Supercritical fluid preparation method of insoluble drug nanoparticles and supercritical granulation device

Abstract

The invention relates to the technical field of pharmaceutical preparations and devices, in particular to a supercritical fluid preparation method of insoluble drug nanoparticles and a supercritical granulation device.The preparation method comprises the following steps that an insoluble drug solution is prepared; mixing the prepared indissolvable drug solution with the supercritical fluid in front of a nozzle at a specified temperature and pressure; the supercritical fluid is used as an anti-solvent, and the solution and the supercritical fluid form drug particles in front of a nozzle; reducing the pressure of the material through a nozzle, forming a gas phase by the solvent and gas, forming a solid phase by the drug particles, separating and drying the solid phase, and collecting nano particles; the gas phase is condensed and then subjected to gas-liquid separation, and both the gas and the solvent can be recycled. According to the preparation method, a green process is adopted, no toxic solvent exists in the whole process, GMP specifications are met, the efficient drug loading effect is achieved, drug crystallization is avoided through the supercritical technology, and molecular-level dispersion is achieved. The morphology and the drug loading capacity of the nanoparticles are accurately controlled by adjusting parameters such as pressure and temperature.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations and devices, and particularly relates to a method for preparing nanoparticles of poorly soluble drugs by supercritical fluid and a supercritical granulation device. Background Art

[0002] Poorly soluble drugs (such as the anticancer drug axitinib and the antifungal drug itraconazole) have poor bioavailability due to low water solubility. Traditional nanoparticle preparation techniques (such as the emulsification method and the solvent evaporation method) have problems such as residual organic solvents, uneven particle size distribution, and complex processes. Although poligelatin (a gelatin derivative) has good biocompatibility and biodegradability, it is difficult to efficiently combine it with poorly soluble drugs by conventional methods.

[0003] The formation of particles using supercritical fluids has been studied for decades, and many methods have been developed. Using supercritical CO2 and nitrogen as green solvents can replace toxic organic solvents and avoid the risk of residues. By adjusting parameters such as pressure and temperature, the morphology and drug loading of nanoparticles can be precisely controlled using the supercritical granulation method. Process continuity can be achieved, which is beneficial for scale-up production. Summary of the Invention

[0004] One of the objectives of the present invention is to provide a method for preparing nanoparticles of poorly soluble drugs by supercritical fluid, which has a simple preparation method and can precisely control the morphology and drug loading of nanoparticles.

[0005] Another objective of the present invention is to provide a supercritical granulation device with a simple structure, which can achieve process continuity and is beneficial for scale-up production.

[0006] The solution adopted by the present invention to achieve the first objective is: a method for preparing nanoparticles of poorly soluble drugs by supercritical fluid, comprising the following steps:

[0007] Step 1: Prepare a solution of the poorly soluble drug;

[0008] Step 2: Mix the prepared solution of the poorly soluble drug with the supercritical fluid in front of the nozzle at a specified temperature and pressure;

[0009] Step 3: The supercritical fluid serves as an antisolvent, and the solution and the supercritical fluid form drug particles in front of the nozzle;

[0010] Step 4: The material is depressurized through the nozzle, the solvent and the gas form a gas phase, the drug particles form a solid phase, and the solid phase is separated, dried and then the nanoparticles are collected; the gas phase is condensed and then subjected to gas-liquid separation, and both the gas and the solvent can be recycled.

[0011] Preferably, in the above Step 1, the preparation of the solution of the poorly soluble drug includes two methods, which are respectively:

[0012] A. Mix gelatin polypeptide injection with pure water or a buffer solution with a pH value of 6.5 ± 0.1 to prepare a gelatin polypeptide solution with a protein concentration of 1 - 20 mg / mL, where the substitution degree of gelatin polypeptide is 10% - 30% and the molecular weight is 5 - 50 kDa. Prepare a solution of the poorly soluble drug with a co - solvent at a concentration of 1 - 20 mg / mL, and mix the two solutions in a certain mass ratio to form a homogeneous solution to obtain the poorly soluble drug solution.

[0013] B. Use a co - solvent to extract the poorly soluble drug raw material by Soxhlet extraction to obtain the poorly soluble drug solution.

[0014] In method A, after mixing gelatin polypeptide and the poorly soluble drug, combine them through the supercritical antisolvent (SAS - A) technology to form stable nanoparticles, achieving efficient drug loading and controlled release. The newly developed process can also realize the reuse of supercritical gases (carbon dioxide or nitrogen) and solvents, achieving green production and facilitating industrial scale - up.

