Method for controlling particle size of medicine

Abstract

The invention relates to a method for controlling the particle size of a medicine. Specifically, the invention provides a method for preparing a bulk drug with a certain particle size and distribution. According to the preparation method, the particle size and distribution of the raw material medicines can be controlled, and other properties of the corresponding raw material medicines, such as flowability, physical and chemical stability and the like, can be considered at the same time. The method is simple to operate, low in cost and suitable for industrial production. The obtained product is narrow in particle size distribution and good in fluidity, compressibility and physical and chemical stability, and can meet the requirements of different preparation processes.

Description

Technical Field

[0001] The invention relates to the field of chemical medicine, and in particular to a method for controlling the particle size of a drug. Background Art

[0002] Oral administration is currently the most convenient and commonly used route of administration. Oral bioavailability depends on factors such as water solubility, permeability, dissolution rate and first-pass metabolism, among which the most common reasons are poor solubility and low permeability. Among the newly developed chemical drugs, about 40% have poor water solubility, resulting in slow drug absorption and extremely poor bioavailability. Low water solubility is the main problem encountered in the development of new chemical entity formulations and generic drug development. The solubility of a drug is usually intrinsically linked to the particle size of the drug. As the particle size decreases, the specific surface area increases, resulting in greater interaction with the solvent to achieve the purpose of increasing solubility.

[0003] In addition, the particle size distribution of APIs not only affects its own transportation, packaging and storage, but also has a great impact on the entire preparation process, such as premixing / mixing, granulation, drying, whole grain, coating, packaging and tableting. Its impact on preparations is mainly in the following aspects: a) Impact on product performance (such as solubility, bioavailability, content uniformity, stability, etc.); b) Impact on manufacturability (such as fluidity, mixing uniformity, compressibility, etc.), ultimately affecting the safety, efficacy and quality of the drug. When the particle size distribution between product batches is unstable or the particle size distribution is bimodal or multimodal, it will bring some adverse effects to the preparation process, such as stratification and poor mixing uniformity during direct tableting.

[0004] At present, the control of the particle size distribution and size of the API can generally be achieved through two ways. The first way is to control it during the crystallization process, for example, by adjusting the process parameters in the crystallization process (such as cooling rate, stirring rate, anti-solvent drop rate, etc.) to control the particle size distribution of the API. The second way is to micronize the API after the API has been prepared and before the formulation process to reduce the particle size of the API and (or) make the particle size of the API uniform.

[0005] The method of controlling the particle size distribution of APIs through route 1 is not universal, and it is necessary to develop a corresponding crystallization process, i.e., a particle size control process, according to the characteristics of the drug itself. In the crystallization process, adding seed crystals to control the particle size and distribution of the finished product is a common means. Crystallization is a complex process, and different physical and chemical environments will affect the crystallization process, and the influence of the amplification effect needs to be considered during the amplification process. Therefore, controlling the particle size of the finished product by adding seed crystals has high requirements for the size of the seed crystals themselves and the uniformity of the particles. Especially for poorly soluble drugs, the particle size of the API needs to be controlled at a relatively small level, and the API obtained only by conventional crystallization may not meet this requirement. Therefore, it is necessary to add finer seed crystals to obtain API particles with a sufficiently small particle size, uniform distribution, and meeting the requirements of the formulation process.

[0006] When the subsequent preparation process has strict requirements on the particle size of the API, it is necessary to strictly control the crystallization parameters, which brings inconvenience to the actual production and reduces the operability. At this time, controlling the particle size of the API through the second approach is a more direct method, and this method is also a commonly used method in the current pharmaceutical industry. Traditional micronization methods, such as airflow crushing and grinding, rely on mechanical force to crush drug particles. However, the mechanical force during crushing usually exerts a large amount of physical stress on the drug product, thereby destroying its crystal structure, resulting in risks such as product crystal form transformation, decreased crystallinity, or degradation impurities; when dealing with heat-sensitive or unstable active compounds, the temperature increase during the crushing process is also a problem worthy of attention; airflow crushing and grinding can also cause static electricity in the material, which is not conducive to the packaging, transportation and storage of the product. Unconventional particle size control methods such as ultrasound and high shear also have certain limitations. The ultrasonic crushing method is difficult to industrialize and has low production capacity; although high shear can reduce the particle size of the crystal to a certain extent, it is often uneven, resulting in a wide particle size distribution, and the amplification effect is obvious. In actual industrial production, it is likely that the shear crushing efficiency of the small test cannot be achieved.

