阅读说明：本技术 一种米拉贝隆的结晶方法 (Crystallization method of mirabegron ) 是由 刘俊 杜小春 于 2019-10-31 设计创作，主要内容包括：本发明提供了一种米拉贝隆的结晶方法。通过晶体析出后的升温、保温操作,得到一种结晶的米拉贝隆原料药。使用该结晶的米拉贝隆制备得到的缓释片,F2值有了明显的提高,与原研制剂的一致性更高,更有利于保证产品的安全性和有效性。(The invention provides a crystallization method of mirabegron. The crystallized mirabegron bulk drug is obtained through the operations of temperature rise and heat preservation after crystal precipitation. The F2 value of the sustained-release tablet prepared by the crystallized mirabegron is obviously improved, the sustained-release tablet has higher consistency with the original preparation, and the safety and the effectiveness of the product are better ensured.)

1. A crystallization method of mirabegron is characterized by comprising a temperature rise step after crystal precipitation.

2. The crystallization method according to claim 1, further comprising a heat-retention step after the temperature is raised.

3. The crystallization method according to claim 2, characterized in that the incubation time is at least 0.1 hour, preferably at least 0.5 hour, preferably at least 1 hour, preferably at least 3 hours, more preferably in the range of 1-6 hours.

4. The crystallization method according to claim 2, further comprising a step of cooling crystallization after the heat-holding.

5. The crystallization method according to claim 1 or 2, further comprising a step of warming for dissolution.

6. The crystallization method according to claim 1 or 2, further comprising a step of cooling crystallization after the temperature-raising dissolution.

7. The crystallization method according to claim 1, characterized by comprising the steps of:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1) to separate out crystals;

(3) after the crystal is separated out, heating, keeping the temperature after the temperature is raised to the target temperature, and keeping the temperature for at least 0.1 hour;

(4) and cooling and crystallizing to obtain the mirabegron crystal.

8. The crystallization method according to any one of claims 1 to 7, wherein the solvent is a mixed solvent of a polar solvent and water, wherein the polar solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, isopropanol, n-butanol, and propylene glycol, preferably from one or more of methanol, ethanol, isopropanol, n-butanol, and propylene glycol, and more preferably from one or two of methanol and ethanol.

9. The crystallization method according to claim 8, wherein the ratio of the polar solvent to water in the mixed solvent is in the range of 1:9 to 9:1(v/v), preferably in the range of 1:4 to 4:1(v/v), preferably in the range of 1:2 to 2:1(v/v), and more preferably in the range of 1:1 (v/v).

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a crystallization method of mirabegron.

Background

Mirabegron is chemically known as (R) -2- (2-amino-1, 3-thiazol-4-yl) -4' - [2- (2-hydroxy-2-phenylethyl) amino ] ethyl ] phenylacetamide with CAS number 223673-61-8, developed by Antalax corporation and first marketed in Japan in 2011. And subsequently marketed in the united states, the european union.

Mirabegron is a beta-adrenergic receptor agonist and is indicated for the treatment of overactive bladder with symptoms of urge incontinence, urgency and frequency. Overactive bladder is a syndrome characterized by symptoms of urgency which can be manifested hydrodynamically as detrusor overactivity, as well as other forms of urethro-bladder dysfunction. Patients with overactive bladder often have great mental stress and great treatment difficulty. The successful marketing of mirabegron, the first orally effective beta 3 adrenoceptor agonist drug for the treatment of overactive bladder, fills the gap in the treatment of overactive bladder with beta adrenoceptor agonists. The mirabegron has the following structural formula:

at present, only one mirabegron preparation sold in the domestic market is a sustained-release tablet produced by Anstela of the original research manufacturer, so that the mirabegron imitation drug with the quality and the curative effect consistent with those of the original preparation is researched, more choices are provided for patients, the drug cost of the patients is reduced, the accessibility of the drug is improved, the medical service level is improved, and other important economic and social benefits are achieved.

