阅读说明：本技术 二氢吡啶类降压药物原料药微粉化的新方法 (New method for micronizing raw material medicines of dihydropyridine antihypertensive drugs ) 是由 李孝常 李冰 李春正 陈军 季永明 季俊虬 苗青 于 2019-09-19 设计创作，主要内容包括：本申请提供一种二氢吡啶类降压药物原料药微粉化的新方法,涉及生物药物制剂技术领域。一种二氢吡啶类降压药物原料药微粉化的新方法,包括：将二氢吡啶类降压药物原料药溶解于第一溶剂,将溶解有二氢吡啶类降压药物原料药的第一溶剂加入到第二溶剂中以实现二氢吡啶类降压药物反溶剂重结晶；第一溶剂包括低级脂肪醇或脂肪族酮类化合物；第二溶剂包括水、含有电解质的水溶液或表面活性剂的水溶液。该方法能够进一步提高非洛地平和其他二氢吡啶类降压药物口服制剂的体内生物利用度。(The application provides a new micronization method of raw material medicines of dihydropyridine antihypertensive drugs, and relates to the technical field of biological pharmaceutical preparations. A new micronization method for bulk drugs of dihydropyridine antihypertensive drugs comprises the following steps: dissolving a dihydropyridine antihypertensive drug raw material drug in a first solvent, and adding the first solvent in which the dihydropyridine antihypertensive drug raw material drug is dissolved into a second solvent to realize the recrystallization of the dihydropyridine antihypertensive drug anti-solvent; the first solvent comprises lower aliphatic alcohol or aliphatic ketone compound; the second solvent includes water, an aqueous solution containing an electrolyte, or an aqueous solution of a surfactant. The method can further improve the in vivo bioavailability of the oral preparation of felodipine and other dihydropyridine antihypertensive drugs.)

1. A novel micronization method for bulk drugs of dihydropyridine antihypertensive drugs is characterized by comprising the following steps:

Dissolving a dihydropyridine antihypertensive drug raw material drug in a first solvent, and adding the first solvent in which the dihydropyridine antihypertensive drug raw material drug is dissolved into a second solvent for anti-solvent recrystallization;

The first solvent comprises a lower aliphatic alcohol or an aliphatic ketone compound; the second solvent includes water, an aqueous solution containing an electrolyte, or an aqueous solution containing a surfactant.

2. The novel micronization process for bulk pharmaceutical chemicals of dihydropyridine antihypertensive drug according to claim 1, wherein the lower aliphatic alcohol comprises at least one of ethanol, methanol and isopropanol;

Alternatively, the aliphatic ketone compound comprises acetone.

3. The novel micronization method for bulk drugs of dihydropyridine antihypertensive drugs according to claim 1, characterized in that the electrolyte is pharmaceutically acceptable inorganic salt; optionally, the electrolyte comprises at least one of sodium chloride and sodium sulfate; optionally, in the aqueous solution containing the electrolyte, the mass percentage concentration of the electrolyte is 0.1-1%; optionally, in the aqueous solution containing the electrolyte, the mass percentage concentration of the electrolyte is 0.2-0.6%;

And/or, the surfactant is a pharmaceutically acceptable anionic surfactant; optionally, the surfactant comprises sodium lauryl sulfate; optionally, in the aqueous solution containing the surfactant, the mass percentage concentration of the surfactant is 0.05-0.5%; optionally, in the aqueous solution containing the surfactant, the mass percentage concentration of the surfactant is 0.08-0.3%.

4. The novel micronization method for the bulk drugs of the dihydropyridine antihypertensive drugs according to claim 1, characterized in that the weight-to-volume ratio of the bulk drugs of the dihydropyridine antihypertensive drugs to the first solvent is 1 (1.5-5.5) g/mL; optionally, the weight-volume ratio of the dihydropyridine antihypertensive drug raw material to the first solvent is 1 (2-4) g/mL;

And/or dissolving the dihydropyridine antihypertensive drug raw material in the first solvent at a temperature of more than or equal to 25 ℃ and less than the boiling point of the first solvent.

5. The novel micronization method for bulk drugs of dihydropyridine antihypertensive drugs according to claim 1, characterized in that the temperature of the anti-solvent recrystallization is-5 to 5 ℃.

