CN113278016A - Preparation method of azilsartan with small particle size - Google Patents
Preparation method of azilsartan with small particle size Download PDFInfo
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- CN113278016A CN113278016A CN202110522159.XA CN202110522159A CN113278016A CN 113278016 A CN113278016 A CN 113278016A CN 202110522159 A CN202110522159 A CN 202110522159A CN 113278016 A CN113278016 A CN 113278016A
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Abstract
The application provides a preparation method of small-particle-size azilsartan, wherein the small-particle-size azilsartan is an azilsartan crystal form A with the particle size D90 smaller than 10 mu m, and the preparation method comprises the following steps: dissolving azilsartan in dimethyl sulfoxide or tetrahydrofuran, and filtering; dropwise adding the filtrate into a mixed solution of a water-soluble organic solvent and water under stirring, and crystallizing; filtering, washing and drying to obtain the product. The azilsartan prepared by the invention does not need micropowder, can be directly used in a preparation, and avoids the problems of the increase of degradation impurities and the standard exceeding of related substances after the preparation is micronized. In addition, the method is simple and convenient to operate and high in yield, and the crystallization solvent is a mixed solution of a water-soluble organic solvent and water, so that the residual solvent is easy to remove.
Description
Technical Field
The application relates to the technical field of crystallization, in particular to a preparation method of azilsartan with small particle size.
Background
The information in this background section is disclosed only to enhance understanding of the general background of the application and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Azilsartan (English name Azilsartan, CAS number: 147403-03-0, molecular formula C25H20N4O5) Is an angiotensin II receptor Antagonist (ARB) antihypertensive drug developed by Takeda, Japan, and is used for treating hypertension.
Azilsartan has polymorphism and has solvate, wherein, Chinese patent CN1067890A heterocyclic compound, its preparation and application disclose the structure of Azilsartan and C of Azilsartan solvate25H20N4O5·1/2C4H8O2·1/5H2O preparation process which comprises dissolving methyl 2-ethoxy-1- [ (2' - (2, 5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl) bisphenyl-4-yl ] methyl ] benzimidazole-7-carboxylate in methanol, adding aqueous LiOH solution, followed by reflux heating, adjusting pH to 3 with HCl and evaporating the solvent to dryness. Distributing the residue in water and chloroform, washing the organic layer with water, drying, evaporating the solvent, recrystallizing the obtained crystal product with ethyl acetate to obtain colorless prisms, namely the solvate C of azilsartan25H20N4O5·1/2C4H8O2·1/5H2O, melting point: 156 ℃ and 157 ℃.
A plurality of crystal forms of azilsartan are reported to be known at present, wherein A, B, C, D, E, F, G, H, I, J, K11 crystal forms of azilsartan are disclosed according to Chinese patent application CN103930419A, and each crystal form needs to be prepared by different preparation methods. The crystal form of azilsartan and the preparation method thereof disclosed in the Chinese patent application CN102827153A disclose the crystal form structure of azilsartan and the preparation method thereof, comprising dissolving azilsartan in an organic solvent ethanol, and crystallizing at room temperature; the Chinese patent application CN102766139A discloses an azilsartan polymorphic form A and a preparation method thereof, wherein azilsartan is used as a raw material, and is prepared by mixing azilsartan and anhydrous methanol or anhydrous methanol/water solvent, heating to completely dissolve azilsartan, then cooling and crystallizing, filtering and recovering precipitates. And, the chinese patent application CN103930419A crystal form of azilsartan and its preparation method disclose a preparation method of crystal form a of azilsartan, comprising dissolving azilsartan in DMF to form a solution, adding acetone, heating to about 60 ℃, filtering with a filter head, dropping water at about 60 ℃ to cool to room temperature, filtering the precipitate, vacuum drying at about 50 ℃, drying the obtained sample to form crystal form a.