[0015] In method B, the poorly soluble drug raw material is further increased in the content of active ingredients through Soxhlet extraction, and then prepared into nanoparticles by the supercritical antisolvent method, which can further increase the water solubility of the prepared drug. Combine the efficient cyclic extraction of Soxhlet extraction with the rapid antisolvent precipitation of supercritical fluids to achieve "extraction - purification - nanonization" integration. Use the co - solvent of Soxhlet extraction as the entrainer of supercritical fluids to enhance the dissolution and nano - forming ability of polar drugs. Integrate a supercritical antisolvent (SAS) module in the Soxhlet extraction device, and obtain high - purity nano - drug particles in one step through solvent recycling and supercritical instantaneous nanonization.

[0016] Preferably, the mass ratio of the poorly soluble drug to gelatin polypeptide is 1:2 - 25.

[0017] Preferably, the poorly soluble drug is at least one of paclitaxel, ritonavir, itraconazole, tamoxifen, atorvastatin, ketoconazole; and the co - solvent is ethanol, acetone or dimethyl sulfoxide.

[0018] Preferably, in the second step, the supercritical fluid is carbon dioxide or nitrogen, the pressure is 8 - 30 MPa, the temperature is 35 - 60 °C, and the gas flow rate is 2 - 5 L / min.

[0019] Pump the poorly soluble drug solution and the supercritical fluid into the mixing tube of the supercritical reaction at a volume ratio of (1:5 to 1:20).

[0020] The supercritical fluid acts as an antisolvent, causing the drug in the extract to precipitate instantaneously in supersaturation, while the co - solvent is carried away by the gas and recycled to the system for reuse.

[0021] Preferably, in the fourth step, the particle size of the nanoparticles is 50 - 300 nm.

[0022] The second solution adopted to achieve the object of the present invention is: a supercritical granulation device for implementing the described preparation method, including a gas feeding unit, a liquid feeding unit, a supercritical granulation unit, and a recovery and recycling unit.

[0023] Among them, the supercritical granulation unit includes a mixing tube, a nozzle, a cyclone separator, and a gas-solid centrifugal separator that are connected in sequence. The gas-solid centrifugal separator is connected to the recovery and recycling unit through a pipeline.

[0024] The liquid feeding unit includes a mixing device, a metering and pressurizing pump, and a first heat exchanger that are connected in sequence. The first heat exchanger is connected to the mixing tube through a pipeline.

[0025] The discharge of the gas feeding unit enters the mixing tube and mixes with the discharge of the first heat exchanger.

[0026] The solid discharge of the gas-solid centrifugal separator is the required product. The gas discharge is separated into gas and liquid by the recovery and recycling unit and then transported to the liquid feeding unit and the gas feeding unit respectively for recycling.

[0027] Preferably, the mixing device is a mixing tank or a Soxhlet extractor.

[0028] Preferably, the liquid feeding unit includes a gas tank, a second heat exchanger, a compressor, and a third heat exchanger that are connected in sequence. The third heat exchanger is connected to the mixing tube through a pipeline.

[0029] Preferably, the recovery and recycling unit includes a fourth heat exchanger and a gas-liquid separator that are connected in sequence. The gas-solid centrifugal separator is connected to the fourth heat exchanger through a pipeline. The gas-liquid separator is connected to the gas feeding unit and the mixing device through pipelines respectively.

[0030] The present invention has the following advantages and beneficial effects:

[0031] The preparation method of the present invention adopts a green process, without toxic solvents throughout the process, conforms to GMP specifications, has a high drug loading effect, and the supercritical technology avoids drug crystallization and realizes molecular-level dispersion. By adjusting parameters such as pressure and temperature, the morphology and drug loading of nanoparticles can be accurately controlled.

[0032] The device of the present invention has a simple structure, can realize continuous process, and is suitable for industrial production.

