An integrated microbial testing device and method for poorly soluble powdered drugs.

Abstract

An integrated microbial testing device for poorly soluble powdered pharmaceuticals includes: a tank with a sealable structure, the top of which has a sample inlet and a diluent inlet; a mechanical stirring paddle positioned above the interior of the tank; a low-frequency ultrasonic transducer installed on the lower outer wall of the tank; and a thermostatic jacket covering the outer wall of the tank. This integrated microbial testing device and method for poorly soluble powdered pharmaceuticals firstly solves the problem of filter membrane clogging; the combination of ultrasound and stirring ensures the poorly soluble powder forms a uniform suspension, creating a loose filter cake, significantly increasing the filtration speed. Secondly, it improves microbial release; the ultrasonic cavitation effect disrupts the adsorption of microorganisms by particles, resulting in a higher recovery rate than traditional methods. Simultaneously, it achieves integrated closed operation, avoiding exogenous contamination and personnel exposure during sample transfer. Furthermore, it protects microbial activity; the combination of low-frequency, short-duration ultrasound and thermostatic control greatly enhances microbial survival rate.

Description

Technical Field

[0001] This invention relates to the field of microbial detection technology, specifically to an integrated microbial testing device and method for poorly soluble powdered pharmaceuticals. Background Technology

[0002] Chapter 1105 of the Chinese Pharmacopoeia stipulates that non-water-soluble test samples must be tested for microbial limits using the membrane filtration method. For powdered drugs that are poorly soluble in water, such as amoxicillin raw material, berberine hydrochloride, microcrystalline cellulose, and poorly soluble traditional Chinese medicine extract powder, the existing methods have three major drawbacks: Filter membrane clogging: Powder particles are not completely dissolved and quickly clog the 0.45μm filter membrane when filtered directly, resulting in filtration time of up to several hours or even failure to complete the filtration process. Insufficient microbial release: Microorganisms adhere to the inside or surface of the particles and cannot be washed into the filtrate by simple shaking, resulting in significantly low count results (false negatives). The process is cumbersome and prone to contamination: the traditional process requires manual shaking to dissolve the contents in a container before transferring them to a filtration device. This process exposes the contents to the environment, increasing the risk of external contamination, and is also time-consuming and labor-intensive. Although some studies have attempted to use ultrasonic treatment to help disperse powders, conventional ultrasonic cleaners have uncontrollable energy and are prone to damaging microorganisms; moreover, ultrasonication and filtration are carried out in separate steps, which still poses a risk of transferring contaminants, leaving room for improvement. Summary of the Invention

[0003] (a) Technical problems to be solved To address the shortcomings of existing technologies, this invention provides an integrated microbial testing device and method for poorly soluble powdered pharmaceuticals, thereby resolving the aforementioned problems.

[0004] (II) Technical Solution To achieve the above objectives, at least one embodiment of this disclosure provides an integrated microbial testing device for poorly soluble powdered pharmaceutical products, comprising: The container has a sealable structure and is equipped with a sample feeding port and a diluent inlet at the top. A mechanical stirring paddle is disposed above the interior of the tank; A low-frequency ultrasonic transducer is installed on the lower part of the outer wall of the tank, with a frequency of 20 to 40 kHz; A thermostatic jacket covers the outer wall of the tank. A microporous filter membrane is installed at the bottom of the tank. A filter membrane support plate is disposed below the microporous filter membrane to support the filter membrane; The vacuum filtration port is located below the filter membrane support plate and communicates with the inside of the tank. A pressure balancing valve, installed on the tank, is used to connect a sterile filter to balance the pressure inside and outside the tank.

[0005] For example, in an integrated microbial testing device for a poorly soluble powdered drug provided in at least one embodiment of this disclosure, the constant temperature jacket covers the middle of the outer wall of the tank.

[0006] For example, in the integrated microbial testing device for poorly soluble powdered pharmaceuticals provided in at least one embodiment of this disclosure, the power and duty cycle of the low-frequency ultrasonic transducer are adjusted, and the power adjustment range is 30 to 100 W; the mechanical stirring paddle is a double-layered blade with an adjustable rotation speed range of 50 to 500 rpm.

