CN110200923B - Method for preparing formononetin ultrafine particles by using supercritical anti-solvent crystallization technology - Google Patents
Method for preparing formononetin ultrafine particles by using supercritical anti-solvent crystallization technology Download PDFInfo
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Abstract
The invention discloses a method for preparing formononetin ultrafine particles by applying a supercritical anti-solvent crystallization technology, which comprises the following steps: (1) preparing an formononetin solution; (2) adjusting the temperature in the crystallization kettle to be constant, and adding CO2Introducing the mixture into a crystallization kettle at a certain flow rate, and adjusting the pressure of the crystallization kettle to be constant; (3) spraying the prepared formononetin solution into a crystallization kettle through a nozzle at the top of the crystallization kettle by a high-efficiency infusion pump; (4) after the sample introduction is finished, continuously introducing CO into the kettle2Releasing the pressure after a certain time, opening the crystallization kettle, and collecting the formononetin ultrafine particles. The method successfully prepares the formononetin ultrafine particles with small particle size and narrow particle size distribution by applying a supercritical anti-solvent crystallization technology, improves the dissolution speed of the medicament, and increases the specific surface area of medicament particles, thereby enhancing the adsorption of the medicament to gastrointestinal mucosa and improving the bioavailability of the medicament. The method has the advantages of mild operation conditions, environmental protection, safety, high efficiency and no organic solvent residue.
Description
Technical Field
The invention belongs to the field of pharmaceutical engineering, and particularly relates to a method for preparing formononetin ultrafine particles by applying a supercritical anti-solvent crystallization technology.
Background
Formononetin (Formononetin), also known as Formononetin and Formononetin, with molecular formula C16H12O4The chemical name of the compound is 7-hydroxy-3- (4-methoxyphenyl) -4H-1-benzopyran-4-ketone, which is widely existed in the plants such as astragalus, liquorice, suberect spatholobus stem, red clover and the like, and is a naturally occurring isoflavone and phytoestrogen. Research shows that formononetin has several pharmacological functions, including antiphlogistic, antitumor, antioxidant, antiarrhythmic, antiatherosclerotic, etc. However, formononetin is almost insoluble in water, is difficult to dissolve out, and has low bioavailability, so that the clinical application of formononetin is greatly limited.
The goal of improving drug solubility can theoretically be achieved by increasing the wettability of the drug, decreasing the particle size of the drug to increase the surface area, and converting the crystalline form of the drug into a more soluble amorphous form, and currently, technical means for achieving this goal are micronization of the drug, addition of solubilizers, chemical modification, self (micro) emulsification, preparation of solid dispersions and inclusion compounds, and the like.
The supercritical anti-solvent crystallization (SAS) is an emerging micronization technology for preparing ultrafine drug particles, and the supersaturation degree of a solution is rapidly increased by utilizing the supercritical characteristics of a fluid, so that a solute is precipitated and separated out. Compared with the traditional crystallization methods such as spray drying, solution evaporation, mechanical grinding, vacuum freeze drying and the like, the SAS method has the characteristics of mild operation conditions, less organic solvent residue of the product, small particle size, narrow particle size distribution, high purity and the like. In addition, the SAS method for the pharmaceutical technology has the advantages of easy separation of crystals, controllable crystal form and little pollution, and has wide development prospect.
At present, no report of preparing the formononetin ultrafine particles by applying a supercritical anti-solvent crystallization technology is found.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for preparing formononetin ultrafine particles by using a supercritical anti-solvent crystallization technology.