[0033] The preparation method and device of the present invention can be widely applied to the dosage form development of poorly soluble drugs such as anti-cancer drugs, anti-fungal drugs, and anti-viral drugs, and have the advantages of high drug loading, low toxicity, and easy large-scale production. Description of the Drawings

[0034] Figure 1Schematic structural diagram of the supercritical granulation device according to Embodiment 1 of the present invention;

[0035] Figure 2 Schematic structural diagram of the supercritical granulation device according to Embodiment 2 of the present invention;

[0036] Figure 3 SEM electron micrograph of the nanoparticles prepared in Embodiment 4 of the present invention;

[0037] Figure 4 Particle size distribution diagram of the nanoparticles prepared in Embodiment 4 of the present invention;

[0038] Figure 5 SEM electron micrograph of the nanoparticles prepared in Embodiment 5 of the present invention;

[0039] Figure 6 Particle size distribution diagram of the nanoparticles prepared in Embodiment 5 of the present invention;

[0040] Figure 1 and Figure 2 In, 1. gas tank; 2. second heat exchanger; 3. compressor; 4. second check valve; 5. third heat exchanger; 6. second temperature measuring instrument; 7. mixing device; 8. first metering and pressurizing pump; 9. first heat exchanger; 10. first temperature measuring instrument; 11. first pressure gauge; 12. first check valve; 13. mixing pipe; 14. nozzle; 15. cyclone separator; 16. gas-solid centrifugal separator; 17. third check valve; 18. fourth heat exchanger; 19. third temperature measuring instrument; 20. gas-liquid separator; 21. second metering and pressurizing pump; 22. second pressure gauge; 23. fourth check valve; 24. third pressure gauge; 25. back pressure valve. Detailed implementation manners

[0041] For a better understanding of the present invention, the following embodiments are further descriptions of the present invention, but the content of the present invention is not limited to the following embodiments only.

[0042] Embodiment 1

[0043] As Figure 1 shown, a supercritical granulation device for implementing the described preparation method includes a gas feeding unit, a liquid feeding unit, a supercritical granulation unit, and a recovery and recycling unit.

[0044] Among them, the supercritical granulation unit includes a mixing pipe 13, a nozzle 14, a cyclone separator 15, and a gas-solid centrifugal separator 16 that are connected in sequence, and the gas-solid centrifugal separator 16 is connected to the recovery and recycling unit through a pipeline;

[0045] The liquid feeding unit includes a mixing device 7, a first metering and pressurizing pump 8, and a first heat exchanger 9 that are connected in sequence, and the first heat exchanger 9 is connected to the mixing pipe 13 through a pipeline;

[0046] The discharge of the gas feeding unit enters the mixing pipe 13 and mixes with the discharge of the first heat exchanger 9;

[0047] The solid discharge of the gas-solid centrifugal separator 16 is the required product, and the gas discharge is separated by the gas-liquid separation in the recovery and recycling unit and then transported to the liquid feeding unit and the gas feeding unit respectively for recycling.

[0048] In this embodiment, the mixing device 7 is a mixing tank.

[0049] In this embodiment, the liquid feeding unit includes a gas tank 1, a second heat exchanger 2, a compressor 3, and a third heat exchanger 5 that are connected in sequence. The third heat exchanger 5 is connected to the mixing pipe 13 through a pipeline.

[0050] In this embodiment, the recovery and recycling unit includes a fourth heat exchanger 18 and a gas-liquid separator 20 that are connected in sequence. The gas-solid centrifugal separator 16 is connected to the fourth heat exchanger 18 through a pipeline. The gas-liquid separator 20 is connected to the gas feeding unit and the mixing device 7 through pipelines respectively.

[0051] Specifically, in the liquid feeding unit, the mixing device 7 is connected to the first metering and pressurizing pump 8 through a pipeline, and a valve is provided between the two. A first temperature measuring instrument 10 and a first pressure gauge 11 are also provided on the first heat exchanger 9. The first heat exchanger 9 is connected to the mixing pipe 13 through a pipeline, and a valve and a first check valve 12 are provided in sequence between the two along the liquid transportation direction.

[0052] In the gas feeding unit, a valve is provided between the gas tank 1 and the second heat exchanger 2. The compressor 3 and the third heat exchanger 5 are connected through a pipeline, and a second check valve 4 and a valve are provided in sequence between the two along the gas transportation direction; a second temperature measuring instrument 6 is provided on the third heat exchanger 5. The third heat exchanger 5 and the mixing pipe 13 are connected through a pipeline, and a valve is provided between the two.

[0053] In the supercritical granulation unit, the nozzle 14 is arranged at the discharge port of the mixing pipe 13. The mixing pipe 13 is of a sleeve structure, wherein the inner layer pipeline transports liquid and the outer layer pipeline transports gas. The liquid and gas are mixed at the nozzle 14. The discharge of the nozzle 14 directly enters the cyclone separator 15. After the large-particle-size particles are separated by the cyclone separator 15, the small particles of the discharge further enter the gas-solid centrifugal separator 16 for drying and screening out the particles with the target particle size. The solid discharge is the subsequent product, and the gas discharge enters the recovery and recycling system.