In the practical application process of the drug, the particle size of the drug is often required to be reduced, and the specific surface area is increased, so that the dissolution rate of the drug is increased, and the drug effect is better exerted. The most common industrial method for preparing the bulk drug with small particle size is mechanical crushing, but heat is often generated in the crushing process, so that azilsartan impurities are increased, and the requirements of the bulk drug are difficult to meet. The existing methods also comprise a method of mixing and crushing the azilsartan and the liquid nitrogen and a method of using a supercritical fluid anti-solvent, and the methods have high requirements on equipment and high operation cost and are difficult to realize industrial mass production. And, it has also been reported to adopt a method of controlling crystallization to improve the particle size, such as dissolving azilsartan in a mixed solvent of alcohol and water, distilling off a mixed solvent of 5-30% of the total weight of the mixed solvent, adding water, cooling to 0-5 ℃ for crystallization; separating solid and dry azilsartan crystals, wherein the particle size of D50 is not less than 3 mu m and not more than 20 mu m, but azilsartan is insoluble in water and slightly soluble in ethanol and methanol, and the method has large solvent consumption and large waste liquid generation amount; and the method comprises the steps of firstly dispersing the azilsartan, then heating and dissolving the dispersed azilsartan and a solvent, distilling, cooling, preserving heat for multiple times, filtering and drying; and also a method comprises the steps of dissolving the azilsartan in N, N-dimethylacetamide at the temperature of 35-40 ℃, slowly adding the azilsartan into a ketone solvent preheated to the temperature of 30-40 ℃ after the azilsartan is dissolved clearly, filtering, and keeping the temperature of the filtrate at 35-40 ℃. Stirring, transferring the filtrate into 4-8 deg.C alcohol solvent, filtering, washing, and drying. These methods are cumbersome and require repeated temperature control.
Disclosure of Invention
The application aims to provide a preparation method of azilsartan crystal form A with small particle size, which is suitable for being directly used by a preparation. The method is simple and easy to operate, and the obtained product can meet the requirement that D90 is less than 10 mu m without a micro powder process and has uniform granularity.
Specifically, the present invention provides the following technical features, and one or a combination of the following technical features constitutes the technical solution of the present invention.
The invention provides a preparation method of small-particle-size azilsartan, wherein the small-particle-size azilsartan is an azilsartan crystal form A with the particle size D90 smaller than 10 mu m, and the preparation method comprises the following steps: dissolving azilsartan in dimethyl sulfoxide or tetrahydrofuran, and filtering; dropwise adding the filtrate into a mixed solution of a water-soluble organic solvent and water under stirring, and crystallizing; filtering, washing and drying to obtain the product.
In an embodiment of the present invention, the dissolution temperature, the mixing temperature, the stirring temperature, and the crystallization temperature are room temperature. Unless otherwise specified, the present invention can be carried out at room temperature, which is defined in the "Chinese pharmacopoeia" 2020 edition for normal temperature (room temperature).
In the embodiment of the present invention, it is critical to obtain crystalline form a of azilsartan with small particle size that azilsartan is preferentially dissolved in dimethyl sulfoxide or tetrahydrofuran, then filtered, and the filtrate is added dropwise to a mixed solution of a water-soluble organic solvent and water under stirring, and the embodiment can be implemented at room temperature. In the research stage, other solvents are tried to be used, and as a result, the crystal form A cannot be obtained, or the temperature needs to be regulated and controlled in the experiment process, particularly, the operation of raising the temperature and reducing the temperature is needed, so that the operation is complicated, or the granularity of the obtained product cannot meet the requirement of directly using the product in a preparation.
In some embodiments of the invention, the water soluble organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, butanone, acetonitrile. In the embodiment of the invention, when methanol, ethanol and acetone which are commonly used are respectively used as organic solvents to be mixed with water, the effect is ideal, and the control stability of yield and granularity is high.
In some embodiments of the invention, the feed volume-to-mass ratio of dimethyl sulfoxide or tetrahydrofuran to azilsartan is 3-10: 1. in the embodiments of the present invention, the inventors found that the dosage ratio of dimethyl sulfoxide or tetrahydrofuran to azilsartan affects the dissolution degree, the particle size of the product and the yield, for example, in some embodiments, the dosage ratio is too low, such as the dosage volume mass ratio of dimethyl sulfoxide or tetrahydrofuran to azilsartan is less than 3:1, and is not easy to dissolve, and when the dosage volume mass ratio of dimethyl sulfoxide or tetrahydrofuran to azilsartan is too high, such as the dosage volume mass ratio of dimethyl sulfoxide or tetrahydrofuran to azilsartan is more than 10:1, the organic solvent is too much, the particle size is increased, and the yield is reduced. In some embodiments, the ratio is 3 to 6:1, which is superior overall.
In some embodiments of the invention, the volume ratio of water to water-soluble organic solvent is from 5 to 20: 1. in embodiments of the invention, the volume ratio of water to water-soluble organic solvent affects the particle size of the product and affects the separation of the product. For example, in some embodiments, too low a volume ratio of water to water-soluble organic solvent, e.g., less than 5:1, may increase the particle size of the product, while too high a volume ratio, e.g., more than 20:1, may present problems with difficult filtration of the product. In some embodiments, the volume ratio is 5 to 15:1, which is superior overall.
