FORM-3A
THE PATENTS ACT, 197

COMPLETE
SPECIFICATION
SECTION 10
TITLE : A METHOD OF PRODUCING CRYSTAL A OF 2-(3-CYANO-
4-ISOBUTYLOXYPHENYL)-4-METHYL-5-THIAZOLECARBOXYLIC ACID FOR USE AS THERAPEUTIC AGENT.
APPLICANT(S): TEIJIN LIMITED, 6-7 MINAMIHOMMACHI, 1-CHOME,
CHUO-KU, OSAKA-SHI, OSAKA 541 0054, JAPAN, A JAPANESE CORPORATION
The following Specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed :-

NOTIFICATION
IND. CL. : 32 F2 (b)
INT. CL. : C 07 D - 277
TITLE : A METHOD OF PRODUCING CRYSTAL A OF 2-Q-CYANO-
4-ISOBUTYLOXYPHENYL)-4-METHYL-5-THIAZOLECARBOXYLIC ACID FOR USE AS THERAPEUTIC AGENT.
APPLICANT : TEIJIN LIMITED, 6-7 MINAMIHOMMACHI, 1-CHOME,
CHUO-KU, OSAKA-SHI, OSAKA 541 0054, JAPAN, A JAPANESE CORPORATION.
INVENTORS : (1) KOICHI MATSUMOTO,
(2) KENZO WATANABE
(3) TOSHIYUKI HIRAMATSU
(4) MITSUTAKA KITAMURA
INTERNATIONAL : PCT/JP99/03258 DATED 18.06.1999 APPLICATION NO
INDIAN IN/PCT/2000/00009/MUM DATED 16.02.2000
APPLICATION NO.
- PRIORITY NO. 10-173079 DATED 19.06.1998 OF JAPAN
APPROPRIATE OFFICE FOR OPPOSITION PROCEEDINGS (RULE 4, PATENTS RULES 1972), PATENT OFFICE BRANCH, MUMBAI -13.
02 CLAIMS
A method of producing crystal A of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid for use as therapeutic agent, said method comprising:
crystallizing 2-(3-crano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid at the start of crystallization in. the presence of a composition of a mixed solvent comprising from 100:0 to 80:20 of methanol and water under at least 50 degree C to produce the desired product.
Comp.specn. 21 pages Drawings: 12 sheets

STATEMENT OF THE APPLICATION FILED ABROAD
INDIAN APPLICATION NO. IN/PCT/2000/00009/MUM FILED ON
16.02.2000

COUNTRY APPLICATION NO. DATE OF FILING STATUS
Argentina P9901 06368 14.12.1999 Pending
Australia 42892/99 15.02.2000 Pending
Bulgaria 104159 16.02.2000 Pending
Brazil PI 9906539-8 17.02.2000 Pending
Canada 2,301,863 18.002.2000 Pending
Chile 3034-99 17.12.1999 Pending
China 99801366.8 18.06.1999 Pending
Colombia 99078740 16.12.1999 Pending
Czechoslovakia PV 2000-582 18.02.2000 Pending
Ecuador SP-99-3280 17.12.1999 Pending
Egypt 1598/99 15.12.1999 Pending
EPC 99957054.2 29.02.2000 Pending
Guatemala PI-990216 16.12.1999 Pending
Croatia P2000 00 92A 18.02.2000 Pending
Hong Kong 01100199.8 08.01.2001 Pending
Hungary P0004325 18.02.2000 Pending
Israel 134,594 17.02.2000 Pending
Indonesia W-2000-0302 17.02.2000 Pending
Iceland 5377 17.02.2000 Pending
Cond