6. The novel micronization method for bulk drugs of dihydropyridine antihypertensive drugs according to any one of claims 1 to 5, wherein the volume ratio of the first solvent to the second solvent is 1 (15-55); optionally, the volume ratio of the first solvent to the second solvent is 1 (20-40).

7. The novel micronization method for bulk pharmaceutical chemicals of dihydropyridine antihypertensive drug according to claim 1, wherein the manner of adding the first solvent dissolved with the bulk pharmaceutical chemicals of dihydropyridine antihypertensive drug to the second solvent comprises adding the first solvent dissolved with the bulk pharmaceutical chemicals of dihydropyridine antihypertensive drug to the second solvent dropwise by a dropping method; or spraying the first solvent dissolved with the dihydropyridine antihypertensive drug raw material into the second solvent by adopting a spraying method.

8. The new micronization method for bulk drugs of dihydropyridine antihypertensive drugs according to claim 7, wherein the dropping speed of the dropping method is 0.5-6.0 mL/min; optionally, the dropping speed of the dropping method is 1.5-4.0 mL/min;

Or the spraying speed of the spraying method is 0.5-3.5mL/min, and the spraying pressure is 20-50 KPa; optionally, the spraying speed of the spraying method is 2.0-2.5 mL/min; optionally, the spraying pressure of the spraying method is 25-45 KPa.

9. The new micronization method for bulk drugs of dihydropyridine antihypertensive drugs according to any of claims 1 to 5 and 7 to 8, characterized in that the first solvent in which the bulk drugs of dihydropyridine antihypertensive drugs are dissolved is added to the second solvent under stirring at a rate of 500 to 1200 r/min; optionally, the stirring rate is 600-1000 r/min.

10. the novel process for micronization of a dihydropyridine hypotensive drug substance according to any one of claims 1 to 5 and 7 to 8, wherein said dihydropyridine hypotensive drug is selected from any one of felodipine, nifedipine, cilnidipine, nitrendipine, nimodipine and amlodipine besylate.

Technical Field

The application relates to the technical field of biological pharmaceutical preparations, in particular to a novel micronization method of raw material medicines of dihydropyridine antihypertensive drugs.

Background

Felodipine (felodipine) is one of the most widely used dihydropyridine antihypertensive drugs at present, and the most commonly used clinical preparations are oral sustained-release preparations and controlled-release preparations. The biopharmacology classification of felodipine is BCSII, belongs to low-solubility high-permeability medicines, improves the solubility of insoluble medicines in a preparation to ensure the medicine absorption in vivo, and is a problem which must be solved by a felodipine sustained-release preparation. Among the many poorly soluble drug solubilization solutions, drug micronization is the most common and convenient, effective means.

Disclosure of Invention

The invention aims to provide a novel micronization method of raw material medicines of dihydropyridine antihypertensive drugs, which can obtain dihydropyridine antihypertensive drug powder with finer granularity and higher yield, thereby further improving the in vivo bioavailability of sustained-release preparations of the dihydropyridine antihypertensive drugs.

in a first aspect, an embodiment of the present application provides a new method for micronizing a bulk drug of a dihydropyridine antihypertensive drug, which includes: dissolving a dihydropyridine antihypertensive drug raw material drug in a first solvent, and adding the first solvent in which the dihydropyridine antihypertensive drug raw material drug is dissolved into a second solvent for anti-solvent recrystallization; the first solvent comprises a lower aliphatic alcohol or an aliphatic ketone; the second solvent includes water, an aqueous solution containing an electrolyte, or an aqueous solution containing an anionic surfactant.

In the implementation process, the dihydropyridine antihypertensive drug is firstly dissolved in the first solvent, and then the second solvent is used as the anti-solvent, because the dihydropyridine antihypertensive drug is insoluble or almost insoluble in the second solvent, and because of the high supersaturation degree formed by the desolvation, the dihydropyridine antihypertensive drug can be separated out instantly, the particle size of the separated dihydropyridine antihypertensive drug powder is obviously reduced, and the purpose of micronization of the dihydropyridine antihypertensive drug is achieved. Experiments prove that after the dihydropyridine antihypertensive drug is micronized, the particle size of the dihydropyridine antihypertensive drug is finer, the distribution range is narrower, and the yield is obviously improved compared with that of the dihydropyridine antihypertensive drug subjected to jet milling. Wherein, the first solvent comprises lower fatty alcohol or aliphatic ketone organic solvent which can be mixed and dissolved with water, and the dihydropyridine antihypertensive drug is easy to dissolve in the polar solvent. And water, an aqueous solution containing electrolyte or an aqueous solution containing an anionic surfactant can be mutually soluble with the two solvents, so that when the first solvent in which the dihydropyridine antihypertensive drug is dissolved is mixed with the second solvent, the anti-solvent recrystallization can be realized. And only one micronization process is needed, so the product loss is less and the yield is high. In the process, a high-temperature process is not needed, and the content of the oxidizable substance in the micronized product is not increased.