When the applicant uses the mirabegron bulk drug sold in the market, the mirabegron sustained release tablet prepared by the existing bulk drug is compared with the original reference preparation, the similarity factor (F2 value) does not exceed 70, and the ideal fitting degree is not reached. As is well known to those skilled in the art, the lower the fitting degree of the imitation drug and the original drug, the more negative the safety and effectiveness of the drug will be, and the technical requirements for the consistency evaluation of the quality and the curative effect of the drug under the current situation will not be met. Therefore, the applicant further screened the prescription and tried to increase the amount of polyethylene glycol, but the F2 value only slightly increased to 71. The applicant further adjusts the types and the proportions of the auxiliary materials in the prescription, and the F2 value is not obviously improved. After a large amount of screening is carried out on the composition proportion of the prescription, the applicant unexpectedly finds that the F2 value of the mirabegron bulk drug is obviously improved after the mirabegron bulk drug is crystallized by using the method of the invention and then is further prepared into the sustained release tablet.

Therefore, the invention provides a novel crystallization method of the mirabegron bulk drug. The mirabegron sustained-release tablet prepared from the mirabegron raw material medicine obtained by the crystallization method of the invention has obviously improved in-vitro dissolution fitting degree with the original product, and can better ensure that the preparation product meets the requirement of the consistency evaluation of the quality and the curative effect of the medicine.

Disclosure of Invention

In order to solve the problem of low in vitro dissolution fitting degree of mirabegron sustained release tablets prepared from raw material medicines obtained in the prior art and an original preparation, the invention provides the following technical scheme:

the invention provides a crystallization method of mirabegron, which comprises a temperature rise operation after crystal precipitation. The means for controlling the temperature rise in the present invention is to limit the temperature rise to a level where no significant amount of crystals are dissolved in the system, and with this as a goal, the skilled person will understand and make the temperature selection according to routine procedures, for example: the temperature rise is in the range of 30 to 90 deg.C, preferably 30 to 80 deg.C, preferably 35 to 75 deg.C, preferably 40 to 70 deg.C, preferably 40 to 68 deg.C, preferably 45 to 65 deg.C, preferably 40 to 60 deg.C, preferably 50 to 60 deg.C, more preferably 60 deg.C.

The invention further provides a crystallization method of mirabegron, which also comprises a heat preservation operation after the temperature is raised to reach the target temperature. In the heat preservation operation provided by the invention, the heat preservation time is at least 0.1 hour, or at least 0.5 hour, or at least 1 hour, or at least 3 hours, or the heat preservation time range is 1-6 hours, or the heat preservation time range is 1-3 hours.

The invention further provides a crystallization method of the mirabegron, which comprises cooling crystallization after heat preservation. The temperature reduction rate provided by the invention is in the range of 0.5-50 ℃/hour, or 0.5-40 ℃/hour, or 5-35 ℃/hour, or 5-25 ℃/hour, or 5-15 ℃/hour, or 5-10 ℃/hour, or natural temperature reduction.

The invention further provides a crystallization method of mirabegron, which comprises the steps of heating and dissolving the mirabegron, and cooling and crystallizing. The heating dissolution is to dissolve mirabegron to form a clear solution. The selection of the temperature will be understood by those skilled in the art and will be carried out in accordance with routine practice, for example at a temperature of from 60 to 100 deg.C, or from 70 to 90 deg.C, or from 60 to 90 deg.C, or from 70 to 80 deg.C.

In the cooling crystallization operation provided by the invention, the temperature is reduced to precipitate mirabegron crystals, and the temperature can be selected by a person skilled in the art according to the conventional operation, for example, the cooling temperature is in the range of 0-50 ℃, or 10-50 ℃, or 20-50 ℃, or 30-50 ℃, or 10-45 ℃, or 20-45 ℃, or 10-43 ℃, or 10-40 ℃, or 20-40 ℃.

In the crystallization method of mirabegron provided by the invention, a solvent system is a conventional solvent in the field, and a person skilled in the art can select the solvent according to conventional operations, for example, a mixed solvent composed of a polar solvent and water, wherein the polar solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, isopropanol, n-butanol, propylene glycol, dimethylformamide, dimethyl sulfoxide, acetic acid, formic acid, tetrahydrofuran and pyridine; preferably one or more of methanol, ethanol, acetone, acetonitrile, isopropanol, n-butanol, propylene glycol, dimethylformamide, dimethyl sulfoxide, acetic acid and formic acid; preferably one or more of methanol, ethanol, acetone, acetonitrile, isopropanol, n-butanol and propylene glycol; preferably one or more of methanol, ethanol, isopropanol, n-butanol and propylene glycol; more preferably one or both of methanol and ethanol. In certain embodiments, the ratio of polar solvent to water in the mixed solvent is in the range of 1:9 to 9:1(v/v), preferably in the range of 1:8 to 8:1(v/v), preferably in the range of 1:6 to 6:1(v/v), preferably in the range of 1:4 to 4:1(v/v), preferably in the range of 1:2 to 2:1(v/v), more preferably in the range of 1:1 (v/v).