[0007] For example, in the integrated microbial testing device for poorly soluble powdered pharmaceuticals provided in at least one embodiment of this disclosure, the constant temperature jacket is used to connect to a circulating water bath to control the temperature inside the tank at 20-25°C.

[0008] For example, in the integrated microbial testing device for poorly soluble powdered pharmaceuticals provided in at least one embodiment of this disclosure, the pore size of the microporous filter membrane is 0.45 μm, and the filter membrane support plate is a porous sintered metal plate.

[0009] For example, in the integrated microbial testing device for poorly soluble powdered drugs provided in at least one embodiment of this disclosure, the tank includes a tank top cover, the tank top cover is sealed to the tank by a clamp, and the tank can withstand a pressure of -0.1 to 0.05 MPa.

[0010] According to another aspect of the present invention, a method for performing microbial limit testing on poorly soluble powder pharmaceutical products is also provided, comprising the following steps: S1. Add the poorly soluble powdered drug into the tank through the sample feeding port, and add sterile diluent through the diluent inlet; S2. Turn on the mechanical agitator and low-frequency ultrasonic transducer to disperse the powder into a suspension in the diluent. At the same time, control the temperature inside the tank at 20-25℃ through the constant temperature jacket. The total ultrasonic treatment time is ≤3 minutes. S3. Turn off the agitator and ultrasonic transducer, and turn on the pressure balance valve and vacuum filtration port to perform filtration, so that the liquid passes through the microporous filter membrane and microorganisms are trapped on the filter membrane. S4. Add rinsing solution through the diluent inlet and continue filtration to rinse the filter membrane; S5. Remove the microporous filter membrane and perform incubation and counting.

[0011] For example, in the method for microbial limit testing of a poorly soluble powdered drug provided in at least one embodiment of this disclosure, in step S2, the power of the low-frequency ultrasonic transducer is 30-100 W and the duty cycle is ≤50%; the rotational speed of the mechanical stirring paddle is 100-300 rpm.

[0012] For example, in the method for microbial limit testing of poorly soluble powdered pharmaceutical products provided in at least one embodiment of this disclosure, in steps S1 and S4, the sterile diluent and rinsing solution are both 0.1% peptone aqueous solutions containing 0.1% Tween 80.

[0013] For example, in the method for microbial limit testing of poorly soluble powdered pharmaceutical products provided in at least one embodiment of this disclosure, the poorly soluble powdered pharmaceutical product is one or more of antibiotic raw materials, traditional Chinese medicine extracts, microcrystalline cellulose, or hormone powders.

[0014] (III) Beneficial Effects Compared with the prior art, the present invention provides an integrated microbial testing device and method for poorly soluble powdered drugs, which has the following beneficial effects: Firstly, it solves the problem of filter membrane clogging. Ultrasonic mixing combined with stirring makes the insoluble powder a uniform suspension, forming a loose filter cake, which greatly improves the filtration speed. Secondly, it improves the release of microorganisms. The ultrasonic cavitation effect destroys the adsorption of microorganisms by particles, and the recovery rate is higher than that of traditional methods. At the same time, it realizes integrated closed operation, avoiding exogenous contamination and personnel exposure during sample transfer. It also protects the activity of microorganisms. Low-frequency, short-time ultrasound combined with constant temperature control greatly improves the survival rate of microorganisms. Attached Figure Description

[0015] To more clearly illustrate the technical solutions of the embodiments of this disclosure, the accompanying drawings of the embodiments will be briefly described below. Obviously, the drawings described below only relate to some embodiments of this disclosure and are not intended to limit this disclosure.

[0016] Figure 1 This is a schematic diagram of the structure of an integrated microbial testing device for a poorly soluble powdered drug according to the present invention.

[0017] In the diagram: 1. Stainless steel sealed tank; 2. Tank top cover; 3. Sample feeding port; 4. Diluent inlet; 5. Mechanical stirrer; 6. Low-frequency ultrasonic transducer; 7. Ultrasonic power controller; 8. Thermostatic jacket; 9. Microporous filter membrane; 10. Filter membrane support plate; 11. Vacuum filtration port; 12. Waste liquid discharge valve; 13. Pressure balancing valve; 14. Sight glass. Detailed Implementation

[0018] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] It should be understood that in the various embodiments of the present invention, the sequence number of each process does not imply the order of execution. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present invention.