-2-
Japan 10-173079 19.06.1998 Pending
Jamaica 18/1/3971 17.12.1999 Pending
Korea 7001666678/2000 7001678/2000 18.02.2000 Pending
PCT PCT/JP99/03258 18.06.1999 Pending
U.Arab Eirates 10/2000 19.02.2000 Pending
Bosnia & Herzegobina BAP00542A 18.02.2000 Pending
Malaysia PI 9905565 17.12.1999 Pending
Mexico 2000001399 09.02.2000 Pending
New Zealand 503326 13.03.2000 Pending
Norway 20000789 17.02.2000 Pending
Peru 1282.99 17.12.1999 Pending
Philippines 1-1999-03228 17.12.1999 Pending
Pakistan 1103/99 17.12.1999 Accepted
Poland P.338780 18.12.2000 Pending
Russian Federation 2000107108 17.03.2000 Pending
Saudi Arabia 99 20 0845 27.12.1999 Pending
Singapore 200000837-5 18.02.2000 Granted
Slovakia PV 2000-220 18.02.2000 Pending
Thailand 054549 14.12.1999 Pending
Turkey 2000/458 18.02.2000 Granted
Republic of China 88122172 16.12.1999 Pending
Ukraine 2000031530 17.03.2000 Pending
U.S.A. 09/485,861 17.02.2000 Granted
Uruguay 25863 17.12.1999 Pending
Venezuela 1999-2653 20.12.1999 Pending
Viet-Nam S20000139 18.02.2000 Pending
Republic of South Africa 2000/0737 16.02.2000 Granted

VERIFICATION OF TRANSLATION
I, Tsumoru Fukumoto, of c/o A. AOKI, ISHIDA & ASOCIATES, Toranomon 37 Mori Bldg., 5-1, Toranomon 3-chome, Minato-ku, Tokyo, Japan, hereby certify that I am the translator of the documents attached and I state that the following is a true translation to the best of my knowledge and belief of Japanese Patent Application No.10-173079 filed on
June 19, 1998 in the name of TEIJIN LIMITED
DATED this 14th of March , 2000

10-173079 (G967)
[NAME OF DOCUMENT] APPLICATION FOR PATENT
[REFERENCE NUMBER] P31484
[DATE SUBMITED] June 19, 1998
[DESTINATION] To Commissioner, Patent Office
[INTERNATIONAL PATENT CLASSIFICATION] A61K 31/425
[TITLE OF THE INVENTION] Polymorph of 2-(3-cyano-4-
Isobutyloxyphenyl)-4-Methyl-5-Thiazolecarboxylic Acid and Process for Production Thereof
[NUMBER OF CLAIMS] 14
[INVENTOR]
[Address or Residence] c/o Teijin Limited, Iwakuni
Factory, 2-1, Hinodecho,
Iwakuni-shi, Yamaguchi
[Name] Koichi Matsumoto
[INVENTOR]
[Address or' Residence] c/o Teijin Limited, Iwakuni
Factory, 2-1, Hinodecho,
Iwakuni-shi, Yamaguchi
[Name] Kenzo Watanabe

[INVENTOR]
[Address or Residence]
[Name]

c/o Teijin Limited, Iwakuni Factory, 2-1, Hinodecho, Iwakuni-shi, Yamaguchi Toshiyuki Hiramatsu

[INVENTOR]
[Address or Residence]
[Name]

c/o Department of Chemical Engineering Hiroshima University, 1-4-1, Kagamiyama, Higashi-Hiroshima-shi, Hiroshima Mitsutaka Kitamura

[APPLICANT]
[Identification Number] 000003001
[Name of Applicant] TEIJIN LIMITED
[Representative] Shosaku Yasui

[PATENT ATTORNEY]
[Identification Number]
[Patent Attorney]
[Name of Patent Attorney]

100077263
Sumihiro Maeda

[INDICATION OF FEES TO BE PAID]
[Registration Number for Prepayment] [Amount of Fee]

010250 21000

[LIST OF ARTICLES TO BE SUBMITTED]
[Name of Article] Specification [Name of Article] Drawing [Name of Article] Abstract [Number of General Authorization]

1 1 1 9701951

[NEED FOR PROOF] Yes

- SPECIFICATION
Polymorph of 2-(3-cyano-4-
isobutyloxyphenyl)-4-methyl-5- thiazolecarboxylic acid and process for production thereof
<Scope of Claim for Patent>
<Claim 1> A crystalline polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 28 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°.
<Claim 2> A crystalline polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 28 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°.
<Claim 3> A crystalline polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 28 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°.
<Claim 4> A crystalline polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 28 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°.
<Claim 5> A crystalline polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 28 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,
1