[0054] In the recycling system, the gas-solid centrifugal separator 16 is connected to the fourth heat exchanger 18 through a pipeline. A valve and a third check valve 17 are arranged in sequence between them along the gas transportation direction. A third temperature measuring instrument 19 is also arranged on the fourth heat exchanger 18. After the liquid in the gas is condensed by the fourth heat exchanger 18, it is transported to the gas-liquid separator 20 for gas-liquid separation. The gas-liquid separator 20 is connected to the second heat exchanger 2 through a pipeline. A valve, a second metering and pressurizing pump 21, a second pressure gauge 22, and a fourth check valve 23 are arranged in sequence between them along the gas transportation direction. The gas-solid centrifugal separator 16 is also connected to the mixing device 7 through a pipeline, and a valve is arranged between them.

[0055] There is also a connection through a pipeline between the gas tank 1 and the second check valve 4. A third pressure gauge 24 and a back pressure valve 25 are arranged in sequence along the gas reflux direction.

[0056] The working process of this device is as follows: The gas output from the gas tank 1 enters the compressor 3 for pressurization after being dried by the second heat exchanger 2, and then enters the third heat exchanger 5 for heating to make the gas reach the supercritical state and is transported to the outer pipeline of the mixing pipe 13. The liquid material output from the mixing device 7 is pressurized by the first metering and pressurizing pump 8 and then reaches the specified temperature and pressure through the first heat exchanger 9 and is transported to the inner pipeline of the mixing pipe 13 through a pipeline. The supercritical fluid and the solution are mixed at the nozzle 14. The supercritical fluid serves as an anti-solvent, and the mixing with the solution causes an instant decrease in the solvation ability, resulting in the formation of a supersaturated solution of the solute in the solution and triggering crystallization. The solution and the supercritical fluid form nanoparticles in front of the nozzle 14 of the mixing pipe 13; the material is depressurized through the nozzle 14, the solvent and the gas form a gas phase, and the nanoparticles form a solid phase. After being separated by the cyclone separator 15, they enter the gas-solid centrifugal separator 16, and dry nanoparticles are collected at the bottom of the gas-solid centrifugal separator 16; after the gas phase is condensed by the fourth heat exchanger 18, it is separated by the gas-liquid separator 20 again. The gas phase returns to the system for recycling through the second metering and pressurizing pump 21; the liquid passes through the bottom valve of the gas-liquid separator 20 and relies on gravity to flow back to the mixing device 7 from the highest point for recycling.

[0057] Example 2

[0058] As Figure 2 shown, the difference between this embodiment and Embodiment 1 is that the mixing device 7 is a Soxhlet extractor. The supercritical granulation device of this embodiment can be used for raw materials that need to extract effective components from the original raw materials first.

[0059] Example 3

[0060] A method for preparing nanoparticles of a poorly soluble drug by supercritical fluid, comprising the following steps:

[0061] Step 1: Prepare a polygelatin peptide solution with a protein concentration of 1 - 20 mg / mL;

[0062] Step 2: Prepare a solution of the poorly soluble drug and a co-solvent at a concentration of 1 - 20 mg / mL;

[0063] Step 3: Mix the solution prepared in Step 1 and the solution prepared in Step 2 of the poorly soluble drug and polypeptone in a certain mass ratio to form a homogeneous solution;

[0064] Step 4: Mix the solution obtained in Step 3 with a supercritical fluid in front of the nozzle at a specified temperature and pressure;

[0065] Step 5: The supercritical fluid acts as an anti-solvent and rapidly diffuses into the solution, causing the solvent expansion degree to drop suddenly. The solution and the supercritical fluid form drug-polypeptone nanoparticles in front of the nozzle;

[0066] Step 6: The material passes through the nozzle to reduce the pressure. The solvent and the gas form a gas phase, and the drug-polypeptone nanoparticles form a solid phase. The solid phase is separated, dried, and then the nanoparticles are collected; The gas phase is condensed and then undergoes gas-liquid separation, and both the gas and the solvent can be recycled.

[0067] In the said Step 1, mix the polypeptone injection with pure water or a buffer solution with a pH value of 6.5 ± 0.1 to prepare a polypeptone solution. The substitution degree of polypeptone is 10% - 30%, and the molecular weight is 5 - 50 kDa.

[0068] In the said Step 2, the poorly soluble drug is at least one of paclitaxel, ritonavir, itraconazole, tamoxifen, atorvastatin, ketoconazole, and the co-solvent is ethanol, acetone or dimethyl sulfoxide.