[0007] Therefore, there is an urgent need to develop a new, stable, and industrializable powder control method for application in the pharmaceutical field, which can take into account the particle size, physicochemical stability, thermal sensitivity, and yield of the raw materials and can be industrialized. Summary of the invention

[0008] The present invention aims to provide a stable drug particle size control method which can adjust the product particle size and distribution, is easy to operate, and is suitable for industrial production, and specifically relates to a method for controlling the drug particle size and distribution. The drugs include but are not limited to digestive system drugs, respiratory system drugs, urinary system drugs, endocrine and metabolic regulation drugs, nervous system drugs, mental disorder drugs and anti-tumor drugs.

[0009] In a first aspect of the present invention, a method for preparing a bulk drug is provided, the method comprising the steps of: treating a liquid dispersion containing the bulk drug by a high-pressure homogenization method, and then crystallizing from the treated liquid dispersion.

[0010] In another preferred embodiment, the raw materials include but are not limited to digestive system drugs, respiratory system drugs, urinary system drugs, endocrine and metabolic regulation drugs, nervous system drugs, mental disorder drugs and anti-tumor drugs.

[0011] In another preferred embodiment, the particle size of the API is 1 um to 1000 um.

[0012] In another preferred embodiment, the liquid dispersion is obtained by the following method:

[0013] The clear liquid containing the raw material drug is crystallized to obtain the liquid dispersion.

[0014] In another preferred embodiment, the method is carried out by the following scheme 1:

[0015] 1) providing a first mixed system, wherein the first mixed system is a clear solution of the API in a first solvent;

[0016] 2) adding seed crystals to the first mixed system to obtain a second mixed system; wherein the seed crystals are prepared by a high-pressure homogenization method;

[0017] 3) The second mixed system is subjected to a crystallization treatment, and the obtained crystals are separated, which are the API of a certain particle size.

[0018] In another preferred embodiment, the method is carried out by the following scheme 2:

[0019] i) providing a first mixed system, wherein the first mixed system is a clear solution of the API in a first solvent;

[0020] ii) performing a crystallization treatment on the first mixed system to obtain a second mixed system;

[0021] iii) performing high pressure homogenization on the second mixed system to obtain a third mixed system;

[0022] iv) performing crystallization treatment on the third mixed system and separating the obtained crystals, which are the API of a certain particle size.

[0023] In another preferred embodiment, in the step 3), step ii) and step iv), the crystallization treatment comprises crystallization by one or more methods selected from the following group: crystallization by cooling, crystallization by evaporating solvent, crystallization by adding anti-solvent, crystallization by stirring and aging, or a combination thereof.

[0024] In another preferred embodiment, in the step 2) or step iii), the pressure of the high-pressure homogenization is 0 to 2000 bar.

[0025] In another preferred embodiment, in the step 2) or step iii), the pressure of the high-pressure homogenization is 100 to 1500 bar.

[0026] In another preferred embodiment, in step 2) or step iii), the temperature of the high pressure homogenization is -20 to 100°C, preferably 0 to 50°C.

[0027] In another preferred embodiment, in step 2) or step iii), the high pressure homogenization is performed 1 to 10 times.

[0028] In another preferred embodiment, the first solvent is selected from the following group:

[0029] Alcohol solvents, ketone solvents, amide solvents, ester solvents, acid solvents, hydrocarbon solvents, water, or a combination thereof.

[0030] In another preferred embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, 2-ethoxyethanol, cyclohexanol, n-octanol, n-pentanol, or a combination thereof.

[0031] In another preferred embodiment, the amide solvent is selected from the following group: N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.

[0032] In another preferred embodiment, the ester solvent is selected from the following group: ethyl acetate, isopropyl acetate, ethyl lactate, tert-butyl acetate, butyl butyrate, or a combination thereof.

[0033] In another preferred embodiment, the hydrocarbon solvent is selected from the following group: cyclohexane, toluene, p-xylene, m-xylene, isopropylbenzene, chlorobenzene, n-octane, n-hexane, cyclopentane, or a combination thereof.

[0034] In another preferred embodiment, the method comprises the steps of:

[0035] (1) dissolving the API in a solvent at T0° C. to form a first mixed system;

[0036] (2) cooling the first mixed system to T1°C within t1, and then adding the API seed solution to obtain a second mixed system;

[0037] (3) subjecting the second mixed system to high pressure homogenization to obtain a third mixed system;

[0038] (4) cooling the third mixed system to T2°C, stirring for t2 time, and then filtering to obtain a crude drug filter cake;

[0039] (5) Drying the API filter cake at T3°C for t3 time to obtain API with a certain particle size.