In some embodiments of the present invention, the volume ratio of the mixed solvent of the water-soluble organic solvent and water to the filtrate is 10 to 30: 1. in the embodiment of the present invention, the inventors found that when the volume ratio of the mixed solvent of the water-soluble organic solvent and water to the filtrate is too low, for example, less than 10:1, the yield is significantly reduced, and when the volume ratio is too high, for example, more than 30:1, more wastewater is generated, which is not environment-friendly, and the cost for treating wastewater is increased, which is not beneficial for the scale application of the process.
In the embodiment of the present invention, the conditions such as the stirring speed and the drying temperature at the time of dropwise addition of the filtrate should be also noted. In some embodiments of the invention, the stirring speed when the filtrate is dropwise added is 100-250 r/min; in some embodiments of the invention, the washing is a purified water beating wash; in some embodiments of the invention, the amount of purified water used is 5-10 times that mentioned for dimethyl sulfoxide or tetrahydrofuran; in some embodiments of the invention, the drying conditions are 40-50 ℃ forced air drying for 12-20 h.
Compared with the prior art, the invention has the advantages that:
the azilsartan prepared by the invention is the original ground crystal form A, the particle size D90 is less than 10 mu m, no micro powder is needed, the azilsartan can be directly used for preparation, and the problems that degradation impurities are increased after the preparation is micro powder and related substances exceed the standard are avoided; the preparation method is simple and convenient to operate, can be carried out at room temperature, avoids the problem of needing distillation or repeatedly controlling the temperature, has high yield, adopts a mixed solution of a water-soluble organic solvent and water, and is low in solvent consumption and beneficial to removing residual solvent.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application. Embodiments of the present application are described in detail below with reference to the attached drawing figures, wherein:
figure 1 XRD pattern of azilsartan prepared in example 1 of the present invention.
FIG. 2 is a scanning electron micrograph of azilsartan prepared in example 1 of the present invention.
Fig. 3 is a graph showing the results of particle size measurement of azilsartan prepared in example 2 of the present invention, wherein D10 ═ 1.43 μm, D50 ═ 2.36 μm, D90 ═ 4.82 μm, and D99 ═ 9.48 μm.
Fig. 4 is a scanning electron micrograph of azilsartan prepared in example 3 of the present invention.
Detailed Description
The present application is further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present application. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present application can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present application can be used in the conventional manner in the art or in the product specification. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
In a reaction bottle, 15g of azilsartan and 90mL of tetrahydrofuran are added, stirred and dissolved at room temperature, and filtered. The filtrate was added dropwise to 900mL of a mixed solvent of methanol and water (methanol: 100mL of water: 800mL) while maintaining room temperature, at a rotation speed of 160 rpm. After the dropwise addition, the mixture is filtered, and 500mL of water is used for pulping and washing a filter cake. And (3) drying the azilsartan by blowing at the temperature of between 40 and 50 ℃ for 12 hours to obtain 14.5g of azilsartan. Yield: 96.67 percent. The D90 particle size measurement was 8.26. mu.m. The prepared azilsartan is an azilsartan crystal form A, an XRD (X-ray diffraction) crystal pattern of the azilsartan is shown in figure 1, and a scanning electron microscope is shown in figure 2.
Example 2
In a reaction bottle, 30g of azilsartan and 100mL of dimethyl sulfoxide are added, stirred and dissolved at room temperature, and filtered. The filtrate was added dropwise to 1L of a mixed solvent of ethanol-water (ethanol: 100mL of water: 900mL) while maintaining room temperature, at a rotation speed of 200 rpm. After the dropwise addition, the mixture is filtered, and 1L of water is used for pulping and washing a filter cake. And (3) carrying out forced air drying at the temperature of 40-50 ℃ for 16h to obtain 28.5g of azilsartan. Yield: 95.0 percent. The prepared azilsartan is azilsartan crystal form A, the XRD crystal pattern of the azilsartan is basically consistent with that of example 1, the granularity determination D90 is 4.82 mu m, and the granularity determination report is shown in figure 3.
Example 3
In a reaction bottle, 30g of azilsartan and 100mL of dimethyl sulfoxide are added, stirred and dissolved at room temperature, and filtered. The filtrate was added dropwise to 1.2L of a mixed solvent of acetone-water (acetone: 100mL of water: 1100mL) while maintaining room temperature, at a rotation speed of 180 rpm. After the dropwise addition, the mixture is filtered, and 1L of water is used for pulping and washing a filter cake. And (3) carrying out forced air drying at the temperature of 40-50 ℃ for 15h to obtain 28.9g of azilsartan. Yield: 96.33 percent. The prepared azilsartan is an azilsartan crystal form A, the XRD crystal pattern of the azilsartan is basically consistent with that of example 1, the particle size D90 is 7.56 mu m, and the scanning electron microscope shows that the crystal form A is shown in figure 4.
