CN111004191A - Preparation method of large-particle-size febuxostat A crystal - Google Patents
Preparation method of large-particle-size febuxostat A crystal Download PDFInfo
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- CN111004191A CN111004191A CN201911018420.1A CN201911018420A CN111004191A CN 111004191 A CN111004191 A CN 111004191A CN 201911018420 A CN201911018420 A CN 201911018420A CN 111004191 A CN111004191 A CN 111004191A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a preparation method of large-particle-size febuxostat A crystal, which comprises the following steps: adding febuxostat into absolute ethyl alcohol, heating to 75-85 ℃ after uniformly stirring, refluxing for dissolution, filtering while the solution is hot, keeping the temperature of the filtrate at 75-85 ℃, adding water, heating the system to 75-85 ℃ after adding, keeping the temperature of the system at 75-85 ℃ after the system is dissolved, refluxing for 0.5-1.0 h, cooling to 60-63 ℃, adding febuxostat A crystal as seed crystal for induced crystallization under the condition of stirring speed of 150 plus materials at 170r/min, separating out solid from the system, keeping the temperature of the system at 60-63 ℃ for stirring crystallization for a plurality of hours, cooling the program to 35 ℃, keeping the temperature of the system at 31-35 ℃ and stirring for a certain time; the preparation method of the large-particle-size febuxostat A crystal can prepare the large-particle-size febuxostat A crystal, and the febuxostat A crystal with various particle sizes is obtained by crushing and sieving so as to be used in a preparation prescription process, so that the febuxostat tablet meeting the requirements of an original researched dissolution curve is prepared.
Description
Technical Field
The invention belongs to the field of febuxostat preparation, and particularly relates to a preparation method of large-particle-size febuxostat A crystal.
Background
The febuxostat mainly comprises febuxostat, and the chemical name of the febuxostat is 2- [ (3-cyano-4-isobutoxy) phenyl ] -4-methyl-5-thiazolecarboxylic acid. Is a Xanthine Oxidase (XO) inhibitor, is suitable for long-term treatment of hyperuricemia with gout symptoms, but the prior preparation method of febuxostat A crystal comprises the following steps: the invention discloses a novel febuxostat crystal form A and a preparation method (103588723B) thereof, which can only obtain febuxostat A crystals with smaller particle size (D50 ═ 16-25 mu m), but can not obtain febuxostat A crystals with various particle sizes through crushing and sieving, and have lower adaptability.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of large-particle-size febuxostat A crystal, and the preparation method of the large-particle-size febuxostat A crystal can be used for preparing the large-particle-size febuxostat A crystal.
In order to achieve the purpose, the invention is realized by the following technical scheme: a preparation method of large-particle-size febuxostat A crystal comprises the following steps: adding febuxostat into absolute ethyl alcohol, uniformly stirring, heating to 75-85 ℃, refluxing for dissolution, filtering while the solution is hot, keeping the temperature of the filtrate at 75-85 ℃, adding water, heating the system to 75-85 ℃ after the addition is finished, keeping the temperature of the system at 75-85 ℃, refluxing for 0.5-1.0 h, cooling to 60-63 ℃, adding febuxostat A crystals (the particle size is 20-30 microns) as seed crystals to induce crystallization under the condition of stirring speed of 150 and 170r/min, separating out solids from the system, keeping the temperature of the system at 60-63 ℃ for stirring for several hours, cooling to 35 ℃ after the program, keeping the temperature of the system at 31-35 ℃, stirring for a certain time, filtering, leaching and drying to obtain the febuxostat A crystals with large particle size (D (0.9) ═ 70 +/-10 mu m).
As a preferable mode of the invention, when the granularity of the A crystal seed is 20-30 microns (self-made), crystal transformation is not easy to occur when the temperature is kept at 60-63 ℃ for 3h and at 30-33 ℃ for 1h, and the target crystal form A can be obtained, and when the granularity of the A crystal seed is 45-56 microns, the C crystal is obtained, and the target crystal form A cannot be obtained.
As a preferred mode of the invention, the A crystal obtained by crushing can not be used as a seed crystal, otherwise, a C crystal product is obtained.
