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.     

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 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.     

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.     

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.     

超临界溶液快速膨胀法制备二氯二茂钛微粒及催化乙烯聚合

为克服茂金属催化剂得到的聚合物形态难以控制、表观密度较低、易粘釜和不适于气相淤浆聚合等缺点,以超临界溶液快速膨胀过程为手段,以期制得颗粒分布均匀的细微催化剂颗粒,继而得到形态良好的聚合物.作为超临界流体技术的基础,首先测定了二氯二茂钛在超临界丙烷中的溶解度.在此基础上,用RESS方法制得了均匀的超细催化剂颗粒,且系统考察了溶液浓度、预膨胀温度、喷嘴结构和接收距离对沉析颗粒粒径的影响.最后,将RESS所制得的催化剂颗粒进行乙烯淤浆聚合,并分析聚合物形态结构.实验结果表明,在温度为383.15～408.15 K和压力为10～35 MPa范围内,溶解度随温度的增加而增加,随压力的升高而增加,说明在该操作范围内,不存在反向区.RESS操作的结果显示,二氯二茂钛颗粒粒径随溶液浓度的增大而减小,随预膨胀温度的升高而增大,而喷嘴直径的减小和喷嘴长度的增加将使得颗粒粒径增大,而收集距离的增加将使得颗粒粒径先增加后减缓,直至不再变化.通过对原始的催化剂颗粒和RESS制得的催化剂颗粒进行乙烯淤浆聚合表征发现,相比于原始催化剂,由于烯烃催化剂的复制原理,RESS制得的催化剂颗粒的聚合物具有良好的形态.     

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).     

异丙醇铝在超临界丙烷中的溶解度与粒子制备

选用丙烷作溶剂在不同条件下进行超临界溶液快速膨胀（Rapid Expansion of Su-percritical Solution-RESS）制备异丙醇铝超细粒子的实验研究。同时用流动法装置测定了温度为388.15K和403.15K、压力为（21.5～30.5）MPa条件下异丙醇铝在超临界丙烷中的溶解度,并对其进行了关联计算。     

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.     

超临界流体溶液快速膨胀法制备灰黄霉素微细颗粒

研究了通过超临界流体溶液快速膨胀 (RESS)技术制取灰黄霉素微细颗粒的过程 .在自行设计的实验装置上研究了RESS过程各操作变量对所制得的灰黄霉素颗粒粒度的影响 .研究结果表明 ,采用RESS方法可以制得符合粒度要求的灰黄霉素微细化产品     

Fabrication of fine microcapsulated red phosphorus particles by SCF-RESS with a new structure nozzle

A novel process of preparing microencapsulated red phosphorus particles by rapid expansion of supercritical fluids (RESS) was tested, in which a new kind of nozzle and supercritical CO₂ as a solvent were used. The structure of the microencapsulated red phosphorus particles were characterized by scanning electron microscope (SEM) and transmission electron microscope (TEM). These results show that red phosphorus particles can be effectively encapsulated with paraffin by using the method. At the same time, how the moisture absorption ratio of microencapsulated red phosphorus particles was dependent on the experimental conditions was further investigated. The results suggest that paraffin-microencapsulated red phosphorus particles show a lower moisture absorption ratio within the experimental conditions of the extraction column and nozzle temperature of 120°C, extraction column pressure of more than 16 MPa, and a mass flow of core particles (0.5 g/min).     

Preparation of liposomes entrapping essential oil from Atractylodes macrocephala Koidz by modified RESS technique

A modified technique of rapid expansion of supercritical solutions (RESS) was applied to incorporate essential oil extracted from Atractylodes macrocephala Koidz into liposomes. In the modified RESS process, both the liposomal materials and the essential oil were dissolved in the mixture of supercritical carbon dioxide (SC-CO₂)/ethanol and then the solution was sprayed into an aqueous medium through a coaxial nozzle to form liposomes suspension. The encapsulation performance of liposomes could be controlled by changing expansion processing conditions such as pressure, temperature of SC-CO₂ and the amount of ethanol. The entrapment efficiency, drug loading and average particle size of liposomes were found to be 82.18%, 5.18% and 173 nm, respectively, under the optimum conditions of at a pressure of 30 MPa, a temperature of 338 K and a ethanol mole fraction in SC-CO₂ [(x(CH₃CH₂OH)] of 15%. The formed liposomes appeared as double-layered colloidal spheres with a uniform and narrow particle size distribution. The physicochemical properties of liposomes including entrapment efficiency, dissolution rate and stability were complied with the provisions of Chinese pharmacopoeia. All these results indicate that the modified RESS technique is an innovative way for self-assembly of liposomes incorporation of multi-components extracted from Chinese traditional medicines in the SC-CO₂.     

