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.     

超临界快速膨胀法制备植物甾醇超细微粒

通过药物颗粒的微细化,降低其粒度,增大比表面积,进而提高药物颗粒的溶解度,可以有效地改善难溶药物的生物利用度。该文采用超临界流体快速膨胀法(RESS)微细化植物甾醇颗粒。利用SEM分析了沉淀颗粒的形貌及粒径大小。分析了过程参数与所制备颗粒粒度的关系。研究发现,当喷嘴内径Dn从60μm减小到40μm,植物甾醇颗粒粒径由10～20μm减小为5μm;预膨胀压力p0从15MPa增加到25MPa时,颗粒粒径由10～15μm降至5μm;预膨胀温度T0由318K升高到333K时,颗粒粒径由5～10μm减小为1μm,粒径分布也趋于均匀。喷嘴温度Tn对粒径无显著影响。该法制备得到1～20μm无定形植物甾醇微细颗粒,且具有更高的溶解速率,比原料植物甾醇早3h达到饱和溶解度。     

Micronization of the Pharmaceutically Active Agent Genipin by an Antisolvent Precipitation Process

Due to its low water solubility and slow dissolution rate, genipin was micronized by an antisolvent precipitation process using ethanol as solvent and n‐hexane as antisolvent. The effects of various experimental parameters on the mean particle size (MPS) of micronized genipin were investigated. By analysis of variance, only the concentration of the genipin solution has a significant effect on the MPS in genipin micronization. Under the optimum conditions, micronized genipin with an MPS of 1.8 μm was obtained. The micronized genipin was characterized by various methods, e.g., scanning electron microscopy and thermogravimetry. The analysis results indicated that the chemical structure of micronized genipin was not changed, but the crystallinity was reduced. The dissolution rate and solubility of the micronized genipin were 2.08 and 1.64 times that of the raw drug. In addition, the residual amounts of n‐hexane and ethanol were less than the International Conference on Harmonization limit for solvents.     

Preparation of anthracene fine particles by rapid expansion of a supercritical solution process utilizing supercritical CO<Subscript>2</Subscript>

The rapid expansion of a supercritical solution (RESS) process is an attractive technology for the production of small, uniform and solvent-free particles of low vapor pressure solutes. The RESS containing a nonvolatile solute leads to loss of solvent power by the fast expansion of the supercritical solution through an adequate nozzle, which can cause solute precipitation. A dynamic flow apparatus was used to perform RESS studies for the preparation of fine anthracene particles in pure carbon dioxide over a pressure range of 150–250 bar, an extraction temperature range of 50–70 °C, and a pre-expansion temperature range of 70–300 °C. To obtain fine particles, 100, 200 and 300 μm nozzles were used to disperse the solution inside of the crystallizer. Both average particle size and particle size distribution (PSD) were dependent on the extraction pressure and the pre-expansion temperature, whereas extractor temperature did not exert any significant effect. Smaller particles were produced with increasing extraction pressure and preexpansion temperature. In addition, the smaller the nozzle diameter, the smaller the particles and the narrower the PSD obtained.     

用含夹带剂丙酮的超临界CO2快速膨胀法制备灰黄霉素的微细颗粒

Griseofulvin (GF) is an antifungal drug whose pharmaceutical activity can be improved by reducingparticle size. In this study the rapid expansion of supercritical solution (RESS) was employed to micronize GF.Carbon dioxide with cosolvent acetone was chosen as a supercritical mixed solvent. The solubility of GF in super-critical CO2 with cosolvent acetone was measured using a dynamic apparatus at pressures between 12 and 32 MPa,temperatures at 313, 323 and 333K and cosolvent concentration at 1.5, 3.0, 4.5 and 6.0% (by mole). The effect ofpre-expansion pressure, extraction temperature, spraying distance, nozzle size and concentration of cosolvent on theprecipitated particles was investigated. The results show that the mean particle size of griseofulvin precipitated byRESS was less than 1.2 μm. An increase in pre-expansion pressure, extraction temperature, spraying distance andconcentration of cosolvent resulted in a decrease in particle size under the operating condition studied. With thedecrease of nozzle diameter the particle size reduces. The crystallinity and melting point of the original material andthe processed particle by RESS were tested by X-ray diffraction (XRD) and differential scanning calorimetry (DSC).No evident modification in the crystal habit was found under the experimental conditions tested. The morphologyof particles precipitated was analyzed by scanning electron microscopy (SEM).     