As a preferred mode of the invention, the crystal size is reduced by increasing the heat preservation temperature, the crystal size is reduced when the heat preservation time at 60-63 ℃ is too long or too short, and the crystal size is reduced, so the high-temperature heat preservation temperature is preferably 60-63 ℃ and the high-temperature heat preservation time is preferably 3 +/-0.25 h.
As a preferable mode of the invention, when the low-temperature heat preservation temperature is 15-30 ℃, the C crystal is obtained, and when the low-temperature heat preservation temperature is 30-36 ℃, the target crystal form A crystal is obtained, so the low-temperature heat preservation temperature can be 30-36 ℃, preferably 31-35 ℃, and the low-temperature heat preservation time can be 1 +/-0.25 hours.
As a preferred mode of the present invention, when the high temperature holding parameter is 60-63 ℃/3 + -0.25 hour, the low temperature holding parameter is 31-35 ℃/1 + -0.25 hour, and the temperature reduction program is selected as "0.5 hour for reducing the temperature of 62 ℃ to 56 ℃, 0.5 hour for preserving the temperature of 56 ℃, 0.5 hour for reducing the temperature of 56 ℃ to 50 ℃, 0.5 hour for preserving the temperature of 50 ℃ and 1 hour for reducing the temperature of 50 ℃ to 35", the grain size of the A crystal obtained is the largest, so the temperature reduction program is preferred.
The invention has the beneficial effects that:
1. the preparation method of the large-particle-size febuxostat A crystal can prepare the febuxostat A crystal with large particle size (D (0.9) ═ 70 +/-10 mu m) due to specific system and temperature conditions, and the febuxostat A crystal with various particle sizes is obtained by crushing and sieving so as to be used in a preparation prescription process, so that the febuxostat tablet meeting the requirements of an original grinding dissolution curve is prepared.
2. The preparation method of the large-particle-size febuxostat A crystal can be used for preparing the febuxostat A crystal with wider adaptability and is suitable for popularization.
Drawings
FIG. 1 is a flow chart of a preparation method of large-particle-size febuxostat A crystal;
FIG. 2 is a particle size distribution diagram of febuxostat A crystals in a preparation method of large-particle-size febuxostat A crystals;
FIG. 3 is an X-ray diffraction diagram of a preparation method of large-particle-size febuxostat A crystal;
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Referring to fig. 1-3, the present invention provides a technical solution: a preparation method of febuxostat A crystal with large particle size;
example 1:
adding 2.00kg of absolute ethyl alcohol into a dry and clean 5L reaction bottle at room temperature, stirring, then adding 0.50kg of febuxostat, uniformly stirring to obtain a white slurry system (the volume of the system is required to be 1/2-2/3 of the total volume of the reaction kettle), heating the system to 75-85 ℃, refluxing and dissolving, filtering while hot, keeping the temperature of the filtrate at 75-85 ℃, transferring the filtrate into a dry and clean 5L reaction bottle, stirring, adding 0.62kg of water into the filtrate, completing the addition within 0.5-1.0 hour, heating the system to 75-85 ℃ after the addition is completed, keeping the temperature of the system at 75-85 ℃, refluxing for 0.5-1.0 hour, cooling to 60-63 ℃, adding 1.5g of febuxostat A crystal (the granularity is 20-30 microns) as a crystal seed to induce crystallization under the condition that the stirring speed is 150-170r/min, separating out solid from the system, stirring and crystallizing for 3 +/-0.25 hours at the temperature of 60-63 ℃, continuously stirring and naturally cooling to 56 ℃ (the cooling rate is about 2 ℃/10min, and the temperature is reduced from 62 ℃ to 56 ℃ within about 0.5 hour), keeping the temperature and stirring for 0.5 hour, then naturally cooling to 50 ℃ (the cooling rate is about 2 ℃/10min, and the temperature is reduced from 56 ℃ to 50 ℃ within about 0.5 hour), keeping the temperature and stirring for 0.5 hour, then naturally cooling to 35 ℃ (the cooling rate is about 2.5 ℃/10min, and the temperature is reduced from 50 ℃ to 35 ℃ within about 1 hour), keeping the temperature of the system at 31-35 ℃ and stirring for 1.0 +/-0.25 hour, filtering, leaching the obtained filter cake for 1 time by using a mixed solvent of absolute ethyl alcohol and water (a mixed solvent of 180g of absolute ethyl alcohol and 20g of water), obtaining a wet product, placing the wet product into a forced air drying oven, controlling the temperature to be 55-65 ℃, and starting sampling after drying, detecting the moisture, sampling every 2 hours, inspecting, stopping drying when the detected moisture is less than or equal to 0.30%, and discharging when the temperature is reduced to less than or equal to 30 ℃. Febuxostat a crystals having a large particle size (D (0.9) ═ 73 μm) were obtained: 416g, mass yield: 83.2 percent.