[0040] In another preferred embodiment, the method comprises the steps of:

[0041] (1) dissolving the API in a solvent at T0° C. to form a first mixed system;

[0042] (2) adding the API seed crystals to the first mixed system to obtain a second mixed system;

[0043] (3) cooling the second mixed system to T2°C, stirring for t2 time, and then filtering to obtain a crude drug filter cake; and

[0044] (4) Drying the API filter cake at T3°C for t3 time to obtain API with a certain particle size.

[0045] In another preferred embodiment, the temperature T0 in step (1) is 40°C-75°C, preferably T0 is 45°C-70°C.

[0046] In another preferred embodiment, the API seed solution in step (2) is formed by dispersing API seeds in a solvent.

[0047] In another preferred embodiment, the solvent is selected from:

[0048] Alcohol solvents, ketone solvents, amide solvents, ester solvents, acid solvents, hydrocarbon solvents, water, or a combination thereof.

[0049] In another preferred embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, 2-ethoxyethanol, cyclohexanol, n-octanol, n-pentanol, or a combination thereof.

[0050] In another preferred embodiment, the amide solvent is selected from the following group: N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.

[0051] In another preferred embodiment, the ester solvent is selected from the following group: ethyl acetate, isopropyl acetate, ethyl lactate, tert-butyl acetate, butyl butyrate, or a combination thereof.

[0052] In another preferred embodiment, the hydrocarbon solvent is selected from the group consisting of cyclohexane, toluene, p-xylene, m-xylene, isopropylbenzene, chlorobenzene, n-octane, n-hexane, cyclopentane, or a combination thereof.

[0053] In another preferred embodiment, the temperature T1 in step (2) is 35°C-60°C, preferably T1 is 40°C-55°C.

[0054] In another preferred embodiment, the stirring time t1 in step (2) is 1-3.5 h, preferably t1 is 1.5-3 h.

[0055] In another preferred embodiment, the temperature T1 in step (4) is 5°C-20°C, preferably T1 is 10°C-15°C.

[0056] In another preferred embodiment, the stirring time t2 in step (4) is 0.5-1.5 h, preferably t2 is 0.5-1 h.

[0057] In another preferred embodiment, the drying time t3 in step (5) is 4-8 hours, preferably t1 is 5-7 hours.

[0058] In another preferred embodiment, the temperature T3 in step (5) is 45°C-70°C, preferably 50°C-65°C.

[0059] In another preferred embodiment, in step (2), the API seed crystals are prepared by the following steps:

[0060] (a) providing a first solution in which a drug substance is dissolved;

[0061] (b) crystallizing the first solution, and then homogenizing under high pressure to obtain a first homogeneous solution;

[0062] (c) crystallizing the first homogeneous solution to obtain a second homogeneous solution; and

[0063] (d) separating the second homogeneous solution to obtain the API seed crystals.

[0064] In another preferred embodiment, in the step (b), the high-pressure homogenization pressure is 0 to 2000 bar, preferably 100 to 1500 bar, and more preferably 150 bar to 350 bar.

[0065] In another preferred embodiment, in the step (b), the high pressure homogenization is performed 1 to 10 times.

[0066] In another preferred embodiment, the API seed crystals are prepared by the following steps:

[0067] (a) dissolving the API in a solvent at T0°C, filtering and collecting the filtrate;

[0068] (b) cooling the filtrate to T1°C and performing high pressure homogenization at p1 to obtain a first homogenous solution;

[0069] (c) cooling the first homogeneous solution to T2°C and stirring for t1 time to obtain a second homogeneous solution; and

[0070] (d) centrifuging or filtering the second homogenous solution to obtain a filter cake, and drying it at T3°C for time t2 to obtain the API seed crystals.

[0071] In another preferred embodiment, the solvent in step (a) is selected from the following group:

[0072] Alcohol solvents, ketone solvents, amide solvents, ester solvents, acid solvents, hydrocarbon solvents, water, or a combination thereof.

[0073] In another preferred embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, 2-ethoxyethanol, cyclohexanol, n-octanol, n-pentanol, or a combination thereof.

[0074] In another preferred embodiment, the amide solvent is selected from the following group: N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.

[0075] In another preferred embodiment, the ester solvent is selected from the following group: ethyl acetate, isopropyl acetate, ethyl lactate, tert-butyl acetate, butyl butyrate, or a combination thereof.

[0076] In another preferred embodiment, the hydrocarbon solvent is selected from the following group: cyclohexane, toluene, p-xylene, m-xylene, isopropylbenzene, chlorobenzene, n-octane, n-hexane, cyclopentane, or a combination thereof.

[0077] In another preferred embodiment, the temperature T0 in step (a) is 40°C-75°C, preferably T0 is 45°C-70°C.

