CN102407028A - Method for preparing polymer or drug particle by continuous supercritical fluid rapid expansion technology - Google Patents

Abstract

The invention discloses a method for preparing polymer or drug granules by continuous supercritical fluid rapid expansion technology, which comprises the following steps: first dissolving the polymer or drug in one or more organic solvents to form an organic solution, and passing through a high-pressure pump Pump into the supercritical carbon dioxide fluid, so that the organic solution and supercritical carbon dioxide fluid are mixed uniformly to form a mixed fluid, and then the organic solvent and supercritical carbon dioxide are rapidly expanded, resulting in a greatly reduced solubility, so that the solute is supersaturated and precipitated to form particles. The invention overcomes the disadvantage that the current anti-solvent method and rapid expansion method are difficult to granulate the solute partially dissolved in the supercritical carbon dioxide fluid, and can successfully carry out continuous granulation.

Description

A method for preparing polymer or drug particles by continuous supercritical fluid rapid expansion technology

technical field

The invention relates to a method for preparing polymer or drug particles by continuous supercritical fluid rapid expansion technology.

Background technique

A supercritical fluid is a fluid whose temperature and pressure are above the critical point. At present, the most researched supercritical fluid is carbon dioxide. Supercritical carbon dioxide fluid has the advantages of non-toxic, non-flammable, relatively cheap, high dissolving capacity, recyclable, and low critical point. Due to the excellent characteristics of supercritical carbon dioxide fluid, supercritical fluid technology has been widely used in the fields of polymer science, pharmacy and preparation of ultrafine particles. At present, there are two main types of supercritical carbon dioxide fluid technology in the preparation of particles: one is the supercritical carbon dioxide fluid rapid expansion method using supercritical carbon dioxide fluid as a solvent, and the other is supercritical carbon dioxide fluid using supercritical carbon dioxide fluid as an antisolvent Anti-solvent method.

The rapid expansion method of supercritical carbon dioxide fluid is to use the characteristic that the dissolving capacity of supercritical carbon dioxide fluid changes with pressure, so that the supercritical carbon dioxide solution dissolved in solute is sprayed into the sedimentation equipment at high speed through a nozzle, and the supercritical carbon dioxide is rapidly discharged in the precipitator. When the pressure is reduced and it expands into a gaseous state, its ability to dissolve solutes decreases rapidly, and the solution is rapidly supersaturated and crystallizes and precipitates solute particles. In the supercritical carbon dioxide fluid rapid expansion method, the solute needs to be dissolved in the supercritical carbon dioxide fluid first, but since most of the polymers and drugs are basically insoluble in the supercritical carbon dioxide fluid, or have low solubility, it greatly limits the ability of supercritical carbon dioxide Application of the rapid expansion method in the preparation of polymer and drug particles. In addition, the supercritical carbon dioxide fluid rapid expansion method is an intermittent operation mode, with a small processing capacity, and cannot continuously expand production, which hinders its industrial application.

When the polymer or medicine to be granulated is insoluble in supercritical carbon dioxide fluid, a solvent capable of dissolving supercritical carbon dioxide fluid can be selected to dissolve the substance. When the supercritical carbon dioxide fluid as an anti-solvent is in full contact with the solution, the supercritical carbon dioxide fluid rapidly diffuses into the solution, the volume of the solution expands, the density decreases, the solubility decreases, and the solution is supersaturated to nucleate and precipitate solute particles. Fundamentals of the critical carbon dioxide fluid antisolvent method. The supercritical carbon dioxide anti-solvent method overcomes the limitations of the supercritical carbon dioxide fluid rapid expansion method. In this method, drugs and/or polymers can be dissolved in one or more organic solvents and then pumped into the supercritical fluid through a high-pressure pump. The carbon dioxide fluid is anti-solvent, and the drug and/or polymer are supersaturated and co-precipitated to obtain the drug, polymer particles or drug-polymer composite particles.

However, when using supercritical carbon dioxide fluid technology to process polymers or drugs partially dissolved in supercritical carbon dioxide fluid, such as amphiphilic polylactic acid-polyethylene glycol-polylactic acid copolymer (PLA-PEG-PLA), if using Anti-solvent method, when the organic solution of the copolymer is sprayed into the supercritical carbon dioxide fluid, the organic solvent will act as a co-solvent, thereby greatly improving the solubility of the copolymer in the supercritical carbon dioxide fluid, so that the copolymer dissolves or dissolves in a small amount The form of liquid droplets is dispersed in the supercritical carbon dioxide fluid, and the solute is also lost through the vent valve along with the carbon dioxide fluid. There is no supersaturated precipitation in the autoclave due to the effect of anti-solvent, so no sample can be obtained; and if rapid expansion is used However, the low solubility of copolymers in supercritical carbon dioxide fluid and the intermittent operation greatly limit the application of this method to such copolymers.