Example 2:
adding 210g of absolute ethyl alcohol into a dry and clean 500mL reaction bottle at room temperature, stirring, then adding 50g of febuxostat, uniformly stirring to obtain a white slurry system (the volume of the system is required to be 1/2-2/3 of the total volume of the reaction kettle), heating the system to 80 ℃, refluxing and dissolving, filtering while hot, keeping the temperature of the filtrate at 75-85 ℃, transferring the filtrate into the dry and clean 500mL reaction bottle, stirring, adding 60g of water into the filtrate, adding after 0.5-1.0 hour, heating the system to 75-85 ℃ after the addition is finished, keeping the temperature of the system at 75-85 ℃, refluxing for 0.5-1.0 hour, cooling to 62 ℃, adding 0.15g of febuxostat A crystal (the particle size is 20-30 microns) as a seed crystal to induce crystallization under the condition that the stirring speed is controlled at 150r/min, and separating out a solid, keeping the temperature of the system at 60-63 ℃, stirring for crystallization for 3 hours, continuously stirring and naturally cooling to 50 ℃ (the cooling rate is about 2 ℃/10min, the cooling rate is about 62 ℃ to 50 ℃ within about 1 hour), keeping the temperature and stirring for 0.5 hour, then naturally cooling to 45 ℃ (the cooling rate is about 2 ℃/10min, the cooling rate is about 0.5 hour is reduced from 50 ℃ to 45 ℃), keeping the temperature and stirring for 0.5 hour, then naturally cooling to 35 ℃ (the cooling rate is about 3.3 ℃/10min, the cooling rate is about 0.5 hour is reduced from 45 ℃ to 35 ℃), keeping the temperature of the system at 31-35 ℃ and stirring for 1.0 hour, filtering, leaching the obtained filter cake with a mixed solvent of absolute ethyl alcohol and water (a mixed solvent of 90g of absolute ethyl alcohol and 2g of water) for 1 time to obtain a wet product, putting the wet product into a drying air box, controlling the temperature at 55-65 ℃, starting sampling after drying the material for 10 hours, detecting the water, sampling and sending the, when the water content is detected to be less than or equal to 0.30 percent, stopping drying when the water content is qualified, cooling to be less than or equal to 30 ℃, discharging to obtain febuxostat A crystals with large grain diameter (D (0.9) ═ 72 mu m): 40.6g, mass yield: 81.2 percent.
