JP2024091928A - Method for producing stable fine crystals of azilsartan - Google Patents

Abstract

To provide a method for industrially producing azilsartan fine crystals which are stable and easy to formulate.SOLUTION: Provided is a method for producing stable azilsartan having a particle size distribution in terms of an average particle diameter of 3-18 μm. The production method comprises a step of stirring technical azilsartan product powder and a solvent of 1 to 40 times the volume of the technical azilsartan product powder at a stirring temperature between 0°C and a solvent reflux temperature for a stirring time of 5 minutes to 100 hours and does not comprise a step of recrystallization.SELECTED DRAWING: Figure 2

Description

The present invention relates to a method for industrially producing fine crystals of azilsartan. More specifically, the present invention relates to a method for producing stable fine crystals of azilsartan that can be used as is without grinding during formulation.

Azilsartan [2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid: general formula (I)]:
is an antagonist of the angiotensin II (AT1) receptor in vascular smooth muscle, and by selectively inhibiting the binding between angiotensin II and the AT1 receptor, it inhibits vasoconstriction and aldosterone secretion, thereby lowering blood pressure (Patent Document 1, Non-Patent Document 1).

Azilsartan medoxomil [2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl: general formula (II)]:
is a pro-drug that is rapidly hydrolyzed to azilsartan in vivo, and has been approved in the form of its potassium salt by the U.S. Food and Drug Administration (FDA) as a therapeutic drug for hypertension. Patent Document 2 discloses the pharmacological applications and pharmacological activities of azilsartan medoxomil and azilsartan medoxomil potassium salt.

Azilsartan generally has very low solubility in water, so when it is formulated as a pharmaceutical, it requires a microparticulation process to improve solubility.

Patent Document 2 describes that the grinding process usually carried out for pulverization produces decomposition products of azilsartan, particularly azilsartan desethyl form represented by formula (III).

In Patent Document 3, azilsartan having an average particle size of 48.35 μm is pulverized by a high-speed pulverizer to prepare particles having an average particle size of 3.27 μm and 5.22 μm. It is described that when these pulverized products are stored for six months at a temperature of about 25° C. and a humidity of about 60%, the amount of desethylazilsartan represented by formula (III) and azilsartan ethyl ester represented by formula (IV) increases.

Furthermore, Patent Document 3 describes a method for producing stable fine crystals of azilsartan that avoids decomposition of azilsartan due to the grinding operation. That is, it describes that azilsartan is suspended and stirred in tetrahydrofuran, acetonitrile, toluene, etc., filtered, dried, and then recrystallized from an alcoholic solvent or acetone to obtain azilsartan with excellent stability and an average particle size of 5.19 to 8.66 μm. However, because this manufacturing method does not control the particle size, it is difficult to produce azilsartan with the desired particle size.

Patent No. 2645962 Chinese Patent No. 103831159 Chinese Patent No. 108774217

Journal of Medicinal Chemistry. 1996, 39, 5228.

The present invention aims to provide a simple and efficient method for producing azilsartan of the desired particle size. Furthermore, the present invention aims to provide a method for producing azilsartan fine crystals that can maintain high quality and high stability without causing deterioration in quality due to an increase in desethylazilsartan and azilsartan ethyl ester during storage.

That is, the present invention is a method for producing stable azilsartan with a particle size distribution of 3 to 18 μm in average particle diameter, which includes a step of stirring azilsartan bulk powder and a solvent in an amount 1 to 40 times the volume of the azilsartan bulk powder at a stirring temperature of 0°C to the solvent reflux temperature for a stirring time of 5 minutes to 100 hours, and does not include a recrystallization step.

The present invention makes it possible to easily produce high-quality azilsartan with an average particle size of 3 to 18 μm in a high yield. Furthermore, it is possible to obtain highly stable azilsartan microcrystals with little increase in desethylazilsartan and azilsartan ethyl ester during storage. Furthermore, the present invention makes it possible to obtain azilsartan microcrystals that can be used without grinding during formulation.

1 shows the particle size distribution of the azilsartan bulk powder obtained in Production Example 1. 1 shows the particle size distribution of azilsartan obtained in Example 1. 1 shows the particle size distribution of azilsartan obtained in Example 2. 1 shows the particle size distribution of azilsartan obtained in Example 3. 1 shows the particle size distribution of azilsartan obtained in Example 4. 1 shows the particle size distribution of azilsartan obtained in Example 5. 1 shows the particle size distribution of azilsartan obtained in Example 6. 1 shows the particle size distribution of azilsartan obtained in Comparative Example 1.