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1) to separate out crystals;

(3) after the crystal is separated out, heating, keeping the temperature after the temperature is raised to the target temperature, and keeping the temperature for at least 0.1 hour;

(4) and cooling and crystallizing to obtain the mirabegron crystal.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1) to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for at least 0.1 hour after the temperature is raised to the target temperature;

(4) and cooling and crystallizing to obtain the mirabegron crystal.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1) to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature after the temperature is raised to the target temperature for 1-6 hours;

(4) and cooling and crystallizing to obtain the mirabegron crystal.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1) to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for at least 0.1 hour after the temperature is raised to the target temperature;

(4) cooling and crystallizing, wherein the cooling rate is 0.5-40 ℃/hour, and the mirabegron crystal is obtained.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1) to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for 1-6 hours after the temperature is raised to the target temperature;

(4) cooling and crystallizing, wherein the cooling rate is 0.5-40 ℃/hour, and the mirabegron crystal is obtained.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1), wherein the cooling temperature range is 10-50 ℃ to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for at least 0.1 hour after the temperature is raised to the target temperature;

(4) and cooling and crystallizing to obtain the mirabegron crystal.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1), wherein the cooling temperature range is 10-50 ℃ to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for at least 0.1 hour after the temperature is raised to the target temperature;

(4) cooling and crystallizing, wherein the cooling rate is 0.5-40 ℃/hour, and the mirabegron crystal is obtained.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1), wherein the cooling temperature range is 10-50 ℃ to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for 1-6 hours after the temperature is raised to the target temperature;

(4) cooling and crystallizing, wherein the cooling rate is 0.5-40 ℃/hour, and the mirabegron crystal is obtained.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1), wherein the cooling temperature range is 10-50 ℃ to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for at least 0.1 hour after the temperature is raised to the target temperature;

(4) cooling and crystallizing, wherein the cooling rate is 5-35 ℃/hour, and the mirabegron crystal is obtained.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1), wherein the cooling temperature range is 10-43 ℃ to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for 1-6 hours after the temperature is raised to the target temperature;

(4) cooling and crystallizing, wherein the cooling rate is 5-35 ℃/hour, and the mirabegron crystal is obtained.

In another aspect, the present invention provides a crystallization method of mirabegron, comprising the following steps:

(1) adding mirabegron into a solvent, and heating to dissolve the mirabegron to form a solution;

(2) cooling and crystallizing the solution obtained in the step (1), wherein the cooling temperature range is 20-40 ℃ to separate out crystals;

(3) heating up after the crystal is separated out, wherein the temperature range of the heating up is 40-70 ℃, and keeping the temperature for 1-6 hours after the temperature is raised to the target temperature;

(4) cooling and crystallizing, and naturally cooling to obtain the mirabegron crystal.

The mirabegron crystallization method further comprises the step of repeating the operations of heating, heat preservation and cooling crystallization after the mirabegron crystal obtained by the method is obtained, wherein the repetition times are 1-20 times, preferably 5-15 times, and more preferably 9 times.

Detailed Description

In order to further illustrate the present invention and to facilitate an understanding thereof, only some examples are provided and will be described in detail. It will be understood by those skilled in the art that the following examples are not intended to limit the scope of the present invention.

The mirabegron bulk drug used in the invention can be prepared by the technicians in the field according to the prior art.

Comparative example 1

Adding 100g of mirabegron, 300mL of absolute ethyl alcohol and 600mL of purified water into a 2L three-necked bottle, replacing for 3 times by argon, heating to dissolve under stirring, cooling to crystallize after dissolving and clarifying. Filtering, and vacuum drying at 50 deg.C to obtain mirabegron.

Example 1

Adding 122g of mirabegron, 488mL of absolute ethyl alcohol and 488mL of purified water into a 2L three-necked bottle, replacing for 3 times by argon, heating to dissolve under stirring, cooling to 40 ℃ for crystallization after dissolution and clarification, heating to 60 ℃ after a large amount of crystals are separated out, stirring and preserving heat for 1 hour, cooling to 40 ℃ for crystallization, repeating the heating, preserving heat and cooling crystallization processes for 9 times, filtering, and drying in vacuum at 50 ℃ to obtain 111.4g of mirabegron with the yield of 91.3%.

