New Insights into Acrylic Polymer Precipitation by Supercritical Fluids

Nanosystems based on polymers have attracted much attention due to the almost infinite diversity. In the past decades, the application of supercritical fluids for polymeric particle precipitation has been developed as an alternative to conventional processes. Here, precipitation of an acrylic copolymer was attempted by the rapid expansion of supercritical solutions (RESS) and successful by supercritical antisolvent (SAS) processes. In addition, the nanoparticles were characterized with different techniques. The polymer concentration, pressure, temperature, liquid solution flow rate and nozzle diameter effects were also evaluated with regard to particle size and the particle size distribution of this polymer.     

Preparation of poly(L‐lactide) microparticles by a supercritical antisolvent process with a mixed solvent

Poly(L ‐lactide) (PLLA) microparticles were prepared by a supercritical antisolvent (SAS) process with a mixed solvent. Five factors, namely, the molar percentage of acetone, pressure, temperature, flow rate, and concentration of the solution, were optimized by a four‐level orthogonal array design. By analysis of variance, the concentration of the solution showed a significant effect on the PLLA microparticle size. The effects of the mixed solvent (dichloromethane/acetone) at different mixing ratios, pressures, and temperatures on the morphology of the PLLA microparticles were also investigated. The thermal properties of PLLA before and after the SAS process were studied by differential scanning calorimetry. The results indicate that the molar percentage of acetone had a significant effect on the morphology of the PLLA microparticles. The microparticles prepared with the mixed solvent were much smaller than those prepared with dichloromethane alone under the same conditions. Furthermore, the particle size distribution was more uniform in the case of the mixed solvent. The particle size decreased with increasing pressure, whereas it showed no significant change with increasing temperature. The results also show that the thermal properties of PLLA could be improved through the SAS process. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Interactions of phase equilibria,jet fluid dynamics and mass transfer during supercritical antisolvent micronization

Supercritical antisolvent (SAS) precipitation has been successfully used in the micronization of several compounds. Nevertheless, the role of high-pressure vapor–liquid equilibria, jet fluid dynamics and mass transfer in determining particle size and morphology is still debated. In this work, CO₂ has been adopted as supercritical antisolvent and elastic light has been used to acquire information on jet fluid dynamics using thin wall injectors for the investigation of the liquid solvents acetone and DMSO at operating conditions of 40 °C in the pressure range between 6 and 16 MPa. The results show that two-phase mixing after jet break-up is the phenomenon that characterizes the jet fluid dynamics at subcritical conditions. When SAS is performed at supercritical conditions a transition between multi-phase and single-phase mixing is observed by increasing the operating pressure. Single-phase mixing is due to the very fast disappearance of the interfacial tension between the liquid solvent and the fluid phase in the precipitator. The transition between these two phenomena depends on the operating pressure, but also on the viscosity and the surface tension of the solvent. Indeed, single-phase mixing has been observed for acetone very near the mixture critical point, whereas DMSO showed a progressive transition for pressures of about 12 MPa.In the second part of the work, a solute was added to DMSO to study the morphology of the microparticles formed during SAS precipitation at the different process conditions, to find a correlation between particle morphology and the observed jet. Expanded microparticles were obtained working at subcritical conditions; whereas spherical microparticles were obtained operating at supercritical conditions up to the pressure where the transition between multi- and single-phase mixing was observed. Nanoparticles were obtained operating far above the mixture critical pressure. The observed particle morphologies have been explained considering the interplay among high-pressure phase equilibria, fluid dynamics and mass transfer during the precipitation process.     

Supercritical CO2 Spray Drying of Ethyl Cellulose (EC) for Preparing Microparticles

Even though common spray drying has been widely used for drying food and related products, the effect of drying conditions of supercritical CO₂ spray drying on the particle sizes of dried products has not been well studied. The objective of this study was to study the effect of drying conditions and design parameters on the particle sizes of biomaterials dried with supercritical CO₂ spray drying. The ethyl cellulose (EC) microparticles were prepared with supercritical CO₂ as the dry medium using an experimental spray-drying apparatus. This research studied the influences of spray nozzle diameter, mass ratio of gas to liquid, solution concentration, temperature, and pressure on the physical characteristics of ethyl cellulose microparticles. The results indicated that the average size of the dried particles ranged from 1.07 to 9.84 µm. The spray nozzle with 8-mm diameter produced smaller microparticles with narrower distribution than the 4-mm spray nozzle. The average particle size increased with the increase of the ratio of gas to liquid. Also, the average size and distribution of the microparticles increased with the rise of temperature and solution concentration but decreased with the increase of pressure.     