Therefore, the current supercritical carbon dioxide fluid technology cannot perform granulation well when dealing with partially dissolved solutes in the supercritical carbon dioxide fluid.

Contents of the invention

The object of the present invention is to provide a kind of method that continuous type supercritical fluid rapid expansion technology prepares polymer or medicine granule; Disadvantages of granulation, continuous granulation can be successfully performed.

In order to achieve the above object, technical scheme of the present invention is:

A method for preparing polymer or drug particles by continuous supercritical fluid rapid expansion technology, comprising the following steps: first dissolving the polymer or drug in one or more organic solvents to form an organic solution, and pumping it into the supercritical fluid through a high-pressure pump. In the carbon dioxide fluid, the organic solution is uniformly mixed with the supercritical carbon dioxide fluid to form a mixed fluid, and then the organic solvent and supercritical carbon dioxide are rapidly expanded, resulting in a great decrease in the dissolving capacity, so that the solute is supersaturated and precipitated to form particles.

The solute adopts one of the solutes partially dissolved in the supercritical carbon dioxide fluid, the solutes completely dissolved in the supercritical carbon dioxide fluid, and the solutes with higher solubility.

The organic solvent is an organic solvent that is miscible with the supercritical carbon dioxide fluid.

The organic solvent is a non-polar or low-polar organic solvent with a lower boiling point.

Described organic solvent is dichloromethane or acetone.

The organic solution and the supercritical carbon dioxide fluid are uniformly mixed to form a mixed fluid, which is then sprayed into the normal pressure kettle through a nozzle, so that the organic solvent and the supercritical carbon dioxide rapidly expand and the dissolving capacity is greatly reduced.

The organic solution is continuously pumped into the supercritical carbon dioxide fluid through a high-pressure pump and mixed to form a uniform mixed fluid, and at the same time continuously expands rapidly to form particles.

The mixed fluid uses carbon dioxide as an atomizer or other physical dispersion methods in the autoclave to continuously pump the organic solution into the supercritical carbon dioxide fluid through a high-pressure pump and mix to form a uniform mixed fluid.

The use of carbon dioxide as an atomizing agent or other physical dispersion methods in the autoclave refers to one of the supercritical fluid forced dispersion method, ultrasonic enhanced mass transfer supercritical anti-solvent method, and stirring method in the autoclave.

The beneficial effects of the present invention are: the present invention overcomes the disadvantage that the current anti-solvent method and rapid expansion method are difficult to granulate the solute partially dissolved in the supercritical carbon dioxide fluid, and can successfully carry out continuous granulation.

Description of drawings

Fig. 1 is the technological device figure that continuous type supercritical fluid technique of the present invention prepares polymkeric substance or drug granule; (1 steel cylinder, 2 refrigeration systems, 3 high pressure plunger pumps, 4 autoclaves, 5 rapid expansion nozzles, 6 organic solutions, 7 High pressure pump, 8 coaxial nozzles, 9 normal pressure kettle, 10 filter, 11 heat exchanger, 12 air bath, 13 heat exchanger)

Fig. 2 is the scanning electron microscope topography figure of PLA-PEG-PLA particle in the embodiment 1 of the present invention;

Fig. 3 is a particle size distribution diagram of PLA-PEG-PLA particles in Example 1 of the present invention. (Number: quantity, Particle diameter: particle diameter)

Detailed ways

Example 1

Polylactic acid-polyethylene glycol-polylactic acid triblock copolymer (PLA-PEG-PLA) was dissolved in the organic solvent methylene chloride to obtain a 1.0% (wt/v) solution for future use.

Figure 1 is a diagram of the process device for preparing polymer or drug particles by continuous supercritical fluid technology in this embodiment. The device combines the supercritical fluid forced dispersion process and supercritical fluid rapid expansion process, mainly including carbon dioxide delivery system, organic solution Conveyor systems, coaxial nozzles for carbon dioxide and organic solutions, autoclaves, autoclaves, rapid expansion nozzle components.

After the carbon dioxide in the steel cylinder 1 is liquefied by the refrigeration system 2, it is pressurized by the high-pressure plunger pump 3, and then pumped into the autoclave 4 after being heated up by the constant temperature water bath in the pipeline. The rate of carbon dioxide pumping, the rapid expansion nozzle 5 is opened to spray at a certain rate, and the temperature of the external drying box and pipeline water bath of the autoclave is adjusted to keep the pressure and temperature inside the autoclave constant. After the system pressure and temperature are stabilized, the supercritical carbon dioxide passes through the outer channel of the coaxial two-flow nozzle at the top of the autoclave 4, and the PLA-PEG-PLA methylene chloride solution 6 of 1.0% (wt/v) passes through the high-pressure pump 7 through the inner side of the nozzle 8 channel while pumping into the autoclave 4. The system pressure is 12MPa, the temperature is 306K, the flow rate of carbon dioxide is 25NL/h, and the flow rate of the high pressure pump is 1.0ml/min. The organic solution is pumped into the autoclave 4 to form a mixed fluid, and then sprayed into the normal pressure autoclave 9 through another rapid expansion nozzle 5, and PLA-PEG-PLA is supersaturated and precipitated to form particles. After the delivery of the PLA-PEG-PLA organic solution, keep the pressure and temperature constant, and continue to feed carbon dioxide for 30 minutes to keep the conditions of the rapid expansion process stable. Collect products.