The present invention will be described in detail below.

The manufacturing method of the present invention is a method for producing stable azilsartan with a particle size distribution of 3 to 18 μm in average particle diameter, which includes a step of stirring azilsartan bulk powder and a solvent in an amount 1 to 40 times the volume of the azilsartan bulk powder at a stirring temperature of 0°C to the solvent reflux temperature for a stirring time of 5 minutes to 100 hours, and does not include a recrystallization step.

The raw material azilsartan may be azilsartan produced according to the method described in the literature (e.g., Patent Document 1, Non-Patent Document 1, etc.) or commercially available azilsartan. The average particle size of such azilsartan raw material is greater than about 18 μm, and in order to prepare the azilsartan raw material powder used as the raw material of the present invention, it is previously pulverized. There are no particular limitations on the pulverization method, and it can be appropriately selected depending on the purpose. The pulverization is performed using, for example, a jet mill, a pin mill, a feather mill, a ball mill, a hammer mill, or a mortar.

The solvent used for stirring the azilsartan powder may be water, an alcohol-based solvent (e.g., methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and tert-butanol, etc.), an ester-based solvent (e.g., ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and tert-butyl acetate, etc.), an ether-based solvent (e.g., diethyl ether, isopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, and 1,4-dioxane, etc.), a hydrocarbon-based solvent (e.g., benzene, toluene, n-pentane, n-hexane, cyclohexane, and n-heptane, etc.), a ketone-based solvent (e.g., acetone and 2-butanone, etc.), or a halogen-based solvent (e.g., dichloromethane, chloroform, and 1,2-dichloroethane, etc.), either alone or in combination. Preferred solvents are one or more selected from ethanol, ethyl acetate, tetrahydrofuran, toluene, acetone, acetonitrile, and chloroform, and more preferably ethanol.

The amount of the solvent can be 1 to 40 times the volume of the azilsartan bulk powder. The preferred amount of the solvent is 3 to 20 times the volume.

The stirring temperature of the azilsartan drug substance powder and the solvent is in the range of 0°C to the solvent reflux temperature, and is preferably 0 to 80°C, 0 to 70°C, or 50 to 60°C. Here, "solvent reflux temperature" means the temperature at which the solvent refluxes or boils under atmospheric pressure.

The stirring time for the azilsartan powder and the solvent is 5 minutes to 100 hours, and preferably 5 minutes to 48 hours, 5 minutes to 30 hours, or 30 minutes to 30 hours.

The manufacturing method of the present invention does not include a recrystallization step. This is because the azilsartan bulk powder can be converted into stable azilsartan with the desired particle size (average particle size 3 to 18 μm) by stirring it in a solvent without going through a recrystallization step.

A more preferred embodiment of the present invention is a method in which azilsartan bulk powder is stirred with ethanol in an amount 3 to 20 times the volume of the azilsartan bulk powder at a stirring temperature of 50 to 60°C. The stirring time can be 5 minutes to 100 hours, 5 minutes to 48 hours, 5 minutes to 30 hours, or 30 minutes to 30 hours.

The particle size distribution of the azilsartan obtained by the present invention is an average particle size of 3 to 18 μm. In the present invention, azilsartan having a desired particle size distribution can be freely obtained by adjusting the production conditions, particularly the stirring time and stirring temperature. The particle size distribution of the obtained azilsartan can be, for example, about 3 μm or more, about 4 μm or more, about 7 μm or more, about 9 μm or more, about 13 μm or more, or about 17 μm or more, and can be about 18 μm or less, about 14 μm or less, about 11 μm or less, about 8 μm or less, about 5 μm or less, or 4 μm or less. The particle size can be measured by a conventional method, for example, a laser diffraction type particle size distribution analyzer.

The present invention will be described in more detail below with reference to the following examples, but these are merely illustrative and do not limit the present invention, and the scope of the present invention may be changed. As a comparative example, azilsartan was produced according to the method described in Patent Document 3. The purity of the azilsartan obtained in the production examples, examples, and comparative examples was measured by high performance liquid chromatography (HPLC), and the particle size was measured by a laser diffraction particle size distribution analyzer.

(Production Example 1)
Azilsartan bulk substance produced according to the method described in Non-Patent Document 1 was ground in a mortar to obtain an azilsartan bulk substance powder having an average particle size of 2.3 μm. The particle size distribution of the obtained azilsartan bulk substance powder is shown in FIG.