Example 4
The amount of tetrahydrofuran or dimethyl sulfoxide is reduced compared with that of example 1 or example 2, so that the volume mass ratio of tetrahydrofuran or dimethyl sulfoxide to azilsartan conforms to 2: 1. It was found that in both cases, the onset of dissolution of azilsartan at room temperature is made difficult, and although the remaining steps can still be carried out, the implementation of this process is far from ideal.
Example 5
The difference from example 1 or example 2 is that: and increasing the dosage of the tetrahydrofuran or the dimethyl sulfoxide to ensure that the volume mass ratio of the tetrahydrofuran or the dimethyl sulfoxide to the azilsartan conforms to 12: 1. As a result, the yield is reduced to different degrees in both cases, and the yield is reduced more obviously especially in tetrahydrofuran; and the particle size of the azilsartan crystal form A obtained by the two methods is obviously increased, and particularly when tetrahydrofuran is used, D90 is more than 10 mu m.
Example 6
The differences from examples 1,2 or 3 are: the volume ratio of water to the water-soluble organic solvent was reduced, and the amount of water used was adjusted to 500 mL. As a result, the yield is obviously reduced, and the yield is about 90 percent, and particularly when the organic solvent adopts methanol, the yield can be as low as 85 percent.
Example 7
The differences from examples 1,2 or 3 are: the volume ratio of water to the water-soluble organic solvent was increased, and the amount of water used was adjusted to 2000 mL. As a result, the amount of wastewater produced increases, the cost of wastewater treatment increases greatly, and the process cost increases.
Although the present application has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described in the foregoing embodiments, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. A preparation method of small-particle size azilsartan is characterized in that the small-particle size azilsartan is azilsartan crystal form A with the particle size D90 smaller than 10 mu m, and the preparation method comprises the following steps: dissolving azilsartan in dimethyl sulfoxide or tetrahydrofuran, and filtering; dropwise adding the filtrate into a mixed solution of a water-soluble organic solvent and water under stirring, and crystallizing; filtering, washing and drying to obtain the product.
2. The method according to claim 1, wherein the water-soluble organic solvent is one or more selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, and acetonitrile.
3. The production method according to claim 1 or 2, wherein the dissolution temperature and the crystallization temperature are room temperature.
4. The preparation method according to claim 1 or 2, wherein the feeding volume mass ratio of dimethyl sulfoxide or tetrahydrofuran to azilsartan is 3-10: 1.
5. the production method according to claim 1 or 2, wherein the volume ratio of water to the water-soluble organic solvent is 5 to 20: 1.
6. the production method according to claim 1 or 2, wherein the volume ratio of the mixed solvent of the water-soluble organic solvent and water to the filtrate is 10 to 30: 1.
7. the production method according to claim 1 or 2, wherein the stirring speed at the time of dropping the filtrate is 100-250 r/min.
8. The production method according to claim 1 or 2, characterized in that the washing is purified water beating washing.
9. The method according to claim 8, wherein the purified water is used in an amount 5 to 10 times as large as that of dimethylsulfoxide or tetrahydrofuran.
10. The method according to claim 1 or 2, wherein the drying is carried out by air-blast drying at 40-50 ℃ for 12-20 hours.
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Citations (6)
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| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN103705510A (en) * | 2013-12-27 | 2014-04-09 | 华润赛科药业有限责任公司 | Method for preparing azilsartan solid composition |
| CN108774217A (en) * | 2018-09-07 | 2018-11-09 | 浙江宏元药业股份有限公司 | A kind of preparation process of Azilsartan powder material medicine |
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
| JP2019172635A (en) * | 2018-03-29 | 2019-10-10 | 金剛化学株式会社 | Manufacturing method of azilsartan fine crystal |
| CN111454255A (en) * | 2020-06-03 | 2020-07-28 | 迪嘉药业集团有限公司 | Preparation method of small-particle-size azilsartan |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN103705510A (en) * | 2013-12-27 | 2014-04-09 | 华润赛科药业有限责任公司 | Method for preparing azilsartan solid composition |
| JP2019172635A (en) * | 2018-03-29 | 2019-10-10 | 金剛化学株式会社 | Manufacturing method of azilsartan fine crystal |
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
| CN108774217A (en) * | 2018-09-07 | 2018-11-09 | 浙江宏元药业股份有限公司 | A kind of preparation process of Azilsartan powder material medicine |
| CN111454255A (en) * | 2020-06-03 | 2020-07-28 | 迪嘉药业集团有限公司 | Preparation method of small-particle-size azilsartan |
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| Title |
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| CHUN-IL PARK: "Size control of azilsartan by drowning-out crystallization with phase transformation", 《KOREAN J. CHEM. ENG.》 * |
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