[0078] In another preferred embodiment, the temperature T1 in step (b) is -20 to 100°C, preferably 0 to 50°C, more preferably 5°C to 25°C.

[0079] In another preferred embodiment, the temperature T2 in step (c) is 0°C-5°C, preferably T2 is 0°C-2°C.

[0080] In another preferred embodiment, the stirring time t1 in step (c) is 0.5-2.5 h, preferably t1 is 0.5-2 h.

[0081] In another preferred embodiment, the T3 in step (d) is 45°C-70°C, preferably 50°C-65°C.

[0082] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1This is a microscope photograph of the raw material A before homogenization in Example 1-1.

[0084] Figure 2 a is a microscopic photograph of the raw material A after homogenization in Example 1-1.

[0085] Figure 2 b is the particle size distribution diagram of the raw material A after homogenization in Example 1-1.

[0086] Figure 3 a is a microscopic photograph of the raw material A prepared in Example 1-2.

[0087] Figure 3 b is the particle size distribution diagram of the raw material A prepared in Example 1-2.

[0088] Figure 4 a is a microscope photograph of the raw material A prepared in sequence number 2 of step 2-1 of comparative example 1.

[0089] Figure 4 b is the particle size distribution diagram of the raw material A prepared in sequence number 2 of step 2-1 of comparative example 1.

[0090] Figure 5 a is a microscope photograph of the raw material A prepared in sequence number 4 of step 2-1 of comparative example 1.

[0091] Figure 5 b is the particle size distribution diagram of the raw material A prepared in sequence number 4 of step 2-1 of comparative example 1.

[0092] Figure 6 a is a microscope photograph of the raw material A prepared in step 2-2 of comparative example 1.

[0093] Figure 6 b is the particle size distribution diagram of the raw material A prepared in step 2-2 of comparative example 1.

[0094] Figure 7 This is a microscope photograph of the seed crystals of the raw material B prepared in step 1 of Example 2-1.

[0095] Figure 8 a is a microscope photograph of the raw material B prepared in step 2-1 of Example 2-1.

[0096] Figure 8 b is the particle size distribution diagram of the raw material B prepared in step 2-1 of Example 2-1.

[0097] Fig. 9 This is the particle size distribution diagram of the raw material B prepared in step 2-2 of Example 2-1.

[0098] Fig.10This is the particle size distribution diagram of the raw material B prepared in Example 2-2.

[0099] Fig.11 This is the particle size distribution diagram of the raw material B prepared in Example 2-3.

[0100] Fig.12 This is a microscope photograph of the raw material B seed crystals prepared in step 1, sequence number 1 of comparative example 2.

[0101] Fig.13 This is the particle size distribution diagram of the raw material B prepared in step 2 of comparative example 2. DETAILED DESCRIPTION

[0102] After long-term and in-depth research, the inventor unexpectedly discovered a stable drug particle size control method with uniform product particle size distribution, simple and easy operation, and suitable for industrial production. The raw material drug prepared by the method of the present invention has a narrow particle size distribution, good fluidity and compressibility, and is suitable for different preparation processes. The conventional method for controlling the particle size of raw materials solves the problems of uneven particle size distribution, insufficient particle size, static electricity, caking, and poor physical and chemical stability of the product. On this basis, the inventor completed the present invention.

[0103] Terminology

[0104] Unless otherwise specified herein, each abbreviation has a common meaning understood by those skilled in the art.

[0105] As used herein, unless otherwise specified, the terms "API A" and "API B" refer to the amorphous form (form) and / or various crystalline forms (including the various crystalline forms and amorphous forms mentioned herein, and the crystalline forms or amorphous forms (forms) mentioned in various published or unpublished documents or patents) of API A and API B.

[0106] High-pressure homogenization method for producing raw materials

[0107] As used herein, "high pressure homogenization" or "high pressure homogenization method" are used interchangeably and refer to a method of treating a liquid dispersion containing a drug substance with a high pressure homogenizer to obtain a drug substance with a desired particle size.

[0108] High-pressure homogenizers are mainly used in the biological, pharmaceutical, food, chemical and other industries for cell disruption, beverage homogenization, fine chemicals, and the preparation of liposomes, fat emulsions, nanosuspensions, microemulsions, lipid microspheres, emulsions, dairy products, large infusions, dyes, solar panel coatings, and conductive coatings. High-pressure homogenizers can make materials in a suspended state flow through a cavity with a special internal structure (high-pressure homogenization cavity) at high speed under ultra-high pressure, causing the material to undergo structural property changes and ultimately achieve a homogenization effect.