In one possible embodiment, the lower aliphatic alcohol comprises at least one of ethanol, methanol, and isopropanol; alternatively, the aliphatic ketone compound comprises acetone.

In the implementation process, the dihydropyridine antihypertensive drugs are easily dissolved in ethanol, methanol, isopropanol and acetone.

In one possible embodiment, the electrolyte is a pharmaceutically acceptable inorganic salt; optionally, the electrolyte comprises at least one of sodium chloride and sodium sulfate; optionally, the mass percentage concentration of the electrolyte in the electrolyte-containing aqueous solution is 0.1-1%; optionally, the mass percentage concentration of the electrolyte in the electrolyte-containing aqueous solution is 0.2-0.6%.

In the implementation process, because the dihydropyridine antihypertensive drug is generally used for the pharmaceutical preparation, the electrolyte is selected from pharmaceutically acceptable inorganic salts, so that the micronized product of the dihydropyridine antihypertensive drug can be used for producing the pharmaceutical preparation. Wherein, sodium chloride and sodium sulfate are pharmaceutically acceptable substances, and the water solution containing the electrolyte can be mutually soluble with ethanol, methanol, isopropanol and acetone. The method not only can achieve the same micronization technical effect as a pure water solvent, but also ensures that the content of burning residues in the micronized drug raw material medicine does not exceed the standard, and the aqueous solution containing the electrolyte can improve the micronization yield.

In one possible embodiment, the surfactant is a pharmaceutically acceptable anionic surfactant, optionally sodium lauryl sulfate.

In the implementation process, because the dihydropyridine antihypertensive drug is generally used for pharmaceutical preparations, and the surfactant is selected from pharmaceutically acceptable substances, the micronized product of the dihydropyridine antihypertensive drug can be used for producing the drugs. Wherein, the sodium dodecyl sulfate is a pharmaceutically acceptable substance, and the aqueous solution containing the sodium dodecyl sulfate can be mutually soluble with ethanol, methanol, isopropanol and acetone.

In a possible embodiment, the mass percentage concentration of the surfactant in the surfactant-containing aqueous solution is 0.05-0.5%; optionally, the mass percentage concentration of the surfactant in the surfactant-containing aqueous solution is 0.08-0.3%.

In the implementation process, when the concentration of the surfactant in the solution is proper, the micronized powder can obtain the expected particle size of the micropowder, and the yield of the micronized powder can be moderately improved.

In one possible embodiment, the weight-volume ratio of the dihydropyridine antihypertensive drug raw material to the first solvent is 1 (1.5-5.5) g/mL; optionally, the weight-volume ratio of the dihydropyridine antihypertensive drug raw material to the first solvent is 1 (2-4) g/mL;

and/or dissolving the dihydropyridine antihypertensive drug raw material in the first solvent at a temperature of more than or equal to 25 ℃ and less than the boiling point temperature of the first solvent.

in the implementation process, the dihydropyridine antihypertensive drug raw material and the first solvent in the weight-to-volume ratio can ensure that the dihydropyridine antihypertensive drug raw material is fully dissolved in the first solvent, and the dosage of the second solvent is not increased more due to the excessive dosage of the first solvent. Illustratively, when the weight-volume ratio of the dihydropyridine antihypertensive drug raw material to the first solvent is more than 1:5.5g/mL, the dosage of the second solvent is inevitably increased obviously, and the production capacity is undoubtedly reduced. When the weight-volume ratio of the dihydropyridine antihypertensive drug raw material to the first solvent is less than 1:1.5g/mL, the production operation is not facilitated.

In addition, the dihydropyridine antihypertensive drug can be dissolved in the first solvent more sufficiently at a dissolution temperature of 25 ℃ or higher and less than the boiling point temperature of the first solvent.

In one possible embodiment, the temperature of the anti-solvent recrystallization is from-5 to 5 ℃.