24.78. 25.14, 25.74, 26.06, 26.64, 27.92, 28.60, 29.66 and 29.98°.
<Claim 6> An amorphous compound of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid having absorption pattern as shown in Fig. 12 in an infrared spectrophotography.
<Claim 7> A process for production of a crystalline polymorph according to claim 1, characterized by crystallizing under the condition defined by temperature and a composition of a mixed solvent of methanol/water as shown in the region I of Fig. 1.
<Claim 8> A process for production of crystalline polymorph according to claim 2, characterized by drying a crystalline polymorth according to claim 5 by heating under a reduced pressure.
<Claim 9> A process for production of crystalline polymorph according to claim 3, characterized by heating a small amount of a crystalline polymorth according to claim 3 in a mixed solvent of methanol/and water in a suspension.
<Claim 10> A process for production of a crystalline polymorph according to claim 4, characterized by crystallizing under a condition defined by temperature and a composition of a mixed solvent of methanol/water, as shown in the region II of Fig. 1.
<Claim 11> A process for production of a crystalline polymorph according to claim 5, characterized by crystallizing under a condition defined by temperature and a composition of a mixed solvent of methanol/water, as shown in the region III of Fig. 1.
<Claim 12> A process for production of a crystalline polymorph according to claim 5, characterized by crystallizing from a mixed solvent of 2-propanol and water.
<Claim 13> A process for production of a crystalline polymorph according to claim 5, characterized by naturally drying a crystalline polymorph according to claim 4 under a normal condition.
2
<Claim 14> A process for production of amorphous compound according to claim 6, characterized by drying a crystalline polymorph according to claim 4 with heating under a reduced pressure.
<Detailed Description of the Invention> <0001>
<Technical Field to Which the Invention Belongs>
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.
<0002>
Conventional Art>
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.
<0003>
<Chemical Formula 1>

<0004>
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. In addition,
3

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. <0005>
Polymorphism is meaningless unless solid physical properties exert an influence on biological activity 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. <0006>
<Problems to be Solved by the Invention>
Accordingly, an object of the present invention is to confirm crystalline polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, and to provide a technique of selectively producing desired various polymorphs.
<0007>
<Means for Solving the Problems>
When a compound forms two or more crystalline states, these different crystalline states are called crystalline polymorph. 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 20 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.
<0008>
Each of all polymorphs including the amorphous compound exhibits a characteristic absorption pattern in infrared (IR) spectroscopic analysis. Furthermore, sometimes, each
4

polymorph exhibits a different melting point. In this case, the' polymorphism can also be analyzed by differential scanning calorimetry (DSC).
<0009>
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.
<0010>
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 29 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 20 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 20 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.;5>0, 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 20 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

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 28 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°.
<0011>
The present invention also provides an amorphous compound of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which shows an absorption pattern as shown in Fig. 11 in infrared spectroscopic analysis.
<0012>
Furthermore, the present invention provides a method of producing crystal A, under the conditions shown as the region I in Fig. 1, which are defined by a temperature and a composition of a mixed solvent of methanol and water;
a method of producing crystal D, under the conditions shown as the region II in Fig. 1, which are defined by a temperature and a composition of a mixed solvent of methanol and water;
a method of producing crystal G, under the conditions shown as the region III in Fig. 1, which are defined by a temperature and a composition of a mixed solvent of methanol and water;
a method of producing crystal B, which comprises drying crystal G under a reduced pressure with heating;
a method of producing crystal C, which comprises heating in a suspended form in a mixed solvent of methanol and water in the presence of a small amount of crystal C;
a method of producing crystal G, which comprises recrystallizing from a mixed solvent, of 2-propanol and water;
a method of producing crystal G, which comprises air-drying crystal D under a normal atmosphere; and
a method of producing an amorphous compound, which comprises drying crystal D under reduced pressure with heating.
6

