超临界流体快速膨胀法制备微细颗粒

利用超临界流体快速膨胀法(RESS)制备微细颗粒,是近年来兴起的一种很有应用前景的新的粉体技术。笔者就该技术的过程原理、典型实验装置、过程条件的影响因素、近年来国内外的主要研究成果及其存在的问题进行了论述。     

The formation of polymer fibers from the rapid expansion of supercritical fluid solutions

Fibers of organic polymers (polystyrene, cellulose acetate, and polypropylene) were formed by the rapid expansion of supercritical fluid solutions through a small diameter nozzle to ambient temperature and pressure. Solutions were prepared either by dissolving the polymer directly in room temperature pentane, or in an autoclave at elevated temperatures and pressures for less soluble polymers. The fibers were collected on substrates mounted in the expansion jet. The diameters of the fibers formed (typically 1-5 μm) were much smaller than the opening of the nozzle, although fiber diameter was observed to generally increase with nozzle diameter. The aspect ratios of the fibers, produced by this process were on the order of 10³ or larger. Optimum conditions for fiber formation occurred at fluid expansion temperatures near the melting point of the polymer, with particle formation mechanisms favored at higher and lower temperatures.     

Preparation of griseofulvin microparticles by supercritical fluid expansion depressurization process

The supercritical fluid expansion depressurization (SFED) process is a novel technique proposed recently to prepare microparticles with narrow size distribution. The process has shown a very promising potential in pharmaceutical micronization. An SFED experimental apparatus was set up and griseofulvin (GF) microparticles were prepared successfully with the solvent of the mixture of acetone and ethanol. The influences of the operation parameters, including the pressure and temperature in the mixing vessel, the solution concentration and the solution feeding rate, on the particle morphology, size and size distribution were investigated in detail. The results show that approximately spherical particles with size less than 1.5 μm can be prepared successfully by SFED process. The pressure in the mixing vessel and the solution feeding rate are two most effective parameters while the solution concentration is the next, and the temperature in the mixing vessel has little effect on the GF particles. The optimal operation condition for preparing GF micro-particles in the range of this work is: the pressure of 8 MPa and the temperature of 60 °C in the mixing vessel, the solution feeding rate of 9 ml/min and the solution concentration of 15 mg/ml.     

Preparation of cefuroxime axetil nanoparticles by rapid expansion of supercritical fluid technology

As a poorly water-soluble drug, cefuroxime axetil (CFA) features a low solubility and dissolution rate in the gastrointestinal tract, which limits its effective absorption and bioavailability. The objective of this study was production of amorphous CFA nanoparticles directly without any additive by rapid expansion of supercritical solution technology. The effects of process parameters, such as the temperature of nozzle (50-70 °C) and extraction port (60-90 °C) were investigated each in three levels, on the properties of the formed particles by a full factorial design. The particles were then analyzed for differential scanning calorimetry (DSC), X-ray diffraction (XRD), particle size, zeta potential and dissolution properties. Z-average particle size of different nanoparticles was between 158 and 513 nm and zeta potential also changed from − 4.29 to − 42.8 mV. The lowest particle size was seen in sample with nozzle temperature at 60 °C and the extraction temperature at 90 °C. However, when temperatures of nozzle and extraction column were decreased to 50 °C and 75 °C respectively, the particle size was increased to 465 nm. More than 90% of the some nano-sized CFA formulations were dissolved in 3 min and complete dissolution occurred within 20 min, while the commercial CFA did not achieve complete dissolution (only about 50%) during 60 min of the testing period.     