In the anti-solvent recrystallization process, the temperature condition of-5 ℃ is set, which is beneficial to obtaining dihydropyridine antihypertensive drug micro powder with small particle size. When the temperature is higher than 5 ℃, the particle size of the dihydropyridine antihypertensive drug micro-powder with proper particle size is difficult to obtain. When the temperature is less than-5 ℃, the range of reducing the particle size of the particles is limited, and the energy consumption is additionally increased.

In one possible embodiment, the volume ratio of the first solvent to the second solvent is 1 (15-55); optionally, the volume ratio of the first solvent to the second solvent is 1 (20-40).

In the implementation process, the first solvent and the second solvent in the volume ratio can ensure that the micronized particle size meets the index requirement and does not obviously restrict the equipment capacity in future production. When the volume ratio of the first solvent to the second solvent is within the range of 1 (15-55), and the volume ratio of the first solvent to the second solvent is more than 1:40, the particle size of the micronized dihydropyridine antihypertensive drug tends to decrease within a preset particle size range; when the volume ratio of the first solvent to the second solvent is less than 1:20, the particle size of the micronized dihydropyridine antihypertensive drug tends to increase within a preset range.

In one possible embodiment, the manner of adding the first solvent in which the dihydropyridine antihypertensive drug substance is dissolved to the second solvent comprises: dripping the first solvent dissolved with the dihydropyridine antihypertensive drug raw material into the second solvent by adopting a dripping method; or spraying the first solvent dissolved with dihydropyridine antihypertensive drug raw material into the second solvent by adopting a spraying method.

In the implementation process, based on different requirements on different powder particle sizes of target products, a dropping method or a spraying method can be selectively adopted as an anti-solvent for recrystallization on the basis of the proportion of the first solvent and the second solvent, the stirring speed and the crystallization temperature, and the expected purpose can be achieved. Tests prove that the spraying method can obtain the micro-powder with smaller particle size than the dropping method.

In one possible embodiment, the dropping speed of the dropping method is 0.5-6.0 mL/min; optionally, the dropping speed of the dropping method is 1.5-4.0 mL/min;

Or the spraying speed of the spraying method is 0.5-3.5mL/min, and the spraying pressure is 20-50 KPa; optionally, the spraying speed of the spraying method is 2.0-2.5 mL/min; optionally, the spraying pressure of the spraying method is 25-45 KPa.

In the above implementation, the dropping speed enables the first solvent in which the dihydropyridine antihypertensive drug is dissolved to be sufficiently dispersed by the second solvent immediately before the first solvent is dissolved, and the desired micro-scale powder to be rapidly precipitated from the mixed solvent. In addition, in the dropping speed range of 0.5-6.0mL/min, the dropping speed is more than 4.0mL/min, the particle size of the obtained dihydropyridine antihypertensive drug is increased, and when the dropping speed is less than 1.5mL/min, although the particle size of the micro powder can be continuously reduced, the reduction range is limited, and on the contrary, the yield and the production efficiency can be influenced.

Similarly, when the spraying speed is higher than 3.5mL/min, the particle size of the micronized dihydropyridine antihypertensive drug tends to increase, and when the spraying speed is lower than 0.5mL/min, although the particle size is favorably reduced, the reduction range is limited, and the yield and the production efficiency are reduced. When the spray pressure is more than 50KPa, the yield tends to decrease although the particle size of the fine powder is remarkably decreased, and when the spray pressure is less than 20KPa, the particle size of the fine powder is increased, but the yield increase range is limited.

In one possible embodiment, the first solvent dissolved with the dihydropyridine antihypertensive drug raw material is always in a stirring state in the process of adding the first solvent into the second solvent, and the stirring speed is 500-1200 r/min; optionally, the stirring rate is 600-1000 r/min.

in the implementation process, the first solvent containing the dihydropyridine antihypertensive drug raw material can be fully dispersed in the second solvent in the instant by proper spraying pressure and stirring speed. It should be noted that, when the stirring speed is higher than 1200r/min, the effect of reducing the particle size is reduced, and the micronization yield is reduced, and the power consumption is unnecessarily increased, and when the stirring speed is lower than 500r/min, the particle size of the dihydropyridine antihypertensive drug after micronization tends to increase.

In one possible embodiment, the dihydropyridine antihypertensive drug is selected from any one of felodipine, nifedipine, cilnidipine, nitrendipine, nimodipine and amlodipine besylate.

