of about 6.62, 10.82, 13.36, 15.52, 16.74, 17.40, 18.00, 18.70, 20.16, 20.62, 21.90, 23.50, 24.78, 25.18, 34.08, 36.72 and 38.04°;
a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (hereinafter also referred to as crystal D), which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2&thgr; of about 8.32, 9.68, 12.92, 16.06, 17.34, 19.38, 21.56, 24.06, 26.00, 30.06, 33.60 and 40.34°; and
a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (hereinafter also referred to as crystal G), which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2&thgr; of about 6.86, 8.36, 9.60, 11.76, 13.74, 14.60, 15.94, 16.74, 17.56, 20.00, 21.26, 23.72, 24.78. 25.14, 25.74, 26.06, 26.64, 27.92, 28.60, 29.66 and 29.98°.
According to infrared spectroscopic analysis, the crystal A has a characteristic absorption, which can be distinguished from that of other polymorphs, at about 1678 cm
−1
; the crystal B has characteristic absorptions, which can be distinguished from the other polymorphs, at about 1715, 1701 and 1682 cm
−1
; the crystal C has characteristic absorptions, which can be distinguished from the other polymorphs, at about 1703 and 1219 cm
−1
; the crystal D has a characteristic absorption, which can be distinguished from that of other polymorph, at about 1705 cm
−1
; and the crystal G has characteristic absorptions, which can be distinguished from the other polymorph, at about 1703 and 1684 cm
−1
.
That is, the present invention provides a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (crystal A) having a characteristic absorption, which can be distinguished from that of other polymorphs, at about 1678 cm
−1
in infrared spectroscopic analysis;
a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (crystal B) having characteristic absorptions, which can be distinguished from that of other polymorphs, at about 1715, 1701 and 1682 cm
−1
in infrared spectroscopic analysis;
a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (crystal C) having characteristic absorptions, which can be distinguished from that of other polymorphs, at about 1703 and 1219 cm
−1
in infrared spectroscopic analysis;
a polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (crystal D
Hiramatsu Toshiyuki
Kitamura Mitsutaka
Matsumoto Koichi
Watanabe Kenzo
Reamer James H.
Sughrue Mion Zinn Macpeak & Seas, PLLC
Teijin Limited
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