Supercritical CO2 Spray Drying of Ethyl Cellulose (EC) for Preparing Microparticles

Even though common spray drying has been widely used for drying food and related products, the effect of drying conditions of supercritical CO₂ spray drying on the particle sizes of dried products has not been well studied. The objective of this study was to study the effect of drying conditions and design parameters on the particle sizes of biomaterials dried with supercritical CO₂ spray drying. The ethyl cellulose (EC) microparticles were prepared with supercritical CO₂ as the dry medium using an experimental spray-drying apparatus. This research studied the influences of spray nozzle diameter, mass ratio of gas to liquid, solution concentration, temperature, and pressure on the physical characteristics of ethyl cellulose microparticles. The results indicated that the average size of the dried particles ranged from 1.07 to 9.84 µm. The spray nozzle with 8-mm diameter produced smaller microparticles with narrower distribution than the 4-mm spray nozzle. The average particle size increased with the increase of the ratio of gas to liquid. Also, the average size and distribution of the microparticles increased with the rise of temperature and solution concentration but decreased with the increase of pressure.     

过程参数对超临界抗溶剂法共沉淀紫杉醇-PLLA的影响(英文)

Paclitaxel(PTX) is an effective anticancer drug with poor solubility in water.Recently,much effort has been devoted into alternative formulations of PTX for improving its aqueous solubility.In this study,PTX and poly(L-lactic acid)(PLLA) were co-precipitated by a supercritical antisolvent(SAS) process using dichloromethane(DCM) and the mixtures of DCM/ethanol(EtOH) or DCM/dimethyl sulfoxide(DMSO) as the solvent,with super-critical carbon dioxide as the antisolvent.The effects of solvent,solvent ratio,temperature,pressure,polymer con-centration and solution flow rate on particle morphology,mass median diameter(Dp50) and PTX loading were in-vestigated using single-factor method.The particle samples were characterized using X-ray diffraction(XRD),scanning electron microscopy(SEM),laser diffraction particle size analyzer and high pressure liquid chromatogra-phy(HPLC).XRD results indicate that the micronized PTX is dispersed into the PLLA matrix in an amorphous form.SEM indicates that the solvent and the solvent ratio have great effect on the particle morphologies,and particle morphology is good at the volume ratio of DCM/EtOH of 50/50.For the mixed DCM/EtOH solvent,Dp50 increases with the increase of the temperature,pressure,PLLA concentration and solution flow rate,and PTX loading in-creases with pressure.Suitable operating conditions for the experimental system are as follows:DCM/EtOH 50/50(by volume),35 ℃,10-12 MPa,PLLA concentration of 5 g·L-1 and solution flow rate of 0.5 ml·min-1.     

Preparation of poly(L-lactic acid) submicron particles in aerosol solvent extraction system using supercritical carbon dioxide

The aerosol solvent extraction system process (ASES), which is one of the supercritical anti solvent processes (SAS), was used to produce poly(L-lactic acid) (PLLA) into the submicron particles. Dichloromethane (DCM, CH₂Cl₂) and carbon dioxide were selected as a solvent and as an antisolvent for PLLA, respectively. The objective of this study was to investigate the effect of the various process parameters such as temperature, pressure, and solution concentration on PLLA particles. With increasing temperature and pressure, particle size was increased. Also, higher PLLA concentration led to larger particle size and broader particle size distribution. A scanning electron microscope (SEM) was used to observe the morphology and size of PLLA particles recrystallized by ASES process. The mean particle size and its distribution of processed particles were measured by using a laser diffraction particle size analyzer (PSA).     