<0013> .
<Embodiment for Carrying Out the lnvention>
The method of producing various polymorphs according to the present invention includes various methods, and typical examples thereof are as follows.
<0014>
The crystal A is in the form of a metastable crystal form and is obtained under the conditions shown as the region I in Fig. 1, which are defined by a temperature and a composition of a mixed solvent of methanol and water, using a methanol/water reprecipitation method.
<0015>
The methanol/water reprecipitation method is a method of dissolving 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in methanol containing water or anhydrous methanol with heating, adding water slowly with stirring, initiating cooling after or during the addition of water, cooling to a predetermined temperature, collecting the crystal by filtration, and drying the crystal.
<0016>
At this time, the following crystallization condition is preferred to exclusively obtain a desired crystal A. Regarding the solvent used when 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid is dissolved with heating, a ratio of methanol to water is from 100:0 to 80:20, and preferably from 100:0 to 90:10. The dissolving temperature may be 50°C or higher, but is preferably a reflux temperature. The reason is as follows. That is, if the amount of water is increased or the dissolving temperature is low, the solubility is drastically lowered and a large amount of the solvent must be used so as to dissolve a . predetermined amount of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid with heating, which is not economical. The amount of the solvent is influenced by the composition, but may be an amount capable of completely dissolving it on heating. Specifically, the solvent is added
7

in a 5-.to 20-fold, preferably 8- to 15-fold amount by weight relative to the amount of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid. The reason is as follows. That is, if the amount is too small, chemical purity of the resulting crystal is poor. On the other hand, if the amount of the solvent is too large, it is not economical and the recovery of the purified product is lowered sometimes.
<0017>
With stirring a uniform solution of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, water is added to generate a crystal. In this case, the amount of water to be added can be defined as the amount so that a final ratio of methanol to water is within a range from 70:30 to 55:45. In case where a ratio of methanol to water is about 70:30, a final cooling temperature is preferably adjusted to 45°C or higher. In case where a ratio of methanol to water is about 60:40, a final cooling temperature is preferably adjusted to 35°C or higher. In case where a ratio of methanol to water is about 55:45, a final cooling temperature is preferably adjusted to 30°C or higher. Cooling is preferably initiated after the ratio of methanol to water reaches about 80:20, but may be initiated immediately after the completion of the addition of water.
<0018>
Any crystal form of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid can be used as far as the crystal is dissolved completely before the addition of water is initiated. The temperature of water to be added is not critical, but may- be controlled in case where an internal temperature change is expected depending on a scale of an operation. The temperature is suitably within a range from 5 to 95°C, but is preferably from about room temperature to 80°C. A small amount of the crystal A as a seed crystal of the crystal A may be suspended in water to be added.
<0019>
A crystal B is obtained by drying a crystal G under
8

reduced pressure with heating. In this case, the heating temperature is usually 50°C or higher, and preferably from 65
i
to 100°C. If the temperature is too low, it takes a long time to release water of crystallization, which is not suited for practical use. On the other hand, if the temperature is too high, the chemical purity is likely to be lowered by decomposition of the desired substance. The vacuum degree is adjusted according to the heating temperature, but is usually 25 mmHg or less, preferably several mmHg or less.
<0020>
Crystal C is produced by solvent-mediated polymorphic transition. The solvent to be used is preferably a solvent in which 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid is slightly soluble. A mixed solution of methanol and water is usually used. The ratio of methanol to water is from 80:20 to 50:50, and preferably from 70:30 to 60:40. An excess crystal is suspended in such a solvent and a small amount of crystal C is added, followed by heating with stirring. The amount of the crystal C to be added or heating temperature exerts an influence on the completion time of the conversion into the crystal C. Generally, the amount of 'the crystal C is preferably 2% by weight or less relative to the amount of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid to be converted into the crystal C, and usually 1% by weight or less. The crystal form of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid to be converted into the crystal C does not exert an influence on the results of the conversion. The heating temperature exerts an influence on the time required to complete the conversion, but it is not critical as far as the conversion occurs finally. The heating temperature is generally 50°C or higher, and usually 60°C or higher.
<0021>
Crystal D is a methanolate and is obtained by drying a wet product, which has been obtained by recrystallizing from a methanol solvent or a mixed solvent of methanol and water, at
9