In the implementation process, felodipine, nifedipine, cilnidipine, nitrendipine, nimodipine and amlodipine besylate are all suitable for the novel method for micronizing the bulk drugs.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required to be used in the embodiments of the present application will be briefly described below, it should be understood that the following drawings only show some embodiments of the present application and therefore should not be considered as limiting the scope, and it is obvious for those skilled in the art that other related drawings can be obtained from the drawings without inventive efforts.

Fig. 1 is a spectrum of a particle size detection of micronized felodipine provided in example 1 of the present application;

Fig. 2 is a spectrum of a particle size measurement of micronized felodipine provided in example 3 of the present application;

Fig. 3 is a spectrum of a particle size measurement of micronized felodipine provided in example 25 of the present application;

fig. 4 is a spectrum of a particle size measurement of micronized felodipine provided in example 26 of the present application;

Fig. 5 is a spectrum of particle size detection of felodipine after micro-jet milling as provided in comparative example 1 of the present application;

Fig. 6 is a spectrum of particle size detection of felodipine after micro-jet milling as provided in comparative example 2 of the present application.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions of the embodiments of the present application will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

It should be noted that "and/or" in the present application, such as "scheme a and/or scheme B" means that the three modes of scheme a alone, scheme B alone, scheme a plus scheme B may be used.

The following describes a new method for micronization of bulk drugs of dihydropyridine antihypertensive drugs in the embodiments of the present application.

The embodiment of the application provides a novel micronization method of raw material medicines of dihydropyridine antihypertensive drugs, which comprises the following steps:

S1: the dihydropyridine antihypertensive drug raw material medicine is dissolved in a first solvent, and the first solvent comprises lower aliphatic alcohol or aliphatic ketone compounds.

Illustratively, the dihydropyridine antihypertensive drug is selected from any one of felodipine, nifedipine, cilnidipine, nitrendipine, nimodipine, and amlodipine besylate.

In some possible embodiments, the lower aliphatic alcohol comprises at least one of ethanol, methanol, and isopropanol. That is, when the first solvent is a lower aliphatic alcohol, the first solvent may be any one of methanol, ethanol, and isopropyl alcohol, a mixture of two of the three, or a mixture of the three. Wherein the ethanol is optionally pharmaceutically acceptable ethanol.

In one possible embodiment, the aliphatic ketone compound comprises acetone. That is, when the first solvent is selected from aliphatic ketones, the first solvent may be selected from acetone. It is understood that the aliphatic ketone compound may be, in addition to acetone, other water-miscible and pharmaceutically acceptable lower aliphatic ketone solvents.

in a possible embodiment, the weight-to-volume ratio of the dihydropyridine antihypertensive drug to the first solvent is 1: 1.5-5.5 g/mL, or 1: 2-4 g/mL. Such as, but not limited to, any one of 1:1.5g/mL, 1:2g/mL, 1:2.5g/mL, 1:3g/mL, 1:4g/mL, 1:5g/mL, or a range between any two.

In some possible embodiments, the dihydropyridine antihypertensive drug substance is dissolved in the first solvent at a temperature of 25 ℃ or higher and less than the boiling temperature of the first solvent.

The range of the dissolving temperature of the dihydropyridine antihypertensive drug is set to 25 ℃ to the boiling point temperature of the first solvent, and the selection interval of the solvent dissolving temperature is different depending on the type of the selected first solvent and the ratio of the solute to the solvent.

S2: adding the first solvent dissolved with the raw material medicines of the dihydropyridine antihypertensive drugs into a second solvent to realize the recrystallization of the anti-solvent of the dihydropyridine antihypertensive drugs, wherein the second solvent comprises water or an aqueous solution containing electrolyte or surfactant.

When the second solvent is selected from water or an aqueous solution containing an electrolyte or a surfactant, that is, the second solvent may be pure crushed water, an aqueous solution containing an electrolyte, or an aqueous solution containing a surfactant. Illustratively, the water may be selected from purified water. It should be noted that: 1) felodipine and other dihydropyridine antihypertensive drug raw materials are insoluble or almost insoluble or only slightly soluble in the second solvent; 2) the lower aliphatic alcohol or lower aliphatic ketone must be miscible with water or a second solvent containing an aqueous electrolyte or surfactant solution in an arbitrary ratio.