Supercritical antisolvent micronization of cyclodextrins

Micronization of α- and β-cyclodextrins solubilized in dimethylsulfoxide (DMSO) has been successfully performed using the Supercritical AntiSolvent (SAS) precipitation. We obtained sub-microparticles, microparticles and expanded microparticles of both cyclodextrins, ranging from about 0.1 to 11 μm, varying the concentration of the liquid solution from 5 to 200 mg/mL, process temperature (40-60 °C) and pressure (90-180 bar). Particularly, we observed for both materials that, increasing the concentration of the liquid solution, decreasing the pressure or increasing the temperature, the mean particle size increased and the particle size distribution enlarged.We also tried to relate the morphologies obtained to the position of the process operating point with respect to the mixture critical point (MCP) of the ternary system cyclodextrin-DMSO-CO₂.     

超临界流体技术制备三棕榈酸甘油酯微粒

利用气体饱和溶液微粒形成技术实验装置,分别用超临界N2和超临界Co2制备三棕榈酸甘油酯微粒,探讨压力、温度以及喷嘴大小等工艺参数对微粒（粒径、粒径分布和形貌）的影响。结果表明：N2辅助过程得到的微粒基本为球状;预膨胀压力越高,粒径越小,粒径分布越窄;100μm喷嘴下制得的微粒粒径最小,且分布较均匀。CO2辅助过程得到的微粒部分为球状,部分为针状和片状;预膨胀压力越高,粒径越小,粒径分布越窄;喷嘴直径大小对微粒平均粒径及粒径分布影响不大;预膨胀温度升高,颗粒的粒径稍微增大。CO2辅助过程得到的微粒粒径比N2辅助过程得到的微粒粒径稍大,但两者的粒径分布相差不大。     

Preparation of L-PLA submicron particles by a continuous supercritical antisolvent precipitation process

Submicron particles of L-polylactic acid (L-PLA) without residual solvent were prepared by a continuous supercritical antisolvent (SAS) recrystallization process. Methylene chloride (CH₂C1₂) was used as a carrier solvent of L-PLA. Experiments were performed with changing process parameters such as pressure and temperature at constant concentration. Also, L-PLA initial concentrations in methylene chloride were varied from 0.3 to 4 wt%. The flow rates of CO₂ and solution, which were introduced into the precipitator, and nozzle diameter were kept unchanged in all of the experiments. It was found that the SAS process gives fine tuning of particle size and particle size distribution (PSD) by simple manipulations of the process parameters. In all cases of SAS recrystallization experiments, the formed spherical fine particles with a smooth surface were non-agglomerated and free flowing. Mean particle size of the L-PLA microparticles formed was varied from 0.1 to 1 μm by means of adjusting the system pressure and/or temperature.     

Co-precipitation of 10-hydroxycamptothecin and poly (l-lactic acid) by supercritical CO2 anti-solvent process using dichloromethane/ethanol co-solvent

In this study, 10-hydroxycamptothecin (HCPT) and poly (l-lactic acid) (PLLA) are co-precipitated by the supercritical anti-solvent (SAS) process using a mixture of dichloromethane (DCM)/ethanol (EtOH) as co-solvent, and supercritical carbon dioxide as the anti-solvent. The effect of five operating conditions on particle morphology, mass median diameter (Dp₅₀) and HCPT loading is investigated using the single-factor method. The results indicate that HCPT loading can be greatly increased by using DCM/EtOH co-solvent, and the suitable operating conditions for the experimental system are determined. Under suitable conditions, the HCPT loading is 13.3% and Dp₅₀ is 794.5 nm. The drug loaded microparticles are characterized in detail. The SEM images showed that most of the particles were spherical, and PLLA concentration has a major impact on the particle shape. Results of TEM, DSC and XRD indicate that the micronized HCPT is dispersed into the PLLA matrix. For low HCPT loading, most of HCPT existed in the drug loaded microparticles in an amorphous state, but for high HCPT loading, part of the encapsulated drug existed in crystalline form. FT-IR results show that SAS process does not change the chemical structure of HCPT. The result of in vitro drug release test indicated that the crystallinity of HCPT in microparticles affects the control release performance, and the good encapsulated microparticles with higher HCPT loading and higher crystallinity are better.     