a low temperature under a reduced pressure. When this wet product is air-dried at a room temperature under a normal pressure, crystal G is obtained. On the other hand, when the wet product is dried at a high temperature under a reduced pressure, an amorphous compound is obtained. Regarding the drying condition for obtaining the crystal D, the temperature is usually 35°C or lower, and preferably 25°C or lower. In case where the wet product is dried at a room temperature under a reduced pressure to obtain an amorphous compound, the heating temperature is usually 50°C or higher, and preferably from 65 to 100°C. If the heating temperature is too low, it takes a long time to release methanol, which is not suited for practical use. On the other hand, if the temperature is too high, the chemical purity is likely to be lowered by decomposition of the desired substance. The vacuum degree is adjusted according to the heating temperature, but is usually 25 mmHg or less, preferably several mmHg or less. Another method for obtaining the above-described wet product includes a methanol/water reprecipitation method for obtaining the crystal A, wherein the addition of water is terminated when the ratio of methanol to water reached 70:30 and the mixture is cooled as it is and stirred for a long time. In this case, the temperature on stirring for a long time varies depending on the amount of methanol, but the desired wet product can be obtained by maintaining the temperature at 30°C or lower in case where the ratio of methanol to water is 70:30.
<0022>
The crystal G is a hydrate and is obtained by crystallizing a sodium salt of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid from an acid, or drying a wet product, which has been obtained by recrystallization from a mixed solvent of 2-propanol and water, at low temperature under a reduced pressure or air-drying the wet product under a normal pressure. It was previously described that crystal B is obtained when the resulting wet product is dried under a reduced pressure with
10

heating. The ratio of 2-propanol to water is from about 90:10 to 50:50. However, when the amount of water increases, the solubility is drastically lowered and, therefore, it is necessary to properly select the amount. The amount of the mixed solvent of 2-propanol and water is not a critical factor, but the mixed solvent is used in a 5- to 20-fold, preferably 8- to 15-fold amount by weight relative to the amount of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid to be used usually. The crystal G is also obtained by air-drying a wet product of the crystal D, which is obtained by the above-described method, at room temperature under a normal pressure.
<0023>
On the other hand, an amorphous compound can be obtained by drying the crystal D under a reduced pressure with heating. In this case, the heating temperature is usually 50°C or higher, and preferably from 65 to 100°C. If the heating temperature is too low, it takes a long time to release methanol contained, which is not suited for practical use. On the other hand, too high temperature should be avoided to prevent lowering of the chemical purity caused by decomposition of the desired substance. The vacuum degree is adjusted according to the heating temperature, but is usually 25 mmHg or less, preferably several mmHg or less.
<0024>
<Examples>
The following examples further illustrate the present invention in detail, but the present invention is not limited by these examples'."
<0025>
[Example 1]
Production of crystal A of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 114 mL of methanol was added and the compound was dissolved by heating to 65°C with stirring. To
11

the resulting solution, 114 ml of water in which 20 mg of crystal A of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added over 1 hour. Then, the mixed solution was cooled to 35°C. The crystal was collected by filtration and dried at 80°C under a reduced pressure of 2 mmHg for 4 hours. As is apparent from data of XRD and IR, the resulting crystal was crystal A.
<0026>
[Example 2]
Production of crystal C of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 100 mL of a mixed solution of methanol and water in a mixing ratio of 70:30 was added, followed by heating to 65°C with stirring. To the resulting solution, 20 mg of crystal C of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added. The crystal was collected and stirred until conversion into a crystal C is confirmed by IR. After cooling, the crystal was collected by filtration and dried at 80°C under a reduced pressure of 2 mmHg for 4 hours. As is apparent from data of XRD and IR, the resulting crystal was crystal C. <0027>
[Example 3]
Production of crystal D of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 80 mL of methanol was added, followed by heating to 65°C with stirring. Then, the crystal was collected and stirred until conversion into crystal C was confirmed by IR. After cooling, the crystal was collected by filtration and dried at 25°C under a reduced pressure of 2 mmHg for 4 hours. As is apparent from data of XRD and IR, the resulting crystal was crystal D.
<0028>
[Example 4]
12