The above purpose of the invention is realized by the following technical scheme:
a method for preparing formononetin ultrafine particles by using a supercritical anti-solvent crystallization technology comprises the following steps:
(1) preparing an formononetin solution: dissolving formononetin in a mixed solvent of acetone and dimethyl sulfoxide to prepare a formononetin solution, wherein the volume ratio of the acetone to the dimethyl sulfoxide in the mixed solvent is 19: 1;
(2) adjusting the temperature in the crystallization kettle to be constant, and adding CO2Introducing the mixture into a crystallization kettle at a certain flow rate, and adjusting the pressure of the crystallization kettle to be constant;
(3) continuously introducing CO2Maintaining the temperature and pressure in the crystallization kettle unchanged, and simultaneously spraying the formononetin solution into the kettle through a nozzle at the top of the crystallization kettle by a high-efficiency infusion pump;
(4) after the sample introduction is finished, continuously introducing CO2Maintaining the temperature and pressure in the crystallization kettle unchanged, releasing the pressure after maintaining for a certain time, and opening the crystallization kettle to collect the formononetin ultrafine particles after the pressure in the crystallization kettle is reduced to atmospheric pressure.
Further, the concentration of the formononetin solution in the step (1) is 3-9 mg/mL.
Further, in the step (2), the temperature in the crystallization kettle is adjusted to be 34-50 ℃, and the pressure is adjusted to be 8-16 Mpa.
Further, CO in the step (2)2The flow rate is 4-4.5L/min.
Further, the flow rate of the sample injection of the formononetin solution in the step (3) is 1.0-2.6 mL/min.
Further, in the step (4), the pressure is released after the pressure is maintained for 30-60 min.
Has the advantages that:
the method successfully prepares the formononetin ultrafine particles with small particle size and narrow particle size distribution by applying a supercritical anti-solvent crystallization technology, improves the dissolution speed of the medicament, and increases the specific surface area of medicament particles, thereby enhancing the adsorption of the medicament to gastrointestinal mucosa and improving the bioavailability of the medicament. The method has mild operation conditions, better solves the problem of organic solvent residue compared with the prior art, and has the advantages of green, environment-friendly, safe and high-efficiency whole granulation process.
Drawings
Fig. 1 is a schematic structural diagram of experimental equipment, wherein: 1 is CO2A storage tank, 2 is a low-temperature constant-temperature water tank, and 3 is an air compression pump; 4 is CO2A preheating device, 5 is a solution storage tank, 6 is a high-pressure infusion pump, 7 is a crystallization kettle, 8 is a solvent recovery device, and 9 is a volume flow meter;
FIG. 2 is a graph showing the distribution of the particle size of an formononetin bulk drug (a) and an formononetin ultrafine particle (b) prepared in example 2 of the present invention;
FIG. 3 is an IR spectrum of an formononetin bulk drug and the formononetin ultrafine particles prepared in example 2 of the present invention;
FIG. 4 is an XRD pattern of an formononetin bulk drug and the formononetin ultrafine particles prepared in example 2 of the present invention;
FIG. 5 is a DSC chart of formononetin bulk drug and the formononetin ultrafine particles prepared in example 2 of the present invention;
FIG. 6 is a graph showing the dissolution rate contrast between formononetin bulk drug and the formononetin ultrafine particles prepared in example 2 of the present invention.
Detailed Description
The following detailed description of the present invention is provided in connection with the accompanying drawings and examples, but not intended to limit the scope of the invention.
First, experimental material
Formononetin (purity 98%, san river sanderian, Baoji city, China biological development Co., Ltd.); CO 22(purity of>99%, Nanjing Shangyuan industrial gas plant); acetone (analytical grade, Nanjing chemical reagents Ltd.); dimethyl sulfoxide (analytical pure, chemical reagents of national drug group, ltd); distilled water (homemade by university of chinese pharmacy); tween 80 (analytical grade, Nanjing chemical Co., Ltd.).
Helix supercritical particle preparation system (applied separations, USA); HelixSeries model 1500 high pressure infusion pump (applied separations, USA); model TYW-2 air compressor pump (same electromechanical company, Inc., Suzhou); SDC-6 type cryostat (bio-technology ltd, tokyo new york); UV-1800 type UV-visible spectrophotometer (Shimadzu corporation, Japan); MS2000 Malvern laser particle sizer (Malvern, uk); DSC204F1 type differential scanning calorimeter (Nachi, Germany); x-ray powder diffractometer model D8Advance (Bruker, Germany); fourier transform infrared spectrometer model FT/IR-4100 (JASCO, Japan); ZRS-8L intelligent dissolution tester (Tianjin Datianfa science and technology Co., Ltd.).