[0020] It should be understood that in this invention, "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion, for example, a process, method, system, product, or device that includes a series of steps or units is not necessarily limited to those steps or units that are explicitly listed, but may include other steps or units that are not explicitly listed or that are inherent to such process, method, product, or device.

[0021] The applicant's research revealed that non-water-soluble test samples require membrane filtration for microbial limit testing. For poorly soluble powdered drugs, such as amoxicillin raw material, berberine hydrochloride, microcrystalline cellulose, and poorly soluble traditional Chinese medicine extract powder, existing methods suffer from three major drawbacks: 1. Membrane clogging: Incompletely dissolved powder particles quickly clog the 0.45μm membrane during direct filtration, leading to filtration times of several hours or even failure to complete the process. 2. Insufficient microbial release: Microorganisms adhere to the inside or surface of the particles, and simple shaking alone cannot wash them into the filtrate, resulting in significantly lower counts (false negatives). 3. Cumbersome and contaminated operation: Traditional processes require manual shaking to dissolve the powder in a container before transferring it to the filtration device. This transfer process exposes the sample to the environment, increasing the risk of exogenous contamination and is time-consuming and labor-intensive. Although some studies have attempted to use ultrasonic treatment to help disperse the powder, the energy of conventional ultrasonic cleaners is uncontrollable and can easily damage microorganisms. Furthermore, since ultrasonication and filtration are performed in separate steps, there is still a risk of transfer contamination, indicating room for improvement.

[0022] Based on the above ideas, at least one embodiment of this disclosure provides an integrated microbial testing device for poorly soluble powdered pharmaceutical products, such as... Figure 1 As shown, it mainly includes a tank body 1, a mechanical stirring paddle 5, a low-frequency ultrasonic transducer 6, a constant temperature jacket 8, a microporous filter membrane 9, a filter membrane support plate 10, a vacuum filtration port 11, and a pressure balancing valve 13.

[0023] The tank body 1 is made of 316L stainless steel and has a sealable structure. It can withstand pressures of -0.1 to 0.05 MPa. The top of the tank body 1 is equipped with a sample feeding port 3 and a diluent inlet 4. The sample feeding port 3 adopts a quick-opening clamp structure for easy and rapid addition of powder samples. The diluent inlet 4 is equipped with a valve for quantitative addition of diluent and rinsing solution. The tank body 1 includes a tank top cover 2, which is sealed to the tank body by clamps to ensure a fully enclosed operation.

[0024] The mechanical stirring paddle 5 is located inside the upper part of the tank 1. It adopts a double-layer blade structure and is driven by a motor located above the tank. The speed can be adjusted in the range of 50 to 500 rpm, with the preferred operating speed being 100 to 300 rpm. The stirring paddle 5 is located in the upper space inside the tank, and its rotation area does not interfere with the bottom filter membrane. It is used to keep the powder sample in suspension in the diluent.

[0025] The low-frequency ultrasonic transducer 6 is attached to the lower part of the outer wall of the tank 1, with a frequency of 20-40 kHz, preferably 30 kHz. The ultrasonic transducer 6 is controlled by an external ultrasonic power controller, and the power can be adjusted in the range of 30-100W. The duty cycle is adjustable, preferably ≤50%. The ultrasonic transducer 6 is installed at the bottom of the tank so that the ultrasonic energy can directly act on the suspension near the bottom of the tank, generate a cavitation effect to break the agglomeration of powder particles, and promote the release of microorganisms attached to the inside or surface of the particles into the diluent.

[0026] The thermostatic jacket 8 is wrapped around the outer wall of the tank 1, preferably around the middle of the outer wall. The thermostatic jacket 8 is connected to a circulating water bath to control the temperature inside the tank at 20-25°C, preventing damage to microorganisms due to excessive heat generation during ultrasonic treatment, and providing a suitable temperature environment for microorganisms.

[0027] The microporous filter membrane 9 is installed at the bottom of the tank 1 with a pore size of 0.45μm. Below the microporous filter membrane 9, there is a filter membrane support plate 10. The filter membrane support plate 10 is a porous sintered metal plate, which can not only uniformly support the filter membrane and prevent the filter membrane from being damaged during filtration, but also make the filtration fluid evenly distributed, ensuring uniform filtration effect.