Production of crystal G of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 90 mL of methanol was added and the compound was dissolved by heating to 65°C with stirring. To the mixture, 90 mL of water was added over 30 seconds. The solution was cooled to 25°C. The crystal was collected by filtration and air-dried for 2 days. As is apparent from data of XRD and IR, the resulting crystal was crystal G.
<0029>
[Example 5]
Production of crystal G of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (recrystallization from 2-propanol/water solvent)
To 30 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 900 mL of a mixed solution of 2-propanol and water in a mixing ratio of 50:50 was added, followed by heating to 80°C with stirring. This mixture was filtered in a hot state, dissolved again with heating and then cooled to a room temperature. The deposited crystal was collected by filtration and air-dried on a filter paper overnight. As a result of Karl Fisher's water content measurement, the resulting crystal had a water content of 2.7% by weight. As is apparent from data of XRD and IR, the resulting crystal was crystal G.
<0030>
[Example 6]
Production of crystal G of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (recrystallization from methanol/water solvent)
33.4 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was dissolved in 334 mL of a mixture of methanol and water in a mixing ratio of 95:5 by heating with stirring. While the mixture was heated with reflux at an external temperature of 85°C, 119 mL of water was added gradually. Then, 150 mg of crystal C was added and the
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mixture was continuously heated at reflux for 4 hours. After cooling, the reaction product was dried at 80°C under a reduced pressure of 2 mmHg with heating for 6 hours to obtain 33 g of crystal G. As is apparent from data of XRD and IR, the resulting crystal was crystal G.
<0031>
[Example 7]
Production of crystal G of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (production from crystal D)
The resulting crystal D obtained in Example 3 was air-dried on a filter paper overnight. As a result of Karl Fisher's water content measurement, the resulting crystal had a water content of 2.6% by weight. As is apparent from data of XRD and IR, the resulting crystal was crystal G.
<0032>
[Example 8]
Production of crystal B of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
The crystal G obtained in Example 4 was dried at 80°C under a reduced pressure of 2 mmHG with heating for 2 days. As is apparent from data of XRD and IR, the resulting crystal was crystal B.
<0033>
[Example 9]
Production of amorphous compound of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
The crystal D obtained in Example 3 was dried at 80°C under a reduced pressure of 2 mmHg with heating for 4 days. As is apparent from data of IR, the resulting crystal was amorphous compound.
<0034>
<Effects of the Invention>
The crystalline polymorphs of the present invention do not exhibit remarkable differences of properties by the crystalline forms in comparison with those generally observed in pharmaceutical compositions, and any crytalline form can be
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used for pharmaceutical compositions. However, a technique for producing at will each crystalline polymorph is essential to provide a predetermined level of starting material for pharmaceutical composition.
<Brief Description of the Drawings>
<Fig. 1> A crystallization condition chart for polymorphs of the present invention in methanol/wafer solvent.
<Fig. 2> A graph showing one embodiment of a XRD pattern of the crystal A of the present invention.
<Fig. 3> A graph showing one embodiment of a XRD pattern of the crystal B of the present invention.
<Fig. 4> A graph showing one embodiment of a XRD pattern of the crystal C of the present invention.
<Fig. 5> A graph showing one embodiment of a XRD pattern of the crystal D of the present invention.
<Fig. 6> A graph showing one embodiment of an XRD pattern of the crystal G of the present invention.
<Fig. 7> A graph showing one embodiment of an IR absorption curve of the crystal A of the present invention.
<Fig. 8> A graph showing one embodiment of an IR absorption curve of the crystal B of the present invention.
<Fig. 9> A graph showing one embodiment of an IR absorption curve of the crystal C of the present invention.
<Fig. 10> A graph showing one embodiment of an IR absorption curve of the crystal D of the present invention.
<Fig. 11> A graph showing one embodiment of an IR absorption curve of the crystal G of the present invention.
<Fig. 12> A graph showing one embodiment of an IR absorption curve 'of an amorphous compound of the present invention.
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WE CLAIM:-
1 A method of producing crystal A of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid for use as therapeutic agent, said method comprising:
crystallizing 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid at the start of crystallization in the presence of a composition of a mixed solvent comprising from 100:0 to 80:20 of methanol and water under at least 50"C to produce the desired product.
2. A method of producing crystal A of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid for use as therapeutic agent substantially as herein described with reference to the accompanying drawings and foregoing example 1,

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TOTAL P.04