Second, Experimental methods
A flow chart of the method for preparing the formononetin ultrafine particles by applying the supercritical anti-solvent crystallization technology is shown in figure 1, and the operation flow is as follows:
(1) checking the screwing state of each valve to ensure that the whole device is sealed and airtight; starting a low-temperature constant-temperature water tank and an equipment host, setting the temperature, and opening a heating device of a crystallization kettle;
(2) preparing a sample solution, and flushing a high-pressure infusion pump pipeline and a sample injection needle by using a proper amount of the sample solution to ensure that a sample injection system is in a smooth and unblocked state;
(3) after the temperature of the crystallization kettle is constant, installing a sample injection needle, then unscrewing a carbon dioxide steel cylinder valve, starting an air compression pump, opening an air inlet valve, introducing carbon dioxide into the crystallization kettle, and setting the pressure in the crystallization kettle;
(4) when the pressure is constant, the exhaust valve is unscrewed, the exhaust flow value of the carbon dioxide is adjusted, and the carbon dioxide is maintained in a stable state;
(5) starting a sample injection switch of a high-pressure infusion pump, so that the sample solution is injected into the crystallization kettle at a certain flow rate, and injecting 30mL of sample;
(6) after the sample introduction is finished, continuously conveying carbon dioxide into the crystallization kettle, simultaneously maintaining the exhaust flow of the carbon dioxide unchanged, and exhausting residual solvent in the crystallization kettle after 30-60 min;
(7) closing the pressure device of the crystallization kettle, screwing the carbon dioxide steel cylinder, closing the air compression pump, stopping conveying carbon dioxide gas to the crystallization kettle, and simultaneously adjusting the exhaust flow of carbon dioxide so that the pressure reduction process of the crystallization kettle is stably carried out at a certain speed;
(8) and after the pressure of the crystallization kettle is reduced to atmospheric pressure, collecting the product in the kettle.
Third, example
Pre-experiment: CO 22At flow rates below 4L/min, the solvent is not drained in time or even difficult to drain, resulting in a partially viscous final product. Thus selecting CO2The flow rate is 4-4.5L/min.
Example 1: single factor experiment
Single factor experiments: influence of sample injection flow rate on particle size of formononetin
At the crystallization temperature of 42 ℃, the crystallization pressure of 10MPa and CO2Under the conditions that the flow rate is 4-4.5L/min and the mass concentration of formononetin is 5mg/mL, the influence of the injection flow rates of 1.0, 1.4, 1.8, 2.2 and 2.6mL/min on the volume average particle size of formononetin particles is examined, and the volume average particle size is 9.185, 7.860, 6.146, 6.910 and 7.785 mu m respectively, so that the injection flow rate of a better group is determined to be 1.8 mL/min.
Single factor experiments: influence of crystallization pressure on particle size of formononetin
At the crystallization temperature of 42 ℃, the sample injection flow rate is 1.8mL/min, and CO is added2Under the conditions that the flow rate is 4-4.5L/min and the mass concentration of the formononetin is 5mg/mL, the influence of crystallization pressures of 8, 10, 12, 14 and 16MPa on the volume average particle size of the formononetin particles is considered, and the volume average particle size is 7.828, 6.146, 6.500, 7.011 and 8.450 mu m respectively, so that the crystallization pressure of a better group is determined to be 10 MPa.
Single factor experiments: influence of crystallization temperature on particle size of formononetin
At the crystallization pressure of 10MPa, the sample injection flow rate of 1.8mL/min and CO2Under the conditions that the flow rate is 4-4.5L/min and the mass concentration of the formononetin is 5mg/mL, the influence of crystallization pressures of 34, 38, 42, 46 and 50 ℃ on the volume average particle size of the formononetin particles is considered, and the volume average particle size is 8.584, 6.866, 6.146, 6.806 and 6.606 mu m respectively, so that the crystallization temperature of a better group is determined to be 42 ℃.