超临界流体萃取固态物料的动力学模型

萃取速率和萃取量是超临界流体萃取过程设计的重要依据。对超临界流体萃取固态物料的动力学模型进行了评述。分析了各种动力学模型所描述的萃取机理和模型的求解方法 ,并对各种模型进行了比较 ,指出了各自的适用范围。     

Molecular dynamics simulation of the formation of pharmaceutical particles by rapid expansion of a supercritical solution

The formation of pharmaceutical particles by the rapid expansion of a supercritical solution is investigated by molecular dynamics simulation. As a pharmaceutical model substance naproxen, a pain reliever and anti-inflammatory drug, is used. The expansion process is modeled in the simulation method by stepwise increasing the size of the simulation box. Comparison with an accurate reference equation of state for the pure solvent carbon dioxide shows that the simulation system follows an adiabatic expansion path. The expansion of a solution of naproxen in supercritical carbon dioxide leads to a highly supersaturated system that starts to form particles. The nucleation and growth kinetics of this particle formation process is investigated and the effect on the particle structure is analyzed.     

超临界流体制备水溶性药物超细微粒的研究进展

介绍了用超临界流体膨胀减压过程制备水溶性药物超细微粒的基本原理、工艺流程、技术特点、研究现状和主要研究结果,并展望了其发展前景。     

Particle generation for pharmaceutical applications using supercritical fluid technology

In the pharmaceutical industry, an even greater number of products are in the form of particulate solids. Their formation, formulation and the control of their user properties are still not well understood and mastered. Since the mid-1980s, a new method of powder generation has appeared involving crystallisation with supercritical fluids. Carbon dioxide is the most widely used solvent and its innocuity and “green” characteristics make it the best candidate for the pharmaceutical industry. Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti Solvent (SAS) and Particles from Gas Saturated Solutions (PGSS) are three families of processes which lead to the production of fine and monodisperse powders, including the possibility of controlling crystal polymorphism. For the RESS process, the sudden decompression of the fluid in which a solute has been dissolved is the driving force of nucleation. CO₂ is, however, a rather feeble solvent and this is obviously the main limitation of the development of RESS. In the SAS process, CO₂ acts as a non-solvent for inducing the crystallisation of a solute from an organic solution. The versatility of SAS (there is always a proper solvent-antisolvent couple for the studied solute) ensures future developments for very different types of materials. PGSS uses the fact that it is much easier to dissolve CO₂ in organic solutions (or melted compounds) than the contrary. It presents very promising perspectives of industrial development. After almost 20 years of active research, and more than 10 years of process development, this technology is reaching maturity, and very soon commercial drug produced by these techniques are likely to appear.     

Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process

The supercritical fluid enhanced atomization (SEA) process was used to produce cocrystals of six different active pharmaceutical ingredients (APIs): indomethacin, theophylline, caffeine, sulfamethazine, aspirin and carbamazepine. Micrometric cocrystals using the FDA-approved sweetener saccharin (SAC) as a cocrystal former were produced from ethanol solutions using supercritical CO₂ as the atomization enhancing fluid. The corresponding cocrystalline phases were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Particle morphologies and size distributions were analyzed by scanning electron microscopy (SEM) and by aerosizer.The results presented here show the formation of cocrystals of all the APIs selected, evidencing the ability and the potentiality of the SEA technique to generate different pharmaceutical cocrystals. Cocrystal particles produced by SEA had similar mean particle size than those produced by classical grinding methods. Interestingly, a new cocrystal form of theophylline–saccharin (likely with a 1:2 stoichiometry) was obtained by the SEA method that has not been previously reported by traditional screening methods.     

A simplified and generalized model for the rapid expansion of supercritical solutions

A set of analytical equations is derived for the estimation of the average diameter attained by particles that are generated by the rapid expansion of a supercritical solution (RESS). Applying the simplified model to one specific, but nevertheless representative set of experimental conditions for RESS processing, theoretical findings from earlier work could be generally confirmed and new insight was gained. Particles generated by RESS through an expansion device having a cylindrical section with a small aspect ratio will generally not attain average diameters of more than 20–50 nm before passing through the critical cross section since the time available for growth by condensation is limited to a few microseconds. Comparing three different driving mechanisms for growth due to coagulation, it was found that the effects of slip flow differences can be seen as most promising to significantly improve existing RESS models.     