Illustratively, in one possible embodiment, the temperature of the anti-solvent recrystallization is from-5 to 5 ℃. When the second solvent is an aqueous solution containing electrolyte or surfactant, the freezing point of water can be reduced to below zero DEG C, so that the anti-solvent recrystallization of the bulk drugs of the dihydropyridine antihypertensive drugs and other dihydropyridine antihypertensive drugs can be better realized within the temperature range of-5 to 5 ℃.

In one possible embodiment, the electrolyte is a pharmaceutically acceptable inorganic salt. Optionally, the electrolyte comprises any one of sodium chloride and sodium sulfate. Illustratively, the electrolyte may be sodium chloride or sodium sulfate.

Illustratively, the concentration of the electrolyte in the aqueous solution containing the electrolyte is 0.1 to 1% by mass, or 0.2 to 0.6% by mass, such as but not limited to any one of 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8%, 1% by mass or a range between any two.

In one possible embodiment, the surfactant is a pharmaceutically acceptable anionic surfactant.

Optionally, the surfactant is sodium lauryl sulfate. Illustratively, the surfactant concentration in the aqueous solution containing the surfactant is 0.05 to 0.5% by mass, or 0.08 to 0.3% by mass. Such as, but not limited to, any one of 0.05%, 0.08%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, or a range of values between any two.

In one possible embodiment, the volume ratio of the first solvent to the second solvent is 1:15 to 55, or 1:20 to 40, such as but not limited to any one of 1:15, 1:18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, or a range between any two.

In one possible embodiment, the first solvent in which the dihydropyridine antihypertensive drug substance is dissolved is added to the second solvent in such a manner that the first solvent in which the dihydropyridine antihypertensive drug substance is dissolved is added dropwise to the second solvent by a dropping method, or the first solvent in which the dihydropyridine antihypertensive drug substance is dissolved is sprayed to the second solvent by a spraying method.

When a dropping method is employed, the dropping speed of the dropping method is, for example, 0.5 to 6.0mL/min, or 1.5 to 4.0mL/min, such as, but not limited to, any one of 0.5mL/min, 1mL/min, 1.5mL/min, 2mL/min, 3mL/min, 4mL/min, 5mL/min, 6mL/min, or a range between any two thereof.

When a spraying method is employed, illustratively, the spraying rate of the spraying method is 0.5-3.5mL/min, or 1.0-3.0mL/min, such as, but not limited to, any one of 0.5mL/min, 1mL/min, 1.5mL/min, 2mL/min, 3mL/min, 3.5mL/min, or a range between any two.

Illustratively, the spray pressure of the spraying process is from 20 to 50KPa, or from 25 to 45KPa, such as, but not limited to, any one of 20KPa, 25KPa, 30KPa, 40KPa, 45KPa, or a range between any two.

In one possible embodiment, the stirring speed is 500-1200r/min, or 600-1000r/min, all the time in the process of adding the first solvent dissolved with the dihydropyridine antihypertensive drug raw material to the second solvent under stirring. Such as, but not limited to, any one of 500r/min, 600r/min, 800r/min, 1000r/min, 1200r/min, or a range between any two. Optionally, the stirring time is 1-15 min, or 5-10 min, such as but not limited to any one of 1min, 2min, 4min, 5min, 8min, 10min, 12min, 15min, or a range between any two.

in one possible embodiment, after the end of the dropping or spraying operation of the dihydropyridine antihypertensive drug anti-solvent recrystallization, the recrystallized mass is aged at rest. Illustratively, the time of resting aging is from 10 to 60min, or from 15 to 45min, such as, but not limited to, any one of 10min, 15min, 20min, 25min, 30min, 40min, 45min, 50min, 60min, or a range between any two.

In one possible embodiment, after resting for aging, the aged material is filtered to obtain a filter cake. Alternatively, the filtration may be vacuum filtration or centrifugal filtration. Optionally, the filter cake obtained by filtering is repeatedly washed by water until the residual solvent and inorganic salt reach the standard. Wherein the residue may be an inorganic salt and/or a first solvent residue thereof.

After washing, the filter cake is dried. Illustratively, the drying mode can be vacuum drying, and the vacuum degree is in the range of 600-760 mmHg. The drying temperature may be selected from 45 to 65 ℃ or 50 to 60 ℃, for example, but not limited to, 45 ℃, 50 ℃, 55 ℃, 60 ℃, or a range therebetween.

The features and properties of the present application are described in further detail below with reference to examples.