Single factor experiments: influence of mass concentration of raw material medicine on particle size of formononetin
At the crystallization pressure of 10MPa, the crystallization temperature of 42 ℃, the sample injection flow rate of 1.8mL/min and CO2Under the condition that the flow rate is 4-4.5L/min, the influence of the mass concentration of the raw material medicines of 3, 5, 7 and 9mg/mL on the volume average particle size of the formononetin particles is considered, and the volume average particle size is 7.265, 6.146, 6.016 and 7.297 mu m respectively, so that the mass concentration of the raw material medicines of a better group is determined to be 7 mg/mL.
Example 2: preparing the formononetin ultrafine particles by applying a supercritical anti-solvent crystallization technology under the optimized technological parameters
A method for preparing formononetin ultrafine particles by using a supercritical anti-solvent crystallization technology comprises the following steps:
step S1, dissolving the formononetin bulk drug in a mixed organic solvent to obtain an formononetin solution;
step S2, adjusting the temperature in the crystallization kettle to be constant, and adding CO2Introducing the mixture into a crystallization kettle at a certain flow rate, and adjusting the pressure of the crystallization kettle to be constant;
step S3, continuously introducing CO2Maintaining the temperature and pressure in the crystallization kettle unchanged, and simultaneously spraying the prepared formononetin solution into the kettle through a nozzle at the top of the crystallization kettle by a high-pressure infusion pump;
step S4, after the sample injection is finished, continuously introducing CO into the kettle2And (4) releasing the pressure after residual solvent in the crystallization kettle is exhausted for 40min, and collecting the formononetin ultrafine particles after the pressure of the crystallization kettle is reduced to the atmospheric pressure.
Wherein the organic solvent is prepared by mixing acetone and dimethyl sulfoxide in a volume ratio of 19:1, the mass concentration of the formononetin solution is 7mg/mL, the temperature in the crystallization kettle is 42 ℃, the pressure in the crystallization kettle is 10MPa, the sample injection flow rate of the formononetin solution is 1.8mL/min, and CO is introduced into the crystallization kettle at a CO injection flow rate of 1.8mL/min2The flow rate is 4-4.5L/min.
Characterization and analysis of the obtained formononetin ultrafine particles:
particle size analysis
Particle size analysis of formononetin is shown in figure 2, the particle size of the formononetin ultrafine particles prepared by the supercritical anti-solvent crystallization technology is obviously reduced, the particle size of the raw material drug is 30.455 μm, the particle size of the formononetin ultrafine particles is reduced to 5.899 μm, and the particle size distribution of the ultrafine particles is narrowed.
IR analysis
The infrared spectrogram of the formononetin bulk drug and the formononetin ultrafine particles is shown in figure 3, the characteristic absorption peaks of the formononetin ultrafine particles and the bulk drug prepared by the supercritical anti-solvent crystallization technology are almost not separated, which indicates that the supercritical anti-solvent crystallization technology does not change the chemical structure of the drug.
XRD analysis
XRD patterns of the formononetin bulk drug and the formononetin ultrafine particles are shown in figure 4, the characteristic diffraction peaks of the formononetin ultrafine particles prepared by the supercritical anti-solvent crystallization technology are approximately the same as those of the bulk drug, and the supercritical anti-solvent crystallization technology does not change the crystal form of the drug. Further confirmation was obtained by DSC results.
DSC analysis
DSC images of the formononetin bulk drug and the formononetin ultrafine particles are shown in figure 5, the characteristic endothermic peak width of the formononetin ultrafine particles prepared by the supercritical anti-solvent crystallization technology is consistent with that of the bulk drug, and the crystal form of the formononetin treated by the supercritical anti-solvent crystallization technology is not changed.