[0069] In the said Step 3, the mass ratio of the poorly soluble drug to polypeptone is 1:2 - 25.

[0070] In the said Step 4, the supercritical fluid is carbon dioxide or nitrogen, the pressure is 8 - 30 MPa, and the temperature is 35 - 60 °C. The mixed solution and the supercritical fluid are pumped into the mixing tube of the supercritical device at a volume ratio of 1:5 - 1:20. The flow rate of the gas is 2 - 5 L / min.

[0071] In the said Step 6, the particle size of the nanoparticles is 50 - 300 nm, the drug loading is 10% - 30%, and the encapsulation efficiency is ≥ 85%.

[0072] Furthermore, this embodiment further includes the following steps:

[0073] Step 7: After the gas phase formed by the solvent and the gas is condensed by the fourth heat exchanger, it is then separated by a gas-liquid separator, and the gas phase returns to the system for recycling through the second metering and pressurizing pump;

[0074] Step 8: Open the bottom valve of the gas-liquid separator, and the solvent relies on gravity to flow back to the mixing tank from the highest point for recycling.

[0075] Example 4

[0076] Prepare paclitaxel-polygelatin peptide nanoparticles using the apparatus of Example 1, including the following steps:

[0077] (1) Take 10 mL of the prepared polygelatin peptide solution (10 mg / mL) and 10 mL of the paclitaxel solution (3 mg / mL), and place them in a stirring tank and stir for 30 min.

[0078] (2) Open the gas cylinder, start the compressor, set the temperature at the outlet of the second heat exchanger to 45 °C, adjust the back pressure valve, adjust the air pressure to 15 MPa. When the supercritical fluid CO₂ reaches the specified temperature and pressure, it first enters the mixing tube, and the flow rate of CO₂ is 2 - 5 L / min;

[0079] (3) Set the temperature at the outlet of the first heat exchanger to 45 °C, start the first metering and pressurizing pump, and inject it into the mixing tube after heat exchange through the first heat exchanger at a flow rate of 1 ml / min. The solution and scCO₂ are in a volume ratio of 1:10. The solution and scCO₂ form drug-polygelatin peptide nanoparticles in the mixing tube, and are depressurized through a nozzle. The solvent and CO₂ form a gas phase. After condensation and gas-liquid separation, the liquid-phase solvent is recycled, and the gas phase returns to the system. The drug-polygelatin peptide nanoparticles form a solid phase, which is separated by a cyclone separator, and the dried nanoparticles are collected at the bottom of the separator.

[0080] As Figure 3 shown is the SEM image of the paclitaxel-polygelatin peptide nanoparticles prepared in this example. It can be seen from the figure that the nanoparticles prepared in this example are evenly dispersed and have a uniform particle size.

[0081] As Figure 4 shown is the particle size distribution diagram of the paclitaxel-polygelatin peptide nanoparticles prepared in this example. It can be seen from the figure that the average particle size is 170 ± 15 nm, and PDI = 0.163.

[0082] Detected by HPLC, the drug loading of the nanoparticles prepared in this example is 22%, and the encapsulation efficiency is 89%.

[0083] Example 5

[0084] Prepare curcumin nanoparticles using the apparatus of Example 2, including the following steps:

[0085] The difference from Example 4 is: Raw material treatment: 50 g of turmeric root powder (100 mesh) is loaded into a Soxhlet extractor, 70% ethanol is used as the solvent, the liquid-solid ratio is 15:1, and the extraction is carried out for 8 h.

[0086] Supercritical Nanonization: The extract and scCO₂ are mixed at a volume ratio of 1:10 (volume ratio 1:5 - 1:20, preferably 1:10 in this example), and injected into the mixing tube (pressure 18 MPa, temperature 42 °C). The CO₂ flow rate is 3 L / min, and the treatment is continued for 30 min.

[0087] Other operations are the same as in Example 4.

[0088] As Figure 5 shown is the SEM image of the curcumin nanoparticles prepared in this example. It can be seen from the figure that the nanoparticles prepared in this example are evenly dispersed and have a uniform particle size.

[0089] As Figure 6 shown is the particle size distribution diagram of the curcumin nanoparticles prepared in this example. It can be seen from the figure that the average particle size is 85 ± 12 nm (dynamic light scattering, DLS).

[0090] Solubility: The water solubility of the nano-curcumin prepared in this example is more than 40 times higher than that of commercially available curcumin (determined by HPLC).