Effects of extraction temperature, extraction pressure and nozzle diameter on micronization of cholesterol by RESS process

Micronized cholesterol particles were produced via the Rapid Expansion of Supercritical CO₂ Solutions (RESS) process. Taguchi design was used for designing the experimental plan to investigate the effects of three parameters including extraction temperature (40-60 °C), extraction pressure (100-160 bar) and nozzle diameter (0.15-0.24 mm) on the size and morphology of the cholesterol particles produced by the RESS process. The characterization of the particles was carried out using scanning electron microscopy (SEM) and X-ray diffraction (XRD) measurements to evaluate the performance of RESS process. The average particle size of the original material was 55 μm ± (2.84) while the average particle size of cholesterol after size reduction via the RESS process was between the minimum of 0.62 μm ± (0.03) and the maximum of 4.83 μm ± (0.18) depending upon the experimental conditions used. It was observed that both increasing the temperature from 40 to 60 °C and increasing the nozzle diameter from 0.15 to 0.24 mm result a reducing effect on the average particle size, whereas extraction pressure (100-160 bar) change has slight effect on the average particle size.     

Investigation of the rapid expansion of supercritical solution parameters effects on size and morphology of cephalexin particles

The particle size of organic and inorganic materials is vital parameter to determine its final use. Most of the newly developed pharmaceutical materials are poorly soluble or insoluble in the aqueous media such as biological fluids. Particle size reduction of such pharmaceuticals is one of the clues to improve the dissolution rate, adsorption and bioavailability. In this study, the effect of extraction and expansion parameters of the RESS process such as extraction temperature (313–333 K), extraction pressure (140–230 bar), effective nozzle diameter (450–1700 μm), nozzle length (2–15 mm) and spraying distance (1–7 cm) on the size and morphology of the precipitated particles of cephalexin were investigated. The morphology and particle size of the unprocessed and processed (precipitated) particles were examined by the SEM images. The mean particle size of the precipitated particles was between 0.86 and 7.22 μm depending upon the different experimental conditions used. The precipitated cephalexin particles were close to spherical form while the unprocessed particles were irregular or needle in shape.     

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.     

Micronization of creatine monohydrate via Rapid Expansion of Supercritical Solution (RESS)

In the pharmaceutical industry, an even greater number of products are in the form of particulate solids. In the case of pharmaceutical substances the particle size is quite important since it can limit the bioavailability of poorly water soluble drugs. Since the mid-1980s, a new method of powder generation has appeared involving crystallization with supercritical fluids. In this study, RESS was used to micronize the creatine monohydrate particles. The RESS process consists in solvating the product in the fluid and rapidly depressurizing this solution through an adequate nozzle, causing an extremely rapid nucleation of the product into a highly dispersed material. In addition, the effect of six different RESS parameters including, extraction temperature (313-333 K), extraction pressure (140-220 bar), nozzle length (2-15 mm), effective nozzle diameter (450-1700 μm), spraying distance (1-7 cm) and pre-expansion temperature (353-393 K) were investigated on the size and morphology of the precipitated particles of creatine monohydrate. The characterization (size and morphology) of the precipitated particles of creatine monohydrate was determined by scanning electron microscopy (SEM). The results show great reduction in the size of the precipitated particles of creatine monohydrate (0.36-9.06 μm) compared with the original particles of creatine monohydrate. Moreover, a slight change into spherical form was observed for the precipitated particles of creatine monohydrate while the original particles were irregular in shape.     

Micronization of salicylic acid and taxol (paclitaxel) by rapid expansion of supercritical fluids (RESS)

The particle sizes of the pharmaceutical substances are important for their bioavailability. The bioavailability can be improved by reducing the particle size of the drug. In this study, salicylic acid and taxol were micronized by the rapid expansion of supercritical fluids (RESS). Supercritical CO₂ and CO₂ + ethanol mixture were used as solvent. Experiments were carried out to investigate the effect of extraction temperature (318–333 K) and pressure (15–25 MPa), pre-expansion temperature (353–413 K), expansion chamber temperature (273–293 K), spray distance (6–13 cm), co-solvent concentration (ethanol, 1, 2, 3, v/v, %) and nozzle configuration (capillary and orifice nozzle) on the size and morphology of the precipitated salicylic acid particles. For taxol, the effects of extraction pressure (25, 30, 35 MPa) and co-solvent concentration (ethanol, 2, 5, 7, v/v, %) were investigated. The characterization of the particles was determined by scanning electron microscopy (SEM), optical microscopy, and LC–MS analysis.The particle size of the original salicylic acid particles was L/D: 171/29–34/14 μm/μm. Depending upon the different experimental conditions, smaller particles (L/D: 15.73/4.06 μm/μm) were obtained. The particle size of taxol like white crystal powders was reduced from 0.6–17 μm to 0.3–1.7 μm The results showed that the size of the precipitated salicylic acid and taxol particles were smaller than that of original particles and RESS parameters affect the particle size.     