Figure 2 and Figure 3 are the scanning electron microscope topography and particle size distribution diagrams of the PLA-PEG-PLA particles collected in the atmospheric autoclave of this embodiment, respectively. The particles are mainly spherical, with an average particle size of 2.2 microns and a narrow distribution range. The experimental results show that the rapid expansion technology of continuous supercritical carbon dioxide fluid can successfully prepare particles of solute partially dissolved in supercritical carbon dioxide fluid, which overcomes the shortcomings of the anti-solvent method and rapid expansion method, and can be successfully produced continuously. grain.

Example 2

Dissolving ibuprofen in acetone to form a 1% (wt/v) solution, the experimental process is the same as in Example 1, and ibuprofen fine particles can be obtained in the autoclave 9.

Example 3

Polylactide glycolide-polyethylene glycol copolymer (PLGA-PEG) is dissolved in methylene chloride to form a 1% (wt/v) solution, and the experimental process is the same as in Example 1, that is, the 9 to obtain PLGA-PEG fine particles.

Claims (10)

1. A method for preparing polymer or drug granules by continuous supercritical fluid rapid expansion technology, characterized in that it comprises the steps of: first dissolving polymer or medicine in one or more organic solvents to form an organic solution; The pump is pumped into the supercritical carbon dioxide fluid, so that the organic solution and the supercritical carbon dioxide fluid are mixed uniformly to form a mixed fluid, and then the organic solvent and supercritical carbon dioxide are rapidly expanded, resulting in a great decrease in the dissolving capacity, so that the solute is supersaturated and precipitated to form particles. 2. a kind of continuous supercritical fluid rapid expansion technology as claimed in claim 1 prepares the method for polymkeric substance or drug particle, it is characterized in that: described solute adopts the solute that partially dissolves in supercritical carbon dioxide fluid, in supercritical carbon dioxide fluid One of the completely soluble solutes and the more soluble solutes in the critical carbon dioxide fluid. 3. a kind of continuous supercritical fluid rapid expansion technology prepares the method for polymkeric substance or drug granule as claimed in claim 1, it is characterized in that: described organic solvent is the organic solvent that can be miscible with supercritical carbon dioxide fluid . 4. a kind of continuous supercritical fluid fast expansion technique as claimed in claim 3 prepares the method for polymkeric substance or medicine granule, it is characterized in that: described organic solvent is nonpolar or low polarity and boiling point is lower Organic solvents. 5. A method for preparing polymers or drug particles by continuous supercritical fluid rapid expansion technology according to claim 4, characterized in that: the organic solvent is dichloromethane or acetone. 6. A kind of continuous supercritical fluid rapid expansion technology as claimed in claim 1 prepares the method for polymer or drug granule, is characterized in that: described organic solution and supercritical carbon dioxide fluid mix uniformly to form mixed fluid after nozzle Spraying into the autoclave makes the organic solvent and supercritical carbon dioxide expand rapidly, resulting in a great decrease in dissolving capacity. 7. A kind of continuous supercritical fluid rapid expansion technology as claimed in claim 6 prepares the method for polymkeric substance or drug particle, it is characterized in that: described mixed fluid is sprayed into normal pressure through nozzle in the form of gas or liquid fluid Inside the cauldron. 8. a kind of continuous supercritical fluid rapid expansion technology as claimed in claim 1 prepares the method for polymkeric substance or drug particle, it is characterized in that: described organic solution is continuously pumped into supercritical carbon dioxide fluid through high-pressure pump Mixing forms a homogeneous mixed fluid while continuous rapid expansion forms particles. 9. A kind of continuous supercritical fluid rapid expansion technology as claimed in claim 8 prepares the method for polymkeric substance or medicine granule, it is characterized in that: described mixed fluid uses carbon dioxide as atomizer or other physical dispersion in autoclave The mixing method of the method makes the organic solution continuously pumped into the supercritical carbon dioxide fluid through a high-pressure pump and mixed to form a uniform mixed fluid. 10. A kind of continuous supercritical fluid rapid expansion technology as claimed in claim 9 prepares the method for polymer or drug particle, it is characterized in that: described carbon dioxide refers to as atomizing agent or other physical dispersion modes in the autoclave It is one of supercritical fluid forced dispersion method, ultrasonic enhanced mass transfer supercritical antisolvent method, and stirring method in autoclave.

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