[0028] The vacuum filtration port 11 is located below the filter membrane support plate 10 and is connected to the inside of the tank 1. It is used to connect a vacuum pump for filtration operation. A waste liquid discharge valve 12 can also be installed below the vacuum filtration port 11 for discharging waste liquid.

[0029] The pressure balancing valve 13 is installed on the tank body 1 and is used to connect to the 0.22 μm sterile filter. During the filtration operation, opening the pressure balancing valve 13 allows the inside of the tank to communicate with the outside atmosphere. After sterile filtration, pressure balance is achieved while preventing external microbial contamination.

[0030] In addition, two sets of pipe fittings can be installed on the upper surface of the tank body 1. The left pipe fitting is provided with a diluent inlet 4 and a sample feeding port 3 from bottom to top. The right pipe fitting is provided with an observation mirror 14, a tank top cover 2 and a pressure balance valve 13 from bottom to top. The observation mirror 14 is equipped with an illumination device, which makes it easy for operators to observe the dispersion state of the powder in the tank and the filtration process.

[0031] According to another aspect of the present invention, a method for performing microbial limit testing on a poorly soluble powdered pharmaceutical product using the above-described apparatus is also provided, comprising the following steps: S1. Adding Sample and Diluent: Before using the device, assemble tank 1 without the filter membrane. Sterilize the filter membrane separately by performing moist heat sterilization at 121°C for 30 minutes. Under aseptic conditions, install a sterile 0.45μm microporous filter membrane 9, close all valves, weigh an appropriate amount of the poorly soluble powdered drug, and add it to tank 1 through sample inlet 3. Then, add sterile diluent through diluent inlet 4, preferably a 0.1% peptone aqueous solution containing 0.1% Tween 80.

[0032] S2. Ultrasonic dispersion and stirring: Turn on the circulating water bath of the constant temperature jacket 8 to control the temperature inside the tank at 20-25℃. At the same time, turn on the mechanical stirrer 5 and the low-frequency ultrasonic transducer 6 to process the sample. The rotation speed of the stirrer 5 is preferably 100-300 rpm to suspend the powder as a whole in the diluent. The power of the ultrasonic transducer 6 is 30-100W with a duty cycle ≤50% to generate cavitation effect to destroy the agglomeration structure of the powder particles and release the attached microorganisms. The stirring and ultrasonic work together for 1-3 minutes to ensure that the powder is completely dispersed into a uniform suspension and that the activity of the microorganisms is not significantly affected.

[0033] S3. Vacuum Filtration: Turn off the mechanical agitator 5 and the low-frequency ultrasonic transducer 6. First, open the pressure balancing valve 13 to balance the pressure inside and outside the tank. Then, ventilate through the 0.22μm sterile filter. Next, open the vacuum filtration port 11 to connect the vacuum pump for filtration. The liquid passes through the microporous filter membrane 9, and microorganisms and powder particles are trapped on the surface of the filter membrane. Since the powder has been fully dispersed by ultrasonication and stirring, a loosely structured porous filter cake is formed on the filter membrane, rather than the dense hard block formed by powder agglomeration in traditional methods. Therefore, the filtration speed is fast and the filter pores are not blocked.

[0034] S4. Rinse the filter membrane: Add rinsing solution through dilution inlet 4 and continue filtration to rinse the filter membrane for any residual substances that may have antibacterial activity, ensuring that microorganisms can grow normally during culture.

[0035] S5. Membrane culture: Close the vacuum, open the top cover 2 of the tank, use sterile tweezers to remove the microporous filter membrane 9, and place it with the bacterial side up on a suitable culture medium for culture and counting.

[0036] The following describes an integrated microbial testing device and method for poorly soluble powdered pharmaceutical products provided in this disclosure through several specific embodiments.

[0037] Example 1 Microbial limit testing of amoxicillin raw material: The sample was amoxicillin raw material, which is poorly soluble in water and has a particle size D90 of about 50 μm. It is known to have β-lactam antibacterial activity. The test strain was Staphylococcus aureus (CMCC(B)26003), and the concentration of the bacterial suspension was about 100 CFU / mL.