超临界流体快速膨胀法制备超细阿昔洛韦粒子

以二氧化碳作为超临界溶剂,采用超临界溶液快速膨胀技术制备得到超细阿昔洛韦药物粒子,在一定的温度和压力情况下,测定了阿昔洛韦在超临界二氧化碳中的溶解度,考察了各种操作参数对药物粒子粒径的影响,研究了药物粒子粒径随各种操作参数的变化规律。结果表明:阿昔洛韦在超临界二氧化碳中的溶解度较小,在10-5~10-6之间(摩尔分率),溶解度随着温度和压力的升高而增大,不存在文献中所报道的反向区。同时实验结果表明:药物粒子粒径变化对预膨胀温度最敏感,粒径随预膨胀温度的升高而减小;一定范围内随收集距离的增大而增大;在萃取温度较低的情况下,粒子粒径基本随着萃取温度的升高而减小;随着萃取温度的升高,在相对较高预膨胀温度下,粒径随着萃取温度升高而增大。     

Effect of titanium–magnesium catalyst morphology on the properties of polypropylene upon propylene polymerization in a liquid monomer

The effect of the particle size of an IK-8-21 domestic titanium-magnesium catalyst on the properties of polypropylene (PP) produced during the polymerization of propylene in a liquid monomer is studied. Catalysts with particle sizes of 20 to 64 μm are shown to have high activity and identical sensitivity to hydrogen and allow PP to be obtained with a narrow distribution of particles over size, high isotacticity, and close values of crystallinity, melting temperature, and physicomechanical properties. A slight decrease in the activity and bulk density of PP powder is observed when the average size of catalyst particles is increased from 20 to 43 μm. A more notable reduction in the activity and bulk density of PP powder is observed for catalyst with particle sizes of 62 to 64 μm. IK-8-21 catalyst is not inferior to its foreign analogues with respect to the properties of the resulting PP.     

超临界流体快速膨胀法制备超细氟比洛芬粒子

文章选用二氧化碳作为超临界溶剂,采用超临界溶液快速膨胀技术制备超细氟比洛芬药物粒子,在较宽的温度压力范围内测定了氟比洛芬在超临界二氧化碳中的溶解度,考察了各种操作参数对药物粒子粒径的影响,研究了药物粒子粒径随各种操作参数的变化规律。结果表明：在实验考察的范围内,氟比洛芬的溶解度较小,在10-5~10-7之间（摩尔分率）,溶解度随着温度和压力的升高而增大。同时实验结果表明：粒径随预膨胀压力的升高而减小;一定范围内随接收距离的增大而增大;在萃取温度较低的情况下,粒子粒径基本随着萃取温度的升高而减小;随着萃取温度的升高,在相对较高预膨胀温度下,粒径随着萃取温度升高而增大。     

Micronization of Three Active Pharmaceutical Ingredients Using the Rapid Expansion of Supercritical Solution Technology

The rapid expansion of supercritical solution (RESS) technology was applied to recrystallize and micronize three active pharmaceutical ingredients (APIs) of monobenzone, ethylparaben, and kojic acid. All unprocessed (original) APIs had a large mean particle size over 200 μm with wide particle size distribution. Supercritical carbon dioxide served as the solvent to extract each API in a high-pressure vessel. The nearly saturated supercritical solution was then expanded through a capillary spray nozzle to ambient pressure state. The APIs were recrystallized in a very short time period. The final API particles with submicron sizes were obtained with much less intensity of crystallinity. The optimal RESS process parameters and the improved result of the in vitro dissolution test for the API of ethylparaben are reported.     

Preparation and characterization of camptothecin powder micronized by a supercritical antisolvent (SAS) process

Micronized camptothecin (CPT) is prepared with a supercritical antisolvent (SAS) apparatus using dimethyl sulfoxide (DMSO) as solvent and carbon dioxide as antisolvent. Four factors, namely CPT solution concentration and flow rate, precipitation temperature and pressure are optimized by a four-level orthogonal array design (OAD). By analysis of variance (ANOVA), only precipitation pressure has a significant effect on the MPS of micronized CPT. The optimum micronization conditions are determined as follows: CPT solution concentration 1.25 mg/ml, CPT solution flow rate 6.6 ml/min, precipitation temperature 35 °C and precipitation pressure 20 MPa. Under the optimum conditions, micronized CPT with a MPS of 0.25 ± 0.020 μm is obtained. The micronized CPT obtained was characterized by Scanning Electron Microscopy (SEM), Atomic Force Microscope (AFM), High performance liquid chromatography-mass spectrometry (LC-MS), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Differential scanning calorimeters (DSC) and Gas chromatography (GC) analyses. The results showed that the obtained CPT particles have lower crystallinity and SAS micronization process does not induce degradation of CPT. In addition, the residual DMSO is less than the ICH limit for class 3 solvents.     