Example 3:
adding 2.10kg of absolute ethyl alcohol into a dry and clean 5L reaction bottle at room temperature, stirring, then adding 0.50kg of febuxostat, uniformly stirring to obtain a white slurry system (the volume of the system is required to be 1/2-2/3 of the total volume of the reaction kettle), heating the system to 75-85 ℃, refluxing and dissolving, filtering while hot, keeping the temperature of the filtrate at 75-85 ℃, transferring the filtrate into a dry and clean 5L reaction bottle, stirring, adding 0.52kg of water into the filtrate, finishing adding after 0.5-1.0 hour, heating the system to 75-85 ℃ after finishing adding, keeping the temperature of the system at 75-85 ℃, refluxing for 0.5-1.0 hour, cooling to 62 ℃, adding 1.5g of febuxostat A crystal (the particle size is 20-30 micrometers) as seed crystal for inducing crystallization under the condition that the stirring speed is controlled at 160r/min, separating out solid from the system, keeping the temperature of the system at 60-63 ℃, stirring and crystallizing for 3 hours, continuously stirring and naturally cooling to 50 ℃ (the cooling rate is about 2 ℃/10min, and the cooling rate is about 1 hour from 62 ℃ to 50 ℃), stirring for 0.5 hr under heat preservation, naturally cooling to 35 deg.C (cooling rate of about 1.7 deg.C/10 min, cooling from 50 deg.C to 35 deg.C for about 1.5 hr), maintaining the system temperature at 31-35 deg.C, stirring for 1 hr, filtering, leaching the obtained filter cake with mixed solvent of anhydrous ethanol and water (mixed solvent of 180g anhydrous ethanol and 20g water) for 1 time to obtain wet product, placing the wet product into a forced air drying oven, controlling the temperature at 55-65 ℃, starting sampling after drying the material for 14h, detecting the moisture, then sampling and inspecting every 2 h, when the detected moisture is less than or equal to 0.30%, stopping drying when the product is qualified, cooling to less than or equal to 30 ℃, discharging to obtain febuxostat A crystal with large particle size (D (0.9) ═ 69 mu m): 414g, mass yield: 82.8 percent.
Example 4:
adding 200g of absolute ethyl alcohol into a dry and clean 500mL reaction bottle at room temperature, stirring, then adding 50g of febuxostat, uniformly stirring to obtain a white slurry system (the volume of the system is required to be 1/2-2/3 of the total volume of the reaction kettle), heating the system to 80 ℃, refluxing and dissolving, filtering while hot, keeping the temperature of the filtrate at 75-85 ℃, transferring the filtrate into the dry and clean 500mL reaction bottle, stirring, adding 70g of water into the filtrate, adding after 0.5-1.0 hour, heating the system to 75-85 ℃ after the addition is finished, keeping the temperature of the system at 75-85 ℃, refluxing for 0.5-1.0 hour, cooling to 62 ℃, adding 0.15g of febuxostat A crystal (the particle size is 20-30 microns) as a seed crystal to induce crystallization under the condition that the stirring speed is 170r/min, and separating out a solid from the system, keeping the temperature of the system at 60-63 ℃ for stirring and crystallizing for 3 hours, continuously stirring and naturally cooling to 35 ℃ (the cooling rate is about 1.5 ℃/10min, and the temperature is reduced from 62 ℃ to 35 ℃ for about 3 hours), then keeping the temperature of the system at 31-35 ℃ for stirring for 1.0 hour, filtering, leaching the obtained filter cake for 1 time by using a mixed solvent of absolute ethyl alcohol and water (a mixed solvent of 90g of absolute ethyl alcohol and 2g of water) to obtain a wet product, putting the wet product into a blast drying oven, controlling the temperature at 55-65 ℃, starting sampling after drying for 10 hours, detecting the moisture, sampling and inspecting every 2 hours, stopping drying when the detected moisture is less than or equal to 0.30%, cooling to less than or equal to 30 ℃, discharging to obtain the febuxostat A crystal with a large particle size (D (0.9) ═ 63.5 mu m): 42.2g, mass yield: 84.3 percent.
1 ] seed crystal investigation:
【1】 Influence of seed crystal size on crystal form:
【2】 Influence of the particle size of the A seed crystals obtained by crushing on the crystal form:
2, investigation of high-temperature heat preservation temperature and high-temperature heat preservation time:
3, investigation of low-temperature heat preservation temperature and low-temperature heat preservation time:
4' examination of the influence of the cooling procedure on the crystal particle size:
while there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (6)
1. A preparation method of febuxostat A crystal with large particle size is characterized by comprising the following steps: adding febuxostat into absolute ethyl alcohol, uniformly stirring, heating to 75-85 ℃, refluxing for dissolution, filtering while the solution is hot, keeping the temperature of the filtrate at 75-85 ℃, adding water, heating the system to 75-85 ℃ after the addition is finished, keeping the temperature of the system at 75-85 ℃, refluxing for 0.5-1.0 h, cooling to 60-63 ℃, adding febuxostat A crystals (the particle size is 20-30 microns) as seed crystals to induce crystallization under the condition of stirring speed of 150 and 170r/min, separating out solids from the system, keeping the temperature of the system at 60-63 ℃ for stirring for several hours, cooling to 35 ℃ after the program, keeping the temperature of the system at 31-35 ℃, stirring for a certain time, filtering, leaching and drying to obtain the febuxostat A crystals with large particle size (D (0.9) ═ 70 +/-10 mu m).