Photosensitive 2,5-distyrylpyrazine particles produced from rapid expansion of supercritical solutions

Solvent-free, photoreactive particles of 2,5-distyrylpyrazine (DSP) monomer were developed by rapid precipitation from an expanding supercritical chlorodifluoromethane solution. DSP polymer particles were produced by solid-state photopolymerization. DSP particles below a critical diameter of about 0.5 μm were found to be mechanically stable and did not fragment upon photopolymerization. The rate of DSP photopolymerization was shown to be size-sensitive. Nano-scale particles demonstrated superior photoreactivity in the solid state in comparison to micro-scale crystals. UV spectra of DSP at different degrees of conversion were investigated and the extinction coefficients were calculated for the DSP monomer and polymer in sulfuric acid.     

Distribution of solutes between polymer and supercritical fluid by inverse supercritical fluid chromatography

Two methods of inverse supercritical fluid chromatography (ISFC), frontal analysis supercritical fluid chromatography (SFC) and elution SFC, have been compared for the determination of distribution coefficients of solutes between a polymer and a supercritical CO₂. The logarithm of the distribution coefficient showed monotonic decrease with the density of the supercritical fluid (SF). The abnormal-maximum behavior of solute sorption in the polymer phase was explained by the fluid and solute properties, ϕ₂P/P ₂ ^sat . Interesting open-elliptic shapes of sorption and volume-fraction curves were obtained and explained with the fugacity coefficient. Correction to the capacity factor was employed to eliminate the retention due to the adsorption on the surface of the silica support. A model based on the Flory equation and the Peng-Robinson equation of state (EOS) successfully predicted the phase behavior of the ternary solutesupercritical fluid-polymer systems using only interaction parameters obtained from the binary systems. The solute distribution coefficient at infinite dilution was used to calculate the phase equilibrium at finite concentration using a ternary-phase diagram.     

Modeling and calculation of the process of rapid expansion of supercritical fluid yielding nanoparticles

A mathematical model is proposed and the calculation is carried out for the process of rapid expansion of the supercritical fluid containing a dissolved solid compound via a capillary into a volume with specified temperature and pressure. The analysis of sensitivity of the model toward the process parameters makes it possible to choose the most important parameters for producing nanoparticles with preset properties and dimensions. The calculations demonstrate that all the parameters of the expansion process under study have a particular effect on the size of the particles being formed.     

Superhydrophobic polymeric coatings produced by rapid expansion of supercritical solutions combined with electrostatic deposition (RESS-ED)

In this paper we present a method to produce superhydrophobic polymeric coatings by combining the rapid expansion of supercritical solutions (RESS) with electrostatic deposition (ED). A copolymer, poly(vinyl acetate)–poly(vinyl pivalate) was dissolved in a mixture of supercritical carbon dioxide and acetone and sprayed through a nozzle with an applied voltage of 8 kV onto a surface placed on a earthed collector. Spray distance and polymer concentration were altered to find the most suitable spraying conditions. Superhydrophobic surfaces were produced when spraying both with and without a voltage, although the water repellent surfaces could be produced at a larger variety of processing parameters using the RESS-ED technique. The greatest improvement of using the RESS-ED process was that larger and thinner coatings were produced with a more even surface coverage of the created polymer particles compared to spraying without the applied voltage.     

The supercritical fluid extraction of peat using water and aqueous organic solutions

The supercritical fluid extraction of organics from sun- and air-dried peat was investigated using solvents providing different intermolecular solute-solvent forces. Snyder's classification of selectivity groups indicated that acetone-water mixtures capable of large dipole interactions were more successful than those promoting hydrogen-bonding: water (proton donor) and methanol-water mixtures (proton acceptor). Neither solvent densities nor Hildebrand solubility parameters were satisfactory for predicting supercritical solvent effectiveness. At slightly subcritical conditions, both the acetone-water mixtures and methanol-water mixtures were good solvents.     