Preparation of submicron-sized RDX particles by rapid expansion of solution using compressed liquid dimethyl ether

Cyclotrimethylenetrinitramine (RDX) was precipitated to submicron-sized particles with spherical morphology by the rapid expansion from supercritical solution (RESS). Compressed liquid dimethyl ether (DME) was used as a solvent for the RDX. This study examined the influence of extraction temperature (293-333 K), extraction pressure (8-20 MPa) and size of orifice nozzle (50, 100, 200, and 250 μm) on the size and morphology of the RDX particles in the RESS process. The precipitated RDX particles were characterized by using the following instruments: field emission scanning electron microscope (FE-SEM), image analyzer, powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy, and differential scanning calorimetry (DSC). The precipitated RDX particles showed granular and spherical morphologies, submicron-sized particles, and narrow particle size distributions. The mean particle size of the precipitated RDX ranged from 2.48 to 0.36 μm, and the crystallinity of the precipitated RDX decreased. The enthalpy change for the exothermic decomposition of the precipitated RDX (ΔH = 714.4 J/g) was much higher than that of the original RDX (ΔH = 381.5 J/g).     

Formation and stabilization of submicron particles via rapid expansion processes

Submicron particles were produced by rapid expansion of supercritical solution into air (RESS) or an aqueous surfactant solution (RESSAS) to minimize particle growth and to prevent particle agglomeration. Thereby the effect of process conditions on the size of the particles precipitated was investigated. The obtained product was evaluated by measuring particle size by 3-wavelength extinction measurements, dynamic light scattering, specific surface areas by nitrogen gas adsorption, melting behaviour by differential scanning calorimetry, particle morphology by X-ray diffraction, scanning electron micrographs (SEM), and drug loading by high performance liquid chromatography.Prior to the particle formation experiments, the melting temperature of Salicylic acid under CO₂ pressure and the solubility of Salicylic acid in CO₂ were measured. The size of Salicylic acid particles produced via RESS decreased from 230 to 130 nm as the pre-expansion temperature decreased from 388 to 328 K and the specific surface area of the micronized particles was found to be up to 60 times higher than that of the unprocessed material. RESSAS experiments demonstrate that in 1 wt.% Tween 80 solutions Salicylic acid concentrations of 4.6 g/dm³ could be stabilized with particle diameters in the range of 180 nm. Additional experiments show that Ibuprofen nanoparticles with an average size of 80 nm and a drug concentration of 2.4 g/dm³ could be stabilized in 1 wt.% Tween^® 80 solutions. The use of a SDS solution instead of Tween^® 80 results in a stable aqueous suspension of phytosterol nanoparticles, where the average particle size is 50 nm at a drug concentration of 5.6 g/dm³.     

Process performances and characteristics of powders produced using supercritical CO2 as solvent and antisolvent

A carbon dioxide (CO₂) soluble compound (cholesterol) was successfully precipitated either by rapid expansion of SCCO₂ solutions (RESS process, acronym for Rapid Expansion of Supercritical Solution), or from methylene chloride solutions by antisolvent precipitation (SAS-process, acronym for Supercritical Antisolvent process). The same fluid was thus used either as a solvent or as an antisolvent to precipitate cholesterol. Performances of RESS and SAS were compared through the analysis of the particle characteristics and production rates. Differences were related to supersaturation and time scale of nucleation/growth involved in both processes. Polydispersity, large size and elongated shape were characteristics of particles produced by SAS, especially when experiments were performed under conditions of total miscibility of CO₂ and organic solvent. Conditions where vapor-liquid equilibrium exists promoted a confinement of the growth that consequently reduced the final particle size. RESS, by comparison, produced smaller and monodispersed particles. Production of small particles is a key advantage for RESS, but lower production rates and yield might be disadvantages. The combination of the two processes offers the opportunity of tunable sizing of powder, switching from a large production of particles ranging from 10 to 100 μm, to a limited production of fine crystals below 10 μm.     

Micronization of drug particles via RESS process

The rapid expansion of a supercritical solution (RESS) process is an attractive technology for the production of small, uniform and solvent-free particles of low vapour pressure solutes. The RESS containing a nonvolatile solute leads to the loss of solvent power by the fast expansion of the supercritical solution through an adequate nozzle, which can cause solute precipitation. The nozzle configuration plays an important role in RESS method and has a great effect on the size and morphology of the precipitated particles. In this study, ibuprofen was used as a simple test. In addition, besides the nozzle configuration, the effect of other parameters including extraction pressure (140-220 bar), extraction temperature (313-333 K), spraying distance (1-10 cm) and pre-expansion temperature (363-423 K) was investigated on the size and morphology of the precipitated particles of mefenamic acid. The SEM images also show that the precipitated particles of ibuprofen and mefenamic acid had a slight modification in morphology.