In vitro dissolution test
Taking a proper amount of formononetin bulk drug and the formononetin ultrafine particles prepared under the optimized technological parameters, and taking 0.1 percent of Tween 80 solution as a dissolution medium to determine respective dissolution rates. The result is shown in fig. 6, which shows that the dissolution rate of the formononetin ultrafine particles treated by the supercritical anti-solvent crystallization technology is obviously higher than that of the formononetin bulk drug, and the dissolution rate is obviously improved.
The formononetin superfine particles prepared by the invention are fluffy flocculent under the observation of naked eyes, the particle size is reduced by about 80 percent compared with the raw material medicine (about 30 mu m) through the detection of a Malvern laser particle sizer, the recovery rate is high (about 81 percent), and the dissolution rate is also obviously improved. The Fourier infrared spectrum analysis shows that the chemical structure of the formononetin ultrafine particles is not changed compared with the bulk drug; the crystal form of formononetin is consistent before and after treatment according to the analysis of XRD pattern and DSC pattern. The method successfully prepares the formononetin ultrafine particles with small particle size and narrow particle size distribution by applying a supercritical anti-solvent crystallization technology, improves the dissolution speed of the medicament, and increases the specific surface area of medicament particles, thereby enhancing the adsorption of the medicament to gastrointestinal mucosa and improving the bioavailability of the medicament. The method has mild operation conditions, better solves the problem of organic solvent residue compared with the prior art, and has the advantages of green, environment-friendly, safe and high-efficiency whole granulation process.
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.
Claims (1)
1. A method for preparing formononetin ultrafine particles by using a supercritical anti-solvent crystallization technology is characterized by comprising the following steps:
(1) preparing an formononetin solution: dissolving formononetin in a mixed solvent of acetone and dimethyl sulfoxide to prepare a formononetin solution, wherein the volume ratio of the acetone to the dimethyl sulfoxide in the mixed solvent is 19: 1;
(2) adjusting the temperature in the crystallization kettle to be constant, and adding CO2Introducing the mixture into a crystallization kettle at a certain flow rate, and adjusting the pressure of the crystallization kettle to be constant;
(3) continuously introducing CO2Maintaining the temperature and pressure in the crystallization kettle unchanged, and simultaneously spraying the formononetin solution into the kettle through a nozzle at the top of the crystallization kettle by a high-efficiency infusion pump;
(4) after the sample introduction is finished, continuously introducing CO2Maintaining the temperature and pressure in the crystallization kettle unchanged, releasing pressure after maintaining for 40min, and opening the crystallization kettle to collect the formononetin ultrafine particles after the pressure in the crystallization kettle is reduced to atmospheric pressure;
wherein the mass concentration of the formononetin solution in the step (1) is 7mg/mL, and the mass concentration of CO in the step (2)2The flow rate is 4-4.5L/min, the temperature in the crystallization kettle is adjusted to 42 ℃ in the step (2), the pressure is 10MPa, and the sample injection flow rate of the formononetin solution in the step (3) is 1.8 mL/min.
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| CN104650021A (en) * | 2014-12-10 | 2015-05-27 | 中国药科大学 | Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process |
| CN106432389A (en) * | 2016-09-12 | 2017-02-22 | 中国药科大学 | Method for preparing estradiol ultrafine particles with supercritical anti-solvent technology |
| CN109010289A (en) * | 2018-09-06 | 2018-12-18 | 中国药科大学 | A kind of supercritical CO2The method that anti-solvent technology prepares myricetin ultra-fine grain |
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| CN104650021A (en) * | 2014-12-10 | 2015-05-27 | 中国药科大学 | Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process |
| CN106432389A (en) * | 2016-09-12 | 2017-02-22 | 中国药科大学 | Method for preparing estradiol ultrafine particles with supercritical anti-solvent technology |
| CN109010289A (en) * | 2018-09-06 | 2018-12-18 | 中国药科大学 | A kind of supercritical CO2The method that anti-solvent technology prepares myricetin ultra-fine grain |
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