2. The method for preparing febuxostat A crystal with large particle size according to claim 1, which is characterized in that: when the granularity of the A crystal seeds is 20-30 microns (self-made), crystal transformation is not easy to occur when the temperature is kept for 3 hours at 60-63 ℃ and is kept for 1 hour at 30-33 ℃, and the target crystal form A can be obtained, and when the granularity of the A crystal seeds is 45-56 microns, the C crystal is obtained, and the target crystal form A cannot be obtained.
3. The method for preparing febuxostat A crystal with large particle size according to claim 1, which is characterized in that: the A crystal obtained by crushing can not be used as a seed crystal, otherwise, a C crystal product is obtained.
4. The method for preparing febuxostat A crystal with large particle size according to claim 1, which is characterized in that: the granularity of the crystal obtained by increasing the heat preservation temperature is reduced, the heat preservation time at 60-63 ℃ is too long or too short, and the granularity of the obtained crystal is reduced, so the high-temperature heat preservation temperature is preferably 60-63 ℃, and the high-temperature heat preservation time is preferably 3 +/-0.25 h.
5. The method for preparing febuxostat A crystal with large particle size according to claim 1, which is characterized in that: when the low-temperature heat preservation temperature is 15-30 ℃, the C crystal is obtained, and when the low-temperature heat preservation temperature is 30-36 ℃, the target crystal form A crystal is obtained, so that the low-temperature heat preservation temperature can be 30-36 ℃, preferably 31-35 ℃, and the low-temperature heat preservation time can be 1 +/-0.25 hours.
6. The method for preparing febuxostat A crystal with large particle size according to claim 1, which is characterized in that: when the high-temperature heat preservation parameter is 60-63 ℃/3 +/-0.25 hours, the low-temperature heat preservation parameter is 31-35 ℃/1 +/-0.25 hours, and the temperature reduction program selects '0.5 hour when the temperature is reduced to 56 ℃, 0.5 hour when the temperature is reduced to 50 ℃, 0.5 hour when the temperature is maintained to 50 ℃ and 1 hour when the temperature is reduced to 35'), the grain size of the obtained A is the largest, so the temperature reduction program is preferably selected.
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| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| JP2011020950A (en) * | 2009-07-15 | 2011-02-03 | Mitsutaka Kitamura | Method for producing crystal polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid |
| WO2011141933A2 (en) * | 2010-05-12 | 2011-11-17 | Msn Laboratories Limited | Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts |
| CN103588724A (en) * | 2013-09-10 | 2014-02-19 | 杭州华东医药集团生物工程研究所有限公司 | Febuxostat crystal form A and preparation method thereof |
| CN106565627A (en) * | 2016-10-10 | 2017-04-19 | 扬子江药业集团有限公司 | Preparation method for pharmaceutical crystal form of febuxostat |
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2019
- 2019-10-24 CN CN201911018420.1A patent/CN111004191A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| JP2011020950A (en) * | 2009-07-15 | 2011-02-03 | Mitsutaka Kitamura | Method for producing crystal polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid |
| WO2011141933A2 (en) * | 2010-05-12 | 2011-11-17 | Msn Laboratories Limited | Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts |
| CN103588724A (en) * | 2013-09-10 | 2014-02-19 | 杭州华东医药集团生物工程研究所有限公司 | Febuxostat crystal form A and preparation method thereof |
| CN106565627A (en) * | 2016-10-10 | 2017-04-19 | 扬子江药业集团有限公司 | Preparation method for pharmaceutical crystal form of febuxostat |
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Application publication date: 20200414 |