Example 2

Adding 100g of mirabegron, 300mL of absolute ethyl alcohol and 600mL of purified water into a 2L three-necked bottle, replacing for 3 times by argon, heating to dissolve under stirring, cooling to 40 ℃ for crystallization after dissolution and clarification, heating to 60 ℃ after a large amount of crystals are separated out, stirring and preserving heat for 3 hours, closing heating, naturally cooling to crystallize in an oil bath, filtering, and drying in vacuum at 50 ℃ to obtain 92.0g of mirabegron with the yield of 92%.

Example 3

Adding 100g of mirabegron, 300mL of absolute ethyl alcohol and 600mL of purified water into a 2L three-necked bottle, replacing for 3 times by argon, heating to dissolve under stirring, cooling to 40 ℃ for crystallization after dissolution and clarification, heating to 55 ℃ after a large amount of crystals are separated out, stirring and preserving heat for 3 hours, closing heating, naturally cooling to crystallize in an oil bath, filtering, and drying in vacuum at 50 ℃ to obtain 90.0g of mirabegron with the yield of 90%.

Example 4

Adding 100g of mirabegron, 300mL of absolute ethyl alcohol and 600mL of purified water into a 2L three-necked bottle, replacing for 3 times by argon, heating to dissolve under stirring, cooling to 20 ℃ for crystallization after dissolution and clarification, heating to 60 ℃ after a large amount of crystals are separated out, stirring and preserving heat for 3 hours, closing heating, naturally cooling to crystallize in an oil bath, filtering, and drying in vacuum at 50 ℃ to obtain 92.3g of mirabegron with the yield of 92.3%.

Example 5

Adding 150g of mirabegron, 900mL of absolute ethyl alcohol and 450mL of purified water into a 2L three-necked bottle, replacing for 5 times by argon, heating to dissolve under stirring, cooling to 40 ℃ for crystallization after dissolution and clarification, heating to 61 ℃ after a large amount of crystals are separated out, stirring and preserving heat for 3 hours, closing heating, naturally cooling to crystallize in an oil bath, filtering, and drying in vacuum at 50 ℃ to obtain 128.0g of mirabegron, wherein the yield is 85.3%.

Example 6

Adding 150g of mirabegron, 900mL of absolute ethyl alcohol and 450mL of purified water into a 2L three-necked bottle, replacing for 5 times by argon, heating to dissolve under stirring, cooling to 40 ℃ for crystallization after dissolution and clarification, heating to 60 ℃ after a large amount of crystals are separated out, stirring and preserving heat for 5 hours, closing heating, naturally cooling to crystallize in an oil bath, filtering, and drying in vacuum at 50 ℃ to obtain 126.5g of mirabegron, wherein the yield is 84.3%.

Example 7

Adding 500g of mirabegron, 2L of absolute ethyl alcohol and 2L of purified water into a 10L reaction kettle, replacing for 5 times by argon, heating to dissolve under stirring, cooling to 40 ℃ for crystallization after dissolution and clarification, heating to 61 ℃ after a large amount of crystals are separated out, stirring and preserving heat for 3 hours, slowly cooling to crystallize, cooling at the rate of 5 ℃ per hour, cooling to room temperature, centrifuging, and drying in vacuum at 50 ℃ to obtain 449.5g of mirabegron, wherein the yield is 89.9%.

Example 8

Adding 500g of mirabegron, 2L of absolute ethyl alcohol and 2L of purified water into a 10L reaction kettle, replacing 5 times with argon, heating to dissolve under stirring, cooling to 20 ℃ for crystallization after dissolution and clarification, heating to 50 ℃, stirring and preserving heat for 5 hours, then slowly cooling for crystallization, controlling the cooling rate to be 25 ℃ per hour, cooling to room temperature, centrifuging, and drying in vacuum at 50 ℃ to obtain 450.5g of mirabegron, wherein the yield is 90.1%.

Example 9

Adding 500g of mirabegron, 2L of absolute ethyl alcohol and 2L of purified water into a 10L reaction kettle, replacing 5 times with argon, heating to dissolve under stirring, cooling to 10 ℃ for crystallization after dissolution and clarification, heating to 40 ℃, stirring and preserving heat for 5 hours, then slowly cooling to crystallize, controlling the cooling rate to be 15 ℃ per hour, cooling to room temperature, centrifuging, and drying in vacuum at 50 ℃ to obtain 451.8g of mirabegron, wherein the yield is 90.4%.