[0091] Solvent Recovery Rate: The recycling utilization rate of ethanol > 90%, and the waste is reduced by 70%.

[0092] The above is the preferred implementation manner of the present invention. Of course, the scope of rights of the present invention cannot be limited thereby. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and changes can still be made, and these improvements and changes are also regarded as the protection scope of the present invention.

Claims

1. A supercritical fluid preparation method for poorly soluble drug nanoparticles, characterized in that, It includes the following steps: Step 1: Prepare a poorly soluble drug solution; Step 2: Mix the prepared poorly soluble drug solution with a supercritical fluid in front of a nozzle at a specified temperature and pressure; Step 3: Using the supercritical fluid as an anti-solvent, the solution and the supercritical fluid form drug particles in front of the nozzle; Step 4: The material is depressurized through the nozzle, the solvent and the gas form a gas phase, the drug particles form a solid phase, and the solid phase is collected as nanoparticles after separation and drying; the gas phase is subjected to gas-liquid separation after condensation, and both the gas and the solvent can be recycled.

2. The preparation method of the supercritical fluid of the poorly soluble drug nanoparticles according to claim 1, characterized in that, In the above Step 1, the preparation of the poorly soluble drug solution includes two methods, which are respectively: A. Mix the polypeptan injection with pure water or a buffer solution with a pH value of 6.5±0.1 to prepare a polypeptan solution with a protein concentration of 1-20 mg / mL, a polypeptan substitution degree of 10%-30%, and a molecular weight of 5-50 kDa; prepare a solution of the poorly soluble drug and a co-solvent at a concentration of 1-20 mg / mL, and mix the two solutions in a certain mass ratio to form a homogeneous solution to obtain the poorly soluble drug solution; B. The poorly soluble drug solution is prepared by Soxhlet extraction of the poorly soluble drug raw material with a co-solvent.

3. The preparation method of the supercritical fluid of the poorly soluble drug nanoparticles according to claim 2, wherein, The mass ratio of the poorly soluble drug to polypeptan is 1:2-25.

4. The preparation method of the supercritical fluid of the poorly soluble drug nanoparticles according to claim 2, characterized in that, The poorly soluble drug is at least one of paclitaxel, ritonavir, itraconazole, tamoxifen, atorvastatin, ketoconazole; the co-solvent is ethanol, acetone or dimethyl sulfoxide.

5. The preparation method of the supercritical fluid of the poorly soluble drug nanoparticles according to claim 1, characterized in that, In the above Step 2, the supercritical fluid is carbon dioxide or nitrogen, the pressure is 8-30 MPa, and the temperature is 35-60 °C.

6. The preparation method of the supercritical fluid of the poorly soluble drug nanoparticles according to claim 1, characterized in that, In the above Step 4, the particle size of the nanoparticles is 50-300 nm.

7. A supercritical granulation device for implementing the preparation method according to any one of claims 1-6, characterized in that: It includes a gas feeding unit, a liquid feeding unit, a supercritical granulation unit and a recovery and recycling unit, wherein, the supercritical granulation unit includes a mixing tube, a nozzle, a cyclone separator and a gas-solid centrifugal separator connected in sequence, and the gas-solid centrifugal separator is connected to the recovery and recycling unit through a pipeline; The liquid feeding unit includes a mixing device, a metering and pressurizing pump and a first heat exchanger connected in sequence, and the first heat exchanger is connected to the mixing tube through a pipeline; The outlet of the gas feeding unit enters the mixing tube to be mixed with the outlet of the first heat exchanger; The solid outlet of the gas-solid centrifugal separator is the required product, and the gas outlet is subjected to gas-liquid separation by the recovery and recycling unit and then transported to the liquid feeding unit and the gas feeding unit respectively for recycling.

8. The supercritical granulation device according to claim 7, wherein: The mixing device is a mixing tank or a Soxhlet extractor.

9. The supercritical granulation device according to claim 7, characterized in that: The liquid feeding unit includes a gas tank, a second heat exchanger, a compressor, and a third heat exchanger connected in sequence, and the third heat exchanger is connected to the mixing tube through a pipeline.

10. The supercritical granulation device according to claim 7, characterized in that: The recovery and recycling unit includes a fourth heat exchanger and a gas-liquid separator connected in sequence, the gas-solid centrifugal separator is connected to the fourth heat exchanger through a pipeline, and the gas-liquid separator is connected to the gas feeding unit and the mixing device through pipelines respectively.

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