[0038] Operating Procedures: Weigh 5 g of amoxicillin raw material and add 1 mL of Staphylococcus aureus bacterial suspension (approximately 100 CFU). Let it stand at room temperature for 30 minutes to allow the bacteria to adhere to the powder surface. Place the inoculated sample into container 1 and add 100 mL of sterile diluent. Turn on the constant temperature jacket 8 and the circulating water bath, controlling the temperature at 22℃. Simultaneously, turn on the mechanical stirrer 5 at 200 rpm and the low-frequency ultrasonic transducer 6 at 30 kHz, 50 W, and 50% duty cycle, and continue processing for 2 minutes. Turn off the stirring and ultrasonic treatment, turn on the pressure balance valve 13 and the vacuum filtration port 11, and filter under a vacuum of -0.05 MPa. Add 300 mL of rinsing solution and continue filtration and rinsing. Turn off the vacuum, remove the filter membrane, attach it to a TSA plate, and incubate at 33℃ for 3 days. Count the number of colonies.

[0039] Control group 1 used the traditional method, where the sample was manually shaken in an Erlenmeyer flask for 5 minutes and then filtered through a regular membrane filter; control group 2 used the stepwise ultrasonic method, where the sample was ultrasonically treated in a beaker with the same parameters for 2 minutes and then transferred to a regular filter for filtration. The characteristic data are shown in Table 1.

[0040] Table 1 Comparison of Microbial Limit Test Results for Amoxicillin Raw Material The characteristic data show that the filtration time of the device of the present invention is only 45 seconds, which is far superior to the traditional method; the microbial recovery rate reaches 92%. Although the control group 2 used the same ultrasonic parameters, it was processed in an open beaker and then transferred. Not only did some of the bacterial liquid be lost due to the transfer process, but it also did not form an in-situ suspended state when transferred to the filter, resulting in a dense and slightly clogged filter cake, and the recovery rate was only 68%.

[0041] Example 2 Microbial limit test for microcrystalline cellulose (MCC): The sample was microcrystalline cellulose PH102, which is poorly soluble in water and easily swells when it absorbs water. The test strain was Bacillus subtilis (CMCC(B)63501). The operation method was basically the same as in Example 1, except that the ultrasonic treatment time was adjusted to 1.5 minutes. The characteristic data are shown in Table 2.

[0042] Table 2 Comparison of Microcrystalline Cellulose (MCC) Microbial Limit Test Results The filtration process of this invention takes only 35 seconds and has a recovery rate of 88%. Traditional shaking methods are completely unable to complete filtration because the microcrystalline cellulose absorbs water and expands, causing severe clogging of the filter membrane. In stepwise ultrasonic methods, parallel plates are contaminated by environmental bacteria during the transfer process. However, the fully enclosed operation of this invention effectively avoids external contamination.

[0043] Example 3 The effect of ultrasound time on microbial survival rate: To determine the optimal ultrasonic treatment time, Staphylococcus aureus suspension without sample powder was used to evaluate the microbial survival rate under different ultrasonic treatment times. The ultrasonic conditions were 30 kHz frequency, 50 W power, and 50% duty cycle, with the temperature controlled at 22℃ by the constant temperature jacket. The treatment times were 0.5, 1, 2, 3, and 4 minutes, respectively. The bacterial suspension without ultrasonic treatment was used as a control. The characteristic data are shown in Table 3.

[0044] Table 3. Effect of ultrasonic treatment time on the survival rate of Staphylococcus aureus The results showed that the microbial survival rate remained above 91% after 2 minutes of ultrasonic treatment, dropped to 85% after 3 minutes, and plummeted to 72% after 4 minutes of ultrasonic treatment, which was close to the lower limit threshold usually required by the pharmacopoeia for microbial recovery rate. Therefore, choosing a total ultrasonic treatment time of no more than 3 minutes can ensure that the powder is fully dispersed and the microorganisms are effectively released, while keeping the loss of microbial activity within an acceptable range.

[0045] In summary, the integrated microbial testing device and method for poorly soluble powdered drugs provided by this invention, through the synergistic effect of low-frequency ultrasound and mechanical stirring, fully disperses the poorly soluble powder into a uniform suspension in the diluent. During filtration, a loose filter cake is formed on the filter membrane surface, increasing the filtration speed several times. The ultrasonic cavitation effect can effectively destroy the physical adsorption and encapsulation of microorganisms by powder particles, significantly increasing the microbial recovery rate from 10%–30% in traditional methods to 85%–95%, effectively reducing the risk of false negatives. Sample addition, dispersion, filtration, and rinsing are all completed sequentially in the same sealed container, eliminating the need to open the container to transfer samples and avoiding exogenous microbial contamination introduced by open operations in traditional methods. The use of low-frequency, low-power, short-duration ultrasonic processing, combined with precise temperature control by a constant-temperature jacket, minimizes the thermal and mechanical damage of ultrasound to microorganisms, ensuring the authenticity of the test results.

