Method for producing stable fine crystals of azilsartan

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

[Technical Field]

[0001] The present invention relates to a method for industrially producing fine crystals of azilsartan, and more particularly to a method for producing stable fine crystals of azilsartan that can be used as is without pulverization during formulation. [Background technology]

[0002] 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)]: [ka] 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 suppresses vasoconstriction and aldosterone secretion, thereby lowering blood pressure (Patent Document 1, Non-Patent Document 1).

[0003] 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)]: [ka] is a prodrug that is rapidly hydrolyzed to azilsartan in vivo, and its potassium salt form has been approved 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.

[0004] Azilsartan generally has very low solubility in water, and therefore, when it is formulated as a pharmaceutical, it requires a microparticulation process to improve solubility.

[0005] Patent Document 2 describes that the grinding process that is usually carried out to produce fine particles produces decomposition products of azilsartan, particularly azilsartan desethyl derivatives represented by formula (III). [ka]

[0006] Patent Document 3 describes the preparation of 3.27 μm and 5.22 μm particles by pulverizing azilsartan with an average particle size of 48.35 μm using a high-speed pulverizer. It describes that when these pulverized products are stored for 6 months at a temperature of about 25°C and a humidity of about 60%, the amounts of desethylazilsartan represented by formula (III) and azilsartan ethyl ester represented by formula (IV) increase. [ka]

[0007] Furthermore, Patent Document 3 describes a method for producing stable fine crystals of azilsartan that avoids decomposition of azilsartan during the milling process. Specifically, the method describes suspending and stirring azilsartan in tetrahydrofuran, acetonitrile, toluene, or the like, filtering, drying, and then recrystallizing 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 method does not control particle size, it is difficult to produce azilsartan with the desired particle size. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 2645962 [Patent Document 2] Chinese Patent No. 103831159 [Patent Document 3] Chinese Patent No. 108774217 [Non-patent literature]

[0009] [Non-Patent Document 1] Journal of Medicinal Chemistry. 1996, 39, 5228. Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a simple and efficient method for producing azilsartan of a desired particle size. Another object of the present invention is to provide a method for producing azilsartan fine crystals that can maintain high quality and high stability without causing deterioration in quality due to increases in desethylazilsartan and azilsartan ethyl ester during storage. [Means for solving the problem]

[0011] Specifically, the present invention provides a method for producing stable azilsartan having a particle size distribution of 3 to 18 μm in terms of average particle diameter, which comprises 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. [Effects of the Invention]

[0012] According to the present invention, high-quality azilsartan having an average particle size of 3 to 18 μm can be produced simply and in high yield. Furthermore, highly stable fine crystals of azilsartan can be obtained with little increase in desethyl azilsartan and azilsartan ethyl ester during storage. Furthermore, according to the present invention, fine crystals of azilsartan can be obtained that can be used in formulation without milling. [Brief explanation of the drawings]

[0013] [Figure 1] 1 shows the particle size distribution of the azilsartan bulk powder obtained in Production Example 1. [Figure 2] 1 shows the particle size distribution of azilsartan obtained in Example 1. [Figure 3] 1 shows the particle size distribution of azilsartan obtained in Example 2. [Figure 4] 1 shows the particle size distribution of azilsartan obtained in Example 3. [Figure 5] 1 shows the particle size distribution of azilsartan obtained in Example 4. [Figure 6] 1 shows the particle size distribution of azilsartan obtained in Example 5. [Figure 7] 1 shows the particle size distribution of azilsartan obtained in Example 6. [Figure 8] 1 shows the particle size distribution of azilsartan obtained in Comparative Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention will be described in detail below.

[0015] The production method of the present invention is a method for producing stable azilsartan having a particle size distribution of 3 to 18 μm in terms of average particle diameter, which comprises 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.

[0016] The azilsartan bulk substance used as a raw material may be azilsartan produced according to methods 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 bulk substance is greater than approximately 18 μm, and it is previously pulverized to prepare the azilsartan bulk substance powder used as a raw material in the present invention. The pulverization method is not particularly limited and can be appropriately selected depending on the purpose. Pulverization can be performed using, for example, a jet mill, pin mill, feather mill, ball mill, hammer mill, or mortar.

[0017] The solvent used for stirring the azilsartan drug substance powder can be water, alcoholic solvents (e.g., methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and tert-butanol), ester solvents (e.g., ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and tert-butyl acetate), ether solvents (e.g., diethyl ether, isopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, and 1,4-dioxane), hydrocarbon solvents (e.g., benzene, toluene, n-pentane, n-hexane, cyclohexane, and n-heptane), ketone solvents (e.g., acetone and 2-butanone), or halogenated solvents (e.g., dichloromethane, chloroform, and 1,2-dichloroethane), either alone or in combination. Preferred solvents are one or more selected from ethanol, ethyl acetate, tetrahydrofuran, toluene, acetone, acetonitrile, and chloroform, with ethanol being more preferred.

[0018] The amount of the solvent can be 1 to 40 times by volume relative to the azilsartan bulk powder, and preferably 3 to 20 times by volume.