[0109] The inventors unexpectedly discovered that after preliminary crystallization, high-pressure homogenization treatment of the feed liquid can change the morphology of the material, and further crystallization of the treated material can obtain a raw material drug of the desired particle size. Since the method changes the morphology of the material through physical treatment, it is not affected by the type of raw material drug and can be used for the production of any type of raw material drug.

[0110] Methods for controlling drug particle size

[0111] The present invention provides a method for controlling the particle size of a drug, wherein the preparation method is selected from the following group:

[0112] Option 1:

[0113] 1) Providing a clear solution of the API as the first mixing system;

[0114] 2) adding seed crystals to the first mixed system, wherein the seed crystals are not completely dissolved after addition, thereby obtaining a second mixed system; wherein the seed crystal preparation method is high pressure homogenization;

[0115] 3) The second mixed system is subjected to temperature adjustment, evaporation, addition of an anti-solvent and / or stirring and aging treatment to further precipitate a solid, and the solid is collected. The solid is a bulk drug of a certain particle size.

[0116] Option 2:

[0117] 1) Providing a clear solution of the API as the first mixing system;

[0118] 2) adjusting the temperature of the first mixed system, evaporating, adding an anti-solvent, adding seed crystals and / or stirring and aging to precipitate a solid, thereby obtaining a second mixed system;

[0119] 3) homogenizing the second mixed system under high pressure to obtain a third mixed system;

[0120] 4) The third mixed system is subjected to temperature adjustment, evaporation, addition of an anti-solvent and / or stirring and aging treatment to further precipitate a solid, and the solid is collected, wherein the solid is a bulk drug of a certain particle size.

[0121] Furthermore, the high-pressure homogenization pressure is 0 to 2000 bar, preferably 100 to 1500 bar.

[0122] Furthermore, the high pressure homogenization temperature is -20 to 100°C, preferably 0 to 50°C.

[0123] Furthermore, the high pressure homogenization is performed 1 to 10 times.

[0124] Compared with the prior art, the present invention has the following beneficial effects:

[0125] (1) The drug obtained by the method of the present invention has a narrow particle size distribution, better tableting properties and fluidity, and is more conducive to the development and production of formulation technology.

[0126] (2) The method of the present invention can adjust the particle size of the obtained product according to the preparation requirements to meet different single or compound preparation processes.

[0127] (3) While the method of the present invention can stably control the particle size of the drug, it can also take into account other properties of the drug, such as physical and chemical stability, fluidity, and tablet compressibility. This method can obtain high-quality raw material drug particles that meet the particle size distribution requirements. This method can also avoid static electricity, material compaction, etc. that may be caused by other particle size control methods.

[0128] (4) The method of the present invention is simple and easy to operate, has low cost, high production capacity, and is suitable for application in industrial production.

[0129] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not specified in the following examples are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0130] General Methods

[0131] The solvents used in the present invention are all analytically pure. All test methods in the present invention are general methods, and the test parameters are as follows:

[0132] 1. Particle size test method

[0133] Method 1: Particle size test for API A

[0134] Laser particle size analyzer Malvern Mastersizer 2000 Dispersants water Dispersant RI 1.330 Calculation sensitivity ordinary Particle shape irregular Analytical Model General light source Red light Surfactants Twain 80 Sample testing time 10s / 10000snaps Background test time 10s / 10000snaps Stirring speed 2000rpm Shading range 10～20％

[0135] Method 2: Particle size test for API B

[0136]

[0137]

[0138] 2. Bulk density test method

[0139] Particle and powder characteristic analyzer: Ningbo Ruike's FT-2000A

[0140] Bulk density test: Take 10g of sample and put it into 100mL Nessler colorimetric tubes to read the volume. Divide 10g by the volume value to get the bulk density value.

[0141] Tap density test: Take 10g of sample and put it into 100mL Nessler colorimetric tubes respectively. Vibrate until the volume stops decreasing. Read the volume. Divide 10g by the read volume to get the tap density value.

[0142] 3. Microscope

[0143] Instrument: Sunny Optical, SDPTOP BH200P; Magnification: 400 times unless otherwise specified.

[0144] 4. Crushing equipment

[0145] Universal crushing equipment: 1000g swing high-speed universal crusher produced by Wenling Linda Machinery Co., Ltd., model: DFY-1000.

[0146] Airflow pulverizing apparatus: JMQLM-100 supersonic airflow pulverizer produced by Yixing Juneng.

[0147] High-pressure homogenizer: AH-NANO from Antos Nanotechnology (Suzhou) Co., Ltd.

[0148] 5. Tablet pressing

[0149] Instrument: Rotary 8-punch tablet press, ZPS-8 from Shanghai Tianxiang.