[0046] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. An integrated microbial testing device for poorly soluble powdered pharmaceuticals, characterized in that, include: The tank (1) has a sealable structure and is provided with a sample feeding port (3) and a diluent inlet (4) at the top. A mechanical stirring paddle (5) is positioned above the inside of the tank (1); A low-frequency ultrasonic transducer (6) is installed on the lower part of the outer wall of the tank (1) with a frequency of 20 to 40 kHz; A constant temperature jacket (8) is used to cover the outer wall of the tank (1); A microporous filter membrane (9) is installed at the bottom of the tank (1); A filter membrane support plate (10) is disposed below the microporous filter membrane (9) to support the filter membrane; The vacuum filtration port (11) is located below the filter membrane support plate (10) and communicates with the inside of the tank (1); A pressure balancing valve (13) is installed on the tank body (1) and is used to connect a sterile filter to balance the pressure inside and outside the tank body.

2. The integrated microbial testing device for poorly soluble powdered drugs according to claim 1, characterized in that, The thermostatic jacket (8) covers the middle part of the outer wall of the tank (1).

3. The integrated microbial testing device for poorly soluble powdered drugs according to claim 1, characterized in that, It also includes an external ultrasonic power controller for adjusting the power and duty cycle of the low-frequency ultrasonic transducer (6), with the power adjustment range being 30 to 100 W; the mechanical stirring paddle (5) is a double-layered blade with an adjustable speed range of 50 to 500 rpm.

4. The integrated microbial testing device for poorly soluble powdered drugs according to claim 1, characterized in that, The thermostatic jacket (8) is used to connect to the circulating water bath to control the temperature inside the tank at 20-25°C.

5. The integrated microbial testing device for poorly soluble powdered drugs according to claim 1, characterized in that, The microporous filter membrane (9) has a pore size of 0.45 μm, and the filter membrane support plate (10) is a porous sintered metal plate.

6. The integrated microbial testing device for poorly soluble powdered drugs according to claim 1, characterized in that, The tank (1) includes a tank top cover (2), which is sealed to the tank by a clamp, and the tank (1) can withstand a pressure of -0.1 to 0.05 MPa.

7. A method for performing microbial limit testing on poorly soluble powdered pharmaceutical products using the apparatus of claim 1, characterized in that, Includes the following steps: S1. Add the poorly soluble powdered drug into the tank (1) through the sample feeding port (3), and add sterile diluent through the diluent inlet (4); S2. Turn on the mechanical stirring paddle (5) and the low-frequency ultrasonic transducer (6) to disperse the powder into a suspension in the diluent. At the same time, the temperature inside the tank is controlled at 20-25°C by the constant temperature jacket (8). The total ultrasonic treatment time is ≤3 minutes. S3. Turn off the agitator (5) and ultrasonic transducer (6), and turn on the pressure balance valve (13) and vacuum filtration port (11) to perform filtration, so that the liquid passes through the microporous filter membrane (9) and microorganisms are trapped on the filter membrane. S4. Add rinsing solution through the diluent inlet (4) and continue filtration to rinse the filter membrane; S5. Remove the microporous filter membrane (9) and perform culture and counting.

8. The method according to claim 7, characterized in that, In step S2, the power of the low-frequency ultrasonic transducer (6) is 30-100 W and the duty cycle is ≤50%; the rotation speed of the mechanical stirring paddle (5) is 100-300 rpm.

9. The method according to claim 7, characterized in that, In steps S1 and S4, the sterile diluent and rinsing solution are both 0.1% peptone aqueous solutions containing 0.1% Tween 80.

10. The method according to claim 7, characterized in that, The poorly soluble powdered drug is one or more of the following: antibiotic raw materials, traditional Chinese medicine extracts, microcrystalline cellulose, or hormone powders.

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