Precipitation of pharmaceuticals using a supercritical anti‐solvent (SAS) dechnique: A preliminary study

The aims of this research were to investigate the applicability of the supercritical anti‐solvent (SAS) process on the precipitation of pharmaceuticals (andrographolide and acetaminophen). In particular, the goal of this research was to study the influence of pressure at 10 and 24 MPa on particle characteristics (morphology, crystalline structure, polymorphic form, size, size distribution, and precipitation yield), and to compare the precipitation efficiency of SAS process and evaporation process. Scanning electron microscope (SEM), X‐ray diffraction (XRD), and high performance liquid chromatography (HPLC) showed a significant change in particle size, size distribution, morphology, and precipitation yield, respectively. From an analysis of the results it was found that the crystal size of andrographolide and acetaminophen decreased with increasing pressure. The morphology of andrographolide particles changed from slice‐like to column‐like when the pressure was increased. On the other hand, the acetaminophen particles obtained were found to be monoclinic form (I) under both operating pressures. The SAS process produced small uniform shaped crystals, with a narrow size distribution, high precipitation yield and selective precipitation were also observed.     

Processing naproxen with supercritical CO2

Naproxen has been processed with supercritical fluids in order to improve the dissolution rate and bioavailability. Microparticles of naproxen have been obtained by a Rapid Expansion of Supercritical Solutions (RESS) process in which carbon dioxide has been used as a solvent and methanol as a cosolvent. The influence of extraction pressure (200–300 bar) and extraction temperature (60 °C and 100 °C) on the naproxen precipitation has also been investigated. In general, the morphology of the precipitated particles improved and particle size (PS) decreased in comparison to the raw material. Lower extraction pressure and higher extraction temperature led to a smaller particle size. On the other hand, a supercritical antisolvent (SAS) process has been applied due to the relative medium solubility values of naproxen in supercritical carbon dioxide, with precipitation obtained successfully in all cases. The initial concentration of the solution and the solvent effect has both been analysed. Morphologies and mean diameter ranges have been analysed by scanning electron microscopy (SEM) and the influence on crystallinity of both supercritical processes has been evaluated by X-ray diffraction (XRD) measurements.     

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.     

超临界微粒化技术及其催化剂制备方面的应用

超临界流体用于制备超细粒子是一项新的技术,笔者综述了两种形成微粒的方法:超临界快速膨胀法(RESS)和超临界抗溶剂法(SAS),并对以SAS为基础的新技术气溶胶溶剂萃取(ASES)、超临界流体溶液分散法(SEDS)、强化传质超临界抗溶剂过程(SAS-EM)原理进行了简洁的介绍.且简洁介绍了影响粒子尺寸和分布的相关因素.着重说明了超临界流体技术在催化剂方面的应用,最后指出了该技术存在的主要问题和发展前景.     

Influence of pressure, temperature and concentration on the mechanisms of particle precipitation in supercritical antisolvent micronization

In this work, supercritical antisolvent micronization (SAS) is used to produce nanoparticles, microparticles and expanded microparticles of a model compound, gadolinium acetate (GdAc), using dimethylsulfoxide (DMSO) as the liquid solvent with the aim of studying the dependence of particles’ diameter and morphology on some process parameters like pressure, temperature and concentration of the starting solution. Experiments are performed varying the precipitation pressure between 90 and 200 bar, the precipitation temperature between 35 and 60 °C and the concentration of GdAc in the liquid solution in the range from 20 to 300 mg/mL. The experimental evidences show that the formation of particles with specific sizes in the micrometric and nanometric range depends on specific values of each one of these parameters. An explanation of the results is proposed in terms of the competition between two characteristic times of the SAS process that can control the precipitation process. The time of jet break-up of the liquid solution that produces liquid droplet formation, and the dynamic surface tension vanishing time, that induces gas mixing with the precipitation of nanoparticles from the gaseous phase. Indeed, GdAc sub-microparticle, or microparticle (diameter in the range 0.23-1.6 μm with mean diameters in the range 0.28-0.52 μm) formation can be attributed to micro-droplet drying, whereas nanoparticles (mean diameter in the range 90-210 nm) are consistently produced when gas mixing is the possible governing process. In conclusion, the precipitation mechanisms can be modulated varying one SAS parameter a time, thus selecting the range of particle diameters required for the specific application.     