[0150] 6. Chemical purity determination method (HPLC)

[0151] Chromatographic column: Inertsil ODS-3V 4.6MM*250mm, 5μm

[0152] Instrument: Agilent 1260

[0153] Mobile phase A: 10 mM KH2PO4

[0154] Mobile phase B: acetonitrile

[0155] Flow rate: 1.0mL / min

[0156] Detection wavelength: 260nm

[0157] Column temperature: 30°C

[0158] Injection volume: 10 μL

[0159] Sample concentration: 0.5 mg / mL

[0160] Diluent: Mobile phase A: Mobile phase B = 50:50 (v / v)

[0161] Time (min) Mobile phase A (%) Mobile phase B (%) 0 65 35 15 65 35 30 45 55 48 20 80 55 20 80 65 65 35

[0162] Example 1-1: Preparation of API A

[0163] Weigh 200g crude drug A and dissolve it in 2L ethanol at 50℃. Filter and cool the filtrate to 15℃ for 3.5h. Take a small amount of crystal slurry and observe the crystal morphology under a microscope. See the microscope photo for details. Figure 1 . The remaining slurry was homogenized at 15°C and 300 bar. After 1.5 hours of homogenization, the slurry was cooled to 0-2°C and stirred for 1 hour. Centrifuged, the wet cake was vacuum dried at 50°C for 12 hours and weighed constant. 171g of raw material drug A was obtained with a yield of 85.5%. A small amount of dried solid was fully dispersed in water and the solid morphology was observed under a microscope. The microscopic photograph is shown in Figure 2 a; The dried solid is subjected to wet particle size test, and its particle size distribution diagram is shown in Figure 2 b, D10: 2.3μm, D50: 5.3μm, D90: 9.9μm.

[0164] Example 1-2: Preparation of API A

[0165] Weigh 200g crude drug A and dissolve it in 2L ethanol at 50℃. Filter and cool the filtrate to 0-2℃ for 5h. Take a small amount of crystal slurry and observe the crystal morphology under a microscope. The microscopic photo is similar to Figure 1 . The remaining slurry was homogenized at 0-2°C and 300 bar. After the homogenized slurry was heated to 15°C, stirring continued for 1 hour. After another 1.5 hours, the temperature was lowered to 0-2°C and stirring continued for 1 hour. Centrifuged, the wet cake was vacuum dried at 50°C for 12 hours and weighed constant. 170.5 g of raw material drug A was obtained with a yield of 85.3%. A small amount of the dried solid was fully dispersed in water and the solid morphology was observed under a microscope. The microscopic photograph is shown in Figure 3 a; The dried solid is subjected to wet particle size test, and its particle size distribution diagram is shown in Figure 3 b, D10: 2.3μm, D50: 5.4μm, D90: 10.7μm.

[0166] Comparative Example 1: Preparation of API A

[0167] Step 1: Preparation of large particle size API A

[0168] Weigh 200g crude drug A and dissolve it in 2L ethanol at 50℃. Filter, cool the filtrate to 0-2℃ for 5h, and continue stirring for 1h. Take a small amount of crystal slurry and observe the crystal morphology under a microscope. The microscopic photo is similar to Figure 1 The remaining slurry was centrifuged, and the wet cake was vacuum dried at 50°C for 12 hours to a constant weight. 172 g of API A was obtained, with a yield of 86.0%.

[0169] Step 2-1: Grinding API A by different methods

[0170] Weigh 80g of the solid API A prepared in step 1 and crush it several times under a pressure of 0.4MPa. Until the fifth crushing, the static electricity of the material was too large, the material back-sprayed, and it could not be crushed further. Take part of the crushed solid and fully disperse it in water, and observe its morphology under a microscope; take part of the crushed solid for wet particle size test. Microscope photos and particle size data are shown in Table 1.

[0171] Table 1

[0172]

[0173] Step 2-2: High-pressure homogenization and crushing of API A

[0174] Weigh 80g of the solid API A prepared in step 1 and fully disperse it in 800mL of ethanol at 0-2°C. High pressure homogenize at 0-2°C and 300bar. Stir the homogenized slurry at 0-2°C for 1h. Take a small amount of the slurry and observe the solid morphology under a microscope. The microscopic photograph is shown in Figure 6 a. Centrifuge, and dry the wet cake under vacuum at 50°C for 12 hours to a constant weight. Obtain 69 g of API A, with a yield of 86.2%. The solid after drying showed agglomeration, and the solid was subjected to wet particle size test, and its particle size distribution diagram is shown in Figure 6 b. As can be seen from the figure, due to agglomeration, the particle size distribution curve of the dried solid shows serious tailing phenomenon at large particle sizes.