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。     

Supercritical antisolvent precipitation of andrographolide from Andrographis paniculata extracts: Effect of pressure, temperature and CO2 flow rate

Andrographis paniculata extracts were precipitated using the so-called supercritical antisolvent (SAS) technique. Ethanol was used as the solvent and compressed CO₂ as the antisolvent. The effects of process operating conditions (pressure: 5-24 MPa, temperature: 308-328 K and CO₂ flow rate: 0.5-1.5 g/min) on particle size and morphology of precipitated andrographolide were evaluated. X-ray diffraction (XRD) patterns showed significant changes in andrographolide morphology depending on process operating conditions; both column-like and slice-like crystals were observed depending on operating conditions. Crystals with mean diameters of 3.30-228.35 μm were produced, smaller crystals were obtained at high pressure, low temperature and high CO₂ flow rate and vice versa for large crystals. In addition, SAS process also produced high precipitation yields, since solubility of andrographolide is small in the supercritical CO₂ plus ethanol. When operating under subcritical conditions, amorphous particles were produced.     

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。     

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。     

Design and characteristic analysis of a new nozzle for preparing microencapsulated particles by RESS

A new nozzle was designed for the technology of making microencapsulated particles by rapid expansion of supercritical solution (RESS). The design is based on the theory of gas dynamics in which the potential energy of high stagnation pressure is converted totally into effective velocity energy. Therefore, a high momentum of the exit jet can be obtained for improving the capability of removing molten debris quickly. Furthermore, the microencapsulated red phosphorus particles were prepared by RESS with the new nozzle, and the structure and property of the microencapsulated red phosphorus particles were characterized by the SEM images, droplet concentration distributions, and moisture absorption ratio. The results show that the process can effectively encapsulate the red phosphorus particles with the paraffin.     

Preparation and Characterization of Micronized Artemisinin via a Rapid Expansion of Supercritical Solutions (RESS) Method

The particle sizes of pharmaceutical substances are important for their bioavailability. Bioavailability can be improved by reducing the particle size of the drug. In this study, artemisinin was micronized by the rapid expansion of supercritical solutions (RESS). The particle size of the unprocessed white needle-like artemisinin particles was 30 to 1200 μm. The optimum micronization conditions are determined as follows: extraction temperature of 62 °C, extraction pressure of 25 MPa, precipitation temperature 45 °C and nozzle diameter of 1000 μm. Under the optimum conditions, micronized artemisinin with a (mean particle size) MPS of 550 nm is obtained. By analysis of variance (ANOVA), extraction temperature and pressure have significant effects on the MPS of the micronized artemisinin. The particle size of micronized artemisinin decreased with increasing extraction temperature and pressure. Moreover, the SEM, LC-MS, FTIR, DSC and XRD allowed the comparison between the crystalline initial state and the micronization particles obtained after the RESS process. The results showed that RESS process has not induced degradation of artemisinin and that processed artemisinin particles have lower crystallinity and melting point. The bulk density of artemisinin was determined before and after RESS process and the obtained results showed that it passes from an initial density of 0.554 to 0.128 g·cm(-3) after the processing. The decrease in bulk density of the micronized powder can increase the liquidity of drug particles when they are applied for medicinal preparations. These results suggest micronized powder of artemisinin can be of great potential in drug delivery systems.     

Precipitation and encapsulation of β-carotene in PHBV using carbon dioxide as anti-solvent

The main objective of this work was to investigate the application of supercritical carbon dioxide as anti-solvent for the encapsulation of β-carotene in poly(hydroxybutirate-co-hydroxyvalerate) (PHBV) with dichloromethane as organic solvent using the Solution Enhanced Dispersion by Supercritical fluids (SEDS) technique. For the precipitation experiments with pure compounds the parameters investigated were the concentration of β-carotene (4 and 8 mg mL⁻¹) and PHBV (30 mg mL⁻¹) in the organic solution, pressure (from 80 to 200 bar), solution flow rate fixed at 1 mL min⁻¹, anti-solvent flow rate at 40 mL min⁻¹ and constant temperature of 313 K. Pure β-carotene precipitation indicates that an increase in pressure led in most cases to particles with larger sizes, while the opposite trend was verified for pure PHBV precipitation. The morphology of precipitated PHBV particles was spherical and was not influenced by increasing pressure. The morphology of β-carotene microparticles changed from plate-like to leaf-like particles when raising operational pressure, but was not influenced by its concentration in the organic solution as verified by micrographs of scanning electronic microscopy (SEM). For the co-precipitation experiments it was evaluated the effect of β-carotene concentration (2-30 mg mL⁻¹) in the organic solution, at fixed parameters: PHBV concentration (30 mg mL⁻¹) in organic solution, temperature at 313 K, pressure at 80 bar, solution flow rate at 1 mL min⁻¹ and anti-solvent flow rate at 40 mL min⁻¹. The encapsulation data showed that increasing the concentration of β-carotene, keeping fixed the PHBV content, results in higher percentage of solute encapsulated, increasing the encapsulation efficiency.