[0019] The stirring temperature of the azilsartan drug substance powder and the solvent is in the range of 0° C. to the solvent reflux temperature, preferably 0 to 80° C., 0 to 70° C., or 50 to 60° C. Here, the "solvent reflux temperature" refers to the temperature at which the solvent refluxes or boils under atmospheric pressure.

[0020] The stirring time for the azilsartan bulk 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.

[0021] The production method of the present invention does not include a recrystallization step, because azilsartan bulk powder can be converted into stable azilsartan having a desired particle size (average particle size of 3 to 18 μm) by stirring it in a solvent without going through a recrystallization step.

[0022] A more preferred embodiment of the present invention is a method in which azilsartan bulk powder and ethanol in an amount 3 to 20 times the volume of the azilsartan bulk powder are stirred 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.

[0023] 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 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 particle size distribution analyzer. [Example]

[0024] The present invention will be further described in detail below with reference to the following examples, but these are merely illustrative examples and do not limit the present invention, and the scope of the present invention may be varied. Furthermore, 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.

[0025] (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 with an average particle size of 2.3 μm. The particle size distribution of the obtained azilsartan bulk substance powder is shown in Figure 1.

[0026] Example 1 30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder obtained in Preparation Example 1 and having an average particle size of 2.3 μm, and the mixture was stirred at 0°C for 30 minutes. The crystals were collected by filtration, 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 Figure 2.

[0027] Example 2 30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder obtained in Preparation Example 1 and having an average particle size of 2.3 μm, and the mixture was stirred at 50°C for 2 hours. The crystals were collected by filtration, 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 Figure 3.

[0028] Example 3 30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder obtained in Preparation Example 1 and having an average particle size of 2.3 μm, and the mixture was stirred at 50°C for 6 hours. The crystals were collected by filtration, 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 Figure 4.

[0029] Example 4 30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder obtained in Preparation Example 1 and having an average particle size of 2.3 μm, and the mixture was stirred at 50°C for 14 hours. The crystals were collected by filtration, 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 Figure 5.

[0030] Example 5 30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder obtained in Preparation Example 1 and having an average particle size of 2.3 μm, and the mixture was stirred at 50°C for 26 hours. The crystals were collected by filtration, 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 Figure 6.

[0031] Example 6 30.00 g of ethanol was added to 6.00 g of the azilsartan bulk powder obtained in Preparation Example 1 and having an average particle size of 2.3 μm, and the mixture was stirred at 60°C for 48 hours. The crystals were collected by filtration, 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 Figure 7.

[0032] (Comparative Example 1) 25.00 g of azilsartan bulk substance 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 Figure 8.

[0033] (Test Example 1) Storage stability test The azilsartan obtained in Production Example 1, Examples 1 to 6, and Comparative Example 1 was placed in a brown bottle, sealed, and then left in a constant temperature bath 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.

[0034] JPEG0007807101000005.jpg183156 [Industrial Applicability]

[0035] According to the present invention, it is possible to provide stable fine crystals of azilsartan which have a desired particle size distribution and can be used as they are without pulverization during formulation.

Claims

1. The average particle size measured by a laser diffraction particle size distribution analyzer is in the range of 3 to 18 μm.

1. A method for producing azilsartan particles having a desired particle size distribution, comprising: Without including the recrystallization process, azilsartan powder and azilsartan powder at 1 to 40 times the concentration and a volume of a solvent to obtain azilsartan particles, The solvent is methanol, ethanol, 1-propanol, 2-propanol, 1-butanol ethanol, tert-butanol, ethyl acetate, acetone, tetrahydrofuran and water. a solvent selected from the group consisting of methyl methyl ketone, ... The stirring time is adjusted in the range of 5 minutes to 100 hours, and the stirring temperature is adjusted in the range of 0°C to the solvent reflux temperature. to obtain azilsartan particles having a desired particle size distribution.

2. The stirring time is set to 5 minutes to 48 hours, and the stirring temperature is set to 0°C to the solvent reflux temperature. The method according to claim 1, wherein azilsartan particles having a particle size distribution of 3 μm to 4 μm are obtained. 。

3. By setting the stirring time to 5 minutes to 48 hours and the stirring temperature to 50 to 60°C, the particle size distribution The method according to claim 1, wherein the particle size of azilsartan particles obtained is 4 μm or more and 5 μm or less.

4. By setting the stirring time to 5 minutes to 48 hours and the stirring temperature to 50 to 60°C, the particle size distribution The method according to claim 1, wherein the particle size of azilsartan particles obtained is 7 μm or more and 8 μm or less.

5. By setting the stirring time to 5 minutes to 48 hours and the stirring temperature to 50 to 60°C, the particle size distribution The method according to claim 1, wherein the particle size of azilsartan particles obtained is 9 μm or more and 11 μm or less.

6. By setting the stirring time to 5 minutes to 48 hours and the stirring temperature to 50 to 60°C, the particle size distribution The method according to claim 1, wherein the particle size of azilsartan particles obtained is 13 μm or more and 14 μm or less.

7. By setting the stirring time to 5 minutes to 48 hours and the stirring temperature to 50 to 60°C, the particle size distribution The method according to claim 1, wherein the particle size of azilsartan particles obtained is 17 μm or more and 18 μm or less.

Images