[0175] Example 2-1: Preparation of API B

[0176] Step 1: Preparation of seed crystals of API B by high pressure homogenization

[0177] Weigh 150g of API B, disperse it in 1.5L ethyl acetate at 25°C, and homogenize it at a pressure of 1000 bar. Observe the solid morphology after homogenization under a microscope. See the microscope photo for details. Figure 7 From the microscope photos, we can see that the solid particles after homogenization are uniform in size, well dispersed, and not agglomerated. The homogenized slurry was centrifuged, and the solid was vacuum dried at 40℃ for 24 hours to a constant weight. The solid after drying has no static electricity and no agglomeration. The solid after drying was tested by wet particle size method, D10: 1.1μm, D50: 2.5μm, D90: 5.5μm.

[0178] Step 2-1: Preparation of API B with different particle sizes

[0179] Weigh 1 kg crude drug substance B and dissolve it in 18 L isopropanol at 65 °C. Lower the solution temperature to 50 °C for 1.5 hours and add 50 mL of the suspension of drug substance B seed crystals prepared in step 1. Cool to 10 °C for 4 hours and continue stirring at 10 °C for 30 minutes. Filter and dry the wet cake at 65 °C for 6 hours to obtain a constant weight. The dry product mass is 950 g and the yield is 94.5%. Observe the solid morphology under a microscope at a magnification of 40 times. The microscope photo is shown in Figure 8 a. The obtained solid was subjected to wet particle size test, and the obtained particle size distribution diagram is shown in Figure 8 b, D10 is 237.6μm, D50 is 365.6μm, and D90 is 561.7μm.

[0180] Step 2-2: Preparation of API B with different particle sizes

[0181] Weigh 1 kg of crude API B and dissolve it in 18 L of isopropanol at 65 °C. Lower the solution temperature to 50 °C for 1.5 h and add 100 mL of the suspension of API B seed crystals prepared in step 1. Cool to 10 °C for 4 h and continue stirring at 10 °C for 30 min. Filter and dry the wet cake at 65 °C for 6 h to a constant weight. The dry product mass is 951 g and the yield is 94.1%. Perform a wet particle size test on the obtained solid, and the obtained particle size distribution diagram is shown in Fig. 9 , D10 is 173.2μm, D50 is 274.2μm, and D90 is 429.2μm.

[0182] Example 2-2 Preparation of API B

[0183] Weigh 1 kg of crude drug substance B and dissolve it in 18 L of isopropanol at 65 °C. After 2 hours, lower the temperature to 45 °C, and solid will precipitate. Homogenize at 45 °C with 200 bar high pressure. After homogenization, cool the system to 10 °C in 3.5 hours and continue stirring at 10 °C for 30 minutes. Filter, dry the wet cake at 65 °C for 6 hours to a constant weight, the dry product mass is 948 g, and the yield is 94.8%. The obtained solid is subjected to a wet particle size test, and the obtained particle size distribution diagram is shown in Fig.10 , D10 is 254.8μm, D50: 371.2μm, D90: 541.2μm.

[0184] Example 2-3 Preparation of API B

[0185] Weigh 1 kg of crude drug substance B and dissolve it in 18 L of isopropanol at 65 °C. After 3 hours, lower the temperature to 40 °C, and solid will precipitate. Homogenize at 40 °C with 200 bar high pressure. After homogenization, cool the system to 10 °C in 3 hours and continue stirring at 10 °C for 30 minutes. Filter, dry the wet cake at 65 °C for 6 hours to a constant weight, the dry product mass is 941 g, and the yield is 94.1%. The obtained solid is subjected to a wet particle size test, and the obtained particle size distribution diagram is shown in Fig.11 , D10 is 219.8μm, D50: 321.5μm, D90: 470.0μm.

[0186] Comparative Example 2: Preparation of API B

[0187] Step 1: Universal crushing to prepare seed crystals of API B

[0188] 150 g of API B was crushed with a universal grinder for a certain period of time. The morphology of the obtained solid was observed with a microscope, and the obtained solid was subjected to a wet particle size test. The microscope photo and particle size data of the obtained solid are shown in Table 2.

[0189] Table 2

[0190]

[0191] Step 2: Preparation of API B

[0192] Take 1 kg of crude drug B and dissolve it in 18 L of isopropanol at 65 °C. Reduce the solution temperature to 50 °C. Fully disperse 10 g of the drug B seed crystals prepared in step 1, sequence number 2 in 100 mL of n-heptane, and then add it to the isopropanol solution of drug B. Cool to 10 °C after 4 hours, and continue stirring at 10 °C for 30 minutes. Filter, and the wet cake is dried at 65 °C for 6 hours to a constant weight. The mass of the dry product is 948 g, and the molar yield is 94.3%. The obtained solid is subjected to a wet particle size test, and the obtained particle size distribution diagram is shown in Fig.13 , D10 is 69.5μm, D50 is 269.8μm, and D90 is 509.8μm.