Example 1
30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder having an average particle size of 2.3 μm obtained in Production Example 1, and the mixture was stirred at 0° C. for 30 minutes. The crystals were filtered, washed with ethanol, and then dried at 40° C. to obtain 4.44 g of azilsartan. The particle size distribution of the obtained azilsartan was 3.2 μm in average particle size. The particle size distribution of this azilsartan is shown in FIG. 2.

Example 2
30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder having an average particle size of 2.3 μm obtained in Production Example 1, and the mixture was stirred at 50° C. for 2 hours. The crystals were filtered out, washed with ethanol, and then dried at 40° C. to obtain 5.00 g of azilsartan. The particle size distribution of the obtained azilsartan was 4.6 μm in average particle size. The particle size distribution of this azilsartan is shown in FIG.

Example 3
30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder having an average particle size of 2.3 μm obtained in Production Example 1, and the mixture was stirred at 50° C. for 6 hours. The crystals were filtered out, washed with ethanol, and then dried at 40° C. to obtain 5.25 g of azilsartan. The particle size distribution of the obtained azilsartan was 7.9 μm in average particle size. The particle size distribution of the obtained azilsartan is shown in FIG. 4.

Example 4
30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder having an average particle size of 2.3 μm obtained in Production Example 1, and the mixture was stirred at 50° C. for 14 hours. The crystals were filtered out, washed with ethanol, and then dried at 40° C. to obtain 5.25 g of azilsartan. The particle size distribution of the obtained azilsartan was 10.0 μm in average particle size. The particle size distribution of the obtained azilsartan is shown in FIG.

Example 5
30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder having an average particle size of 2.3 μm obtained in Preparation Example 1, and the mixture was stirred at 50° C. for 26 hours. The crystals were filtered out, washed with ethanol, and then dried at 40° C. to obtain 4.82 g of azilsartan. The particle size distribution of the obtained azilsartan was 13.5 μm in average particle size. The particle size distribution of the obtained azilsartan is shown in FIG.

Example 6
30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder having an average particle size of 2.3 μm obtained in Production Example 1, and the mixture was stirred at 60° C. for 48 hours. The crystals were filtered out, washed with ethanol, and then dried at 40° C. to obtain 5.64 g of azilsartan. The particle size distribution of the obtained azilsartan was 17.1 μm in average particle size. The particle size distribution of the obtained azilsartan is shown in FIG.

(Comparative Example 1)
25.00 g of the azilsartan bulk product produced according to the method described in Non-Patent Document 1 was produced according to the method described in Example 3 of Patent Document 3 to obtain 21.95 g of azilsartan. The average particle size of the obtained azilsartan was 22.2 μm, and the 90% particle size was 48.4 μm. The particle size distribution of this azilsartan is shown in FIG.

Test Example 1 Storage Stability Test The azilsartan obtained in Production Example 1, Examples 1 to 6, and Comparative Example 1 were each placed in a brown bottle, sealed, and then left in a thermostatic chamber at 50° C. for one month. Samples were taken out on the 7th, 14th, and 30th days, and the purity was measured by HPLC. The results are shown in Table 1.

INDUSTRIAL APPLICABILITY The present invention makes it possible to provide stable fine crystals of azilsartan which have a desired particle size distribution and can be used as is without pulverization during formulation.

Claims (7)

A method for producing stable azilsartan having a particle size distribution of 3 to 18 μm in average particle size, comprising:
A production method comprising the step of stirring azilsartan bulk powder and a solvent in an amount 1 to 40 times the volume of the azilsartan bulk powder at a stirring temperature of 0°C to the solvent reflux temperature for a stirring time of 5 minutes to 100 hours, and not including a recrystallization step. The method according to claim 1, wherein the solvent is one selected from water, alcohol-based solvents, ester-based solvents, ether-based solvents, hydrocarbon-based solvents, ketone-based solvents, aprotic polar solvents, and halogen-based solvents, or a mixture of two or more solvents selected from these. The method according to claim 1 or 2, wherein the solvent is one or more selected from ethanol, ethyl acetate, tetrahydrofuran, toluene, acetone, acetonitrile, and chloroform. The method according to any one of claims 1 to 3, wherein the stirring temperature is 0 to 80°C. The method according to any one of claims 1 to 4, wherein the amount of the solvent is 3 to 20 times the volume of the azilsartan bulk powder. The method according to any one of claims 1 to 5, wherein the stirring time is from 5 minutes to 30 hours. The method according to any one of claims 1 to 6, wherein the azilsartan bulk powder and ethanol in an amount 3 to 20 times by volume relative to the azilsartan bulk powder are stirred at 50 to 60°C.