Particle formation in supercritical fluids—Scale-up problem

The process of antisolvent precipitation of particles, termed solution enhanced dispersion by supercritical fluids (SEDS™), is applied to precipitate the model drug, paracetamol, from ethanol solutions. In the SEDS process the substrate solution is quickly mixed in a mixing chamber of the coaxial two-component nozzle with an antisolvent, represented in this case by the supercritical CO₂. Resulting partially mixed, highly supersaturated solution is introduced into the precipitation vessel as a jet, which generates intensive circulation of residual fluids that dilute the fresh supersaturated solution. Nucleation starts in the nozzle chamber, whereas particle growth completes the process in the precipitation vessel. The process is carried out above the mixture critical pressure; the antisolvent is thus completely miscible with the solvent. Under such conditions the macro-, meso-, and micro-mixing processes can affect the particle size distribution (PSD) and should be considered when the process is scaled up. Scaling up considerations of the precipitation process are based on scale-up rules, CFD simulations and experimental data for paracetamol precipitation. In simulations the model presented earlier (Ba?dyga et al., 2004) that is based on the population balance equation and CFD modelling of compressible flow processes is applied. Results of experimental investigations and numerical simulations are applied to verify scale-up strategies for the SEDS processes.     

Co-precipitation of amoxicillin and ethyl cellulose microparticles by supercritical antisolvent process

Microparticles of ethyl cellulose (EC) and amoxicillin (AMC) have been precipitated by a supercritical antisolvent process (SAS) using CO₂ as the antisolvent and a mixture of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) as solvents. Combinations of three temperatures (308, 323 and 333 K) and four pressures (100, 150, 200 and 250 bar) were assessed in the vessel and the rest of the variables were held constant (i.e. CO₂ flow rate, sample flow rate, washing time, nozzle diameter and the amoxicillin:ethyl cellulose ratio). Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and elemental analysis (EA) were used to determine the particle size and shape and to confirm the presence of both compounds in the resulting precipitates. In most cases, mixed amoxicillin and ethyl cellulose particles were produced with sizes in the micrometer range. Pressure and temperature effects on the co-precipitation were investigated. The release behaviour of the microparticles precipitated by the SAS process was evaluated in two biological fluids – simulated gastric and simulated intestinal fluids. Co-precipitated materials allowed a slower drug release rate than pure drug.     

Micronization of taxifolin by supercritical antisolvent process and evaluation of radical scavenging activity

The aim of this study was to prepare micronized taxifolin powder using the supercritical antisolvent precipitation process to improve the dissolution rate of taxifolin. Ethanol was used as solvent and carbon dioxide was used as an antisolvent. The effects of process parameters, such as temperature (35-65 °C), pressure (10-25 MPa), solution flow rate (3-6 mL/min) and concentration of the liquid solution (5-20 mg/mL) on the precipitate crystals were investigated. With a lower temperature, a stronger pressure and a lower concentration of the liquid solution, the size of crystals decreased. The precipitation temperature, pressure and concentration of taxifolin solution had a significant effect. However, the solution flow rate had a negligible effect. It was concluded that the physicochemical properties and dissolution rate of crystalline taxifolin could be improved by physical modification such as particle size reduction using the supercritical antisolvent (SAS) process. Further, the SAS process was a powerful methodology for improving the physicochemical properties and radical scavenging activity of taxifolin.     

水力空化混合强化超临界流体辅助雾化制备罗红霉素超细微粒

分析了超临界流体辅助雾化（SAA）过程,发现饱和器内超临界二氧化碳与溶液的混合是SAA成功的关键因素之一,由此引入了水力空化混合器以强化饱和器内两相间的传质。在自行组建的引入水力空化混合器的超临界流体辅助雾化（SAA-HCM）装置上,以罗红霉素为模型药物,考察了混合器压力、沉淀器温度、溶剂、进料中CO₂与液体溶液流量比（R）和溶液浓度对微粒形态和粒径的影响。结果表明,水力空化混合器能有效地强化两相间的传质,SAA-HCM工艺可制备出罗红霉素超细微粒,大部分微粒形态呈球形,通过改变操作参数可制得粒径在1～3 μm的适于吸入式给药的气溶胶药物微粒和粒径小于1 μm的超细微粒。