[0193] Test Example 1: Stability of API A

[0194] The API A prepared in Example 1 and Comparative Example 1 was placed open at 40°C / 75% RH for 30 days, and the solids before and after the placement were subjected to X-ray powder diffraction test and HPLC purity test. The specific results are shown in Table 3.

[0195] Table 3

[0196]

[0197]

[0198] It can be seen from the data in Table 3 that the raw material drug A obtained in Example 1 has better physicochemical stability than the raw material drug A obtained in Comparative Example 1.

[0199] Test Example 2: Powder properties of API B

[0200] Test Example 2-1: Flowability of API B

[0201] Weigh 10 g of each of the raw material drug B prepared in Example 2-1, Example 2-2, Example 2-3 and Comparative Example 2, and put them into 100 mL Nessler colorimetric tubes to read the volume. Divide 10 g by the volume value read to obtain the bulk density value. After reading the volume, vibrate until the volume no longer decreases, read the volume again, and divide 10 g by the volume value read to obtain the tap density value. The results are shown in Table 4.

[0202] Table 4

[0203]

[0204] It can be seen from the data in Table 4 that the fluidity of the bulk drug B particles obtained in Example 2-1, Example 2-2 and Example 2-3 is better than that of the bulk drug B particles obtained in Comparative Example 2.

[0205] Test Example 2-2: Tableting of API B

[0206] The solid bulk drug B obtained in Example 2-1, Example 2-2, Example 2-3 and Comparative Example 2 was directly tableted. 10 # Shallow arc circular punch. Tablet pressing results are shown in Table 5.

[0207] Table 5

[0208]

[0209]

[0210] The results show that for different APIs, the method of the present invention can obtain APIs of specific particle sizes with good physicochemical stability and mechanical properties.

[0211] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a bulk drug, characterized in that: The method comprises the steps of: treating a liquid phase dispersion containing a raw material drug by a high-pressure homogenization method, and then performing crystallization from the treated liquid phase dispersion.

2. The method according to claim 1, characterized in that The liquid dispersion is obtained by the following method: The clear liquid containing the raw material drug is crystallized to obtain the liquid dispersion.

3. The method according to claim 1, characterized in that The method is carried out by the following scheme 1: 1) providing a first mixed system, wherein the first mixed system is a clear solution of the API in a first solvent; 2) adding seed crystals to the first mixed system to obtain a second mixed system; wherein the seed crystals are prepared by a high-pressure homogenization method; 3) The second mixed system is subjected to a crystallization treatment, and the obtained crystals are separated, which are the API of a certain particle size.

4. The method according to claim 1, characterized in that The method described is carried out by the following scheme 2: i) providing a first mixed system, wherein the first mixed system is a clear solution of the API in a first solvent; ii) performing a crystallization treatment on the first mixed system to obtain a second mixed system; iii) performing high pressure homogenization on the second mixed system to obtain a third mixed system; iv) performing crystallization treatment on the third mixed system and separating the obtained crystals, which are the API of a certain particle size.

5. The method according to claim 3 or 4, characterized in that In the step 3), step ii) and step iv), the crystallization treatment comprises crystallization by one or more methods selected from the group consisting of: crystallization by cooling, crystallization by evaporating solvent, crystallization by adding anti-solvent, crystallization by stirring and aging, or a combination thereof.

6. The method according to claim 3 or 4, characterized in that In the step 2) or step iii), the pressure of the high-pressure homogenization is 0 to 2000 bar.

7. The method according to claim 3 or 4, characterized in that In the step 2) or step iii), the pressure of the high-pressure homogenization is 100 to 1500 bar.

8. The method according to claim 4, characterized in that In step (2), the raw material drug seed crystals are prepared by the following steps: (a) providing a first solution in which a drug substance is dissolved; (b) crystallizing the first solution, and then homogenizing under high pressure to obtain a first homogeneous solution; (c) crystallizing the first homogeneous solution to obtain a second homogeneous solution; and (d) separating the second homogeneous solution to obtain the API seed crystals.

9. The method according to claim 8, characterized in that In the step (b), the high-pressure homogenization pressure is 0 to 2000 bar, preferably 100 to 1500 bar, and more preferably 150 bar to 350 bar.

10. The method according to claim 8, characterized in that In the step (b), the high pressure homogenization is performed 1 to 10 times.

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