Micronization of fenofibrate by rapid expansion of supercritical solution

Micronization of fenofibrate was investigated using rapid expansion of supercritical solution (RESS) process. Effects of pressure, temperature and nozzle on particle size were optimized using Taguchi's orthogonal array and analyzed using XRD, DSC, FT-IR, SEM, laser diffractometer and dissolution testing. Processed fenofibrate retained crystalline structure and has a similar chemical structure with unprocessed fenofibrate. The average particle size of fenofibrate was reduced from its original 68.779 ± 0.146 μm to 3.044 ± 0.056 μm under the optimum condition (T at 35 °C, P at 200 bar and nozzle diameter at 200 μm). The processed fenofibrate showed an enhanced dissolution rate by 8.13 times.     

Formation of ultrafine aspirin particles through rapid expansion of supercritical solutions (RESS)

The performance of pharmaceuticals in biological systems can be enhanced by reducing the particle size of pharmaceuticals. Rapid expansion from supercritical solution (RESS) has provided a promising alternative to comminute contaminant-free particles of heat-sensitive materials such as drugs. In this work, aspirin has been successfully precipitated by the RESS technology. The performances of the RESS process under different operating conditions are evaluated through the analysis of the particle characteristics. Our results show that extraction pressure and extraction temperature can significantly affect the morphology and size of the precipitated particles whereas the nozzle diameter and pre-expansion temperature are not observed to apparently influence the RESS particles. The RESS process could produce ultrafine spherical particles (0.1-0.3 μm) of aspirin as reflected by SEM observations.     

Micronization of ketoprofen by the rapid expansion of supercritical solution process

The particle size of the pharmaceutical substances is important for their bioavailability (the percentage of the drug absorbed compared to its initial dosage). The absorption rate can be increased by reducing particle size of the drug particles. This study was conducted to investigate the effects of the extraction pressure (140–220 bar), extraction temperature (308–338 K), nozzle length (2–15 mm), effective nozzle diameter (450–1700 μm), and collection distance (1–10 cm) on the size and morphology of the precipitated ketoprofen particles. The characterization (size and morphology) of the particles was investigated using scanning electron microscopy (SEM). The average particle size of the original material was 115.42 μm, while the average particle size of the micronized particles is between 0.35 and 7.03 μm near to quisi-spherical, needle and irregular shape depending upon the experimental conditions.     

Preparative-scale supercritical fluid extraction/supercritical fluid chromatography of corn bran

A preparative-scale supercritical fluid extraction/supercritical fluid chromatography (SFE/SFC) procedure has been developed for the removal of oil from corn bran to obtain fractions enriched with free sterols and ferulate-phytosterol esters (FPE). Operational parameters from an analytical-scale supercritical fluid fractionation technique were translated to and optimized on a home-built, preparatory-scale SFE/SFC apparatus. SFE was performed at 34.5 MPa and 40°C using supercritical carbon dioxide. These conditions did not result in exhaustive extraction of the corn bran, but yielded about 96% of the available oil. SFC was conducted in three steps, followed by reconditioning of the sorbent bed. Preparative-scale SFE/SFC of corn bran produced a fraction enriched greater than fourfold in free sterols and 10-fold in FPE, suggesting that such a scheme could be used industrially to produce a functional food ingredient.     

超临界流体技术制各类胡萝卜素纳米颗粒

Based on the solubility in supercritical CO2, two strategies in which CO2 plays different roles are used to make quercetine and astaxanthin particles by supercritical fluid technologies. The experimental results showed that micronized quercetine particles with mean particle size of 1.0-1.5 µm can be made via solution enhanced dis-persion by supercritical fluids (SEDS) process, in which CO2 worked as turbulent anti-solvent; while for astaxan-thin, micronized particles with mean particle size of 0.3-0.8 µm were also made successfully by rapid expansion supercritical solution (RESS) process.