Example 10

Adding 500g of mirabegron, 2L of methanol and 2L of purified water into a 10L reaction kettle, replacing for 5 times by argon, heating to dissolve under stirring, cooling to 25 ℃ for crystallization after dissolution and clarification, heating to 60 ℃, stirring and preserving heat for 3 hours, then slowly cooling for crystallization, controlling the cooling rate to be 35 ℃ per hour, cooling to room temperature, centrifuging, and drying in vacuum at 50 ℃ to obtain 457.3g of mirabegron, wherein the yield is 91.5%.

Example 11

Adding 500g of mirabegron, 1.5L of propylene glycol and 1.5L of purified water into a 10L reaction kettle, replacing 5 times with argon, heating to dissolve under stirring, cooling to 30 ℃ for crystallization after dissolution and clarification, heating to 65 ℃, stirring and preserving heat for 3 hours, then slowly cooling to crystallize, controlling the cooling rate to be 35 ℃ per hour, cooling to room temperature, centrifuging, and drying in vacuum at 50 ℃ to obtain 404.4g of mirabegron, wherein the yield is 80.9%.

Example 12 Mirabegron sustained Release tablet preparation

The mirabegron sustained release tablets are prepared in parallel according to the following preparation method, and the mirabegron prepared in the comparative example 1, the example 2 and the example 5 is selected as the raw material medicine.

The preparation method of the mirabegron sustained release tablet (1500 tablets) comprises the following steps: 75g of mirabegron, 94.5g of polyethylene oxide, 190.2g of polyethylene glycol and 11.25g of hydroxypropyl cellulose are weighed and put into a boiling granulator and granulated by pure water. The granules thus prepared were mixed with 0.6g of dibutylhydroxytoluene, and then with 3.75g of magnesium stearate to obtain intermediate granules, which were then tabletted.

Example 13 Release test

1. Test samples: mirabegron sustained release tablets (batch No. 18C21/44) originally ground and marketed; example 12 sustained Release Mirabegron tablet

2. The test method comprises the following steps: dissolving media with pH6.8 and pH1.0 are respectively prepared according to the Chinese pharmacopoeia 2015 edition, and the release rate is determined according to the second method of the method for determining the dissolution rate and the release rate of 0931 according to the fourth general rule of the Chinese pharmacopoeia 2015 edition, and the rotating speed is 100 r/min. The release of the sample was measured using high performance liquid chromatography and the cumulative release at each time point was calculated. Calculating the F2 value according to a method for calculating a similar factor (F2) in the technical guidance principle of dissolution test of common oral solid preparations. The results obtained are shown in table 1 below:

TABLE 1 comparison of F2 values with the original study

As can be seen from the dissolution results, the F2 value of the sustained-release tablet prepared from the mirabegron bulk drug obtained by the crystallization method is obviously improved compared with that of a comparative example, wherein the F2 value is improved from 53 to 89 and 81 in a dissolution medium with the pH of 6.8; in the dissolution medium at ph1.0, the F2 value increased from 60 to 93 and 87, and in both media the F2 value was greater than 80. Therefore, after the mirabegron bulk drug prepared by the crystallization method is further prepared into a sustained-release tablet, the F2 value of the preparation can be effectively improved, the equivalent degree of the obtained product and the original product is higher, the consistency of the product quality can be better ensured, and the quality requirement of the state on the imitation drugs is met.

Example 14 Mirabegron tablet intermediate content assay

1. Test materials: mirabegron intermediate particles prepared in example 12;

2. the test method comprises the following steps: detecting the content of mirabegron by using high performance liquid chromatography to intermediate particles obtained in the preparation process of the mirabegron sustained release tablet;

TABLE 2 content test results of mirabegron sustained-release tablets

From the above results, it can be seen that the use of the intermediate granules prepared in comparative example 1, below the lower limit of the content standard, leads to product failure. The unqualified content of the intermediate granules can cause the concentration of the active ingredients in the finished product preparation to be lower, and the excessive or insufficient concentration of the active ingredients in the sustained-release tablet can influence the release of the active ingredients in vivo, further influence the absorption metabolism and distribution of the medicine and finally influence the curative effect of the medicine. The preparation prepared from the bulk drugs obtained by the crystallization method can ensure that the content of intermediate particles is qualified, successfully solves the problem and provides guarantee for the product quality.