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.     

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.     

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.     

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.     

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.     

Surface coating with poly(trifluoroethyl methacrylate) through rapid expansion of supercritical CO2 solutions

Rapid expansion of supercritical solutions (RESS) of poly(trifluoroethyl methacrylate), poly(TFEMA), was performed to produce ultrafine particles for spray coating application to improve the hydrophobicity of moisture-sensitive biodegradable materials. Carbon dioxide (CO₂) was used as the RESS solvent. Thermoplastic starch/poly(butylene adipate-co-terephthalate) (TPS/PBAT, 60:40 wt/wt) blend was used as the coating substrate. The objectives of this work were to determine the capacity of the RESS process for coating TPS-based material with poly(TFEMA), and to investigate the effect of RESS parameters – i.e. pre-expansion pressure and temperature (P_pre, T_pre) and poly(TFEMA) concentration – on the surface morphology and hydrophobicity of the coated materials. It was found that RESS produced poly(TFEMA) particles precipitated onto the surface of the TPS/PBAT substrate, with particle sizes ranging from 30 nm to several microns, depending on processing parameters. Rapid expansion of fluoropolymer solutions (0.3–1.0 wt%) with P_pre of 331 bar initiated from unsaturated conditions produced nanoparticles with a narrow size distribution of ∼30–70 nm; whereas larger particles with broader size distributions and a lower degree of agglomeration were obtained when supersaturated solutions were expanded with P_pre of 172 bar, especially at T_pre (80 °C) – higher than the glass transition temperature (73 °C) of poly(TFEMA). The surface coverage by the fluoropolymer increased with increasing P_pre and poly(TFEMA) concentration, but decreased with increasing T_pre. In addition, the hydrophobicity of the coated substrate, determined by water contact angle and water vapor transmission rate measurements, increased with increasing surface coverage.     

Formation of submicron poorly water-soluble drugs by rapid expansion of supercritical solution (RESS): Results for Naproxen

Numerous results of multitude investigations indicate that the particular properties of supercritical fluids can be conveniently exploited for the formation of submicron particles. In case of pharmaceutical substances the poor dissolution behaviour and therewith bioavailability of drugs in biological media can be enhanced dramatically by reduction of the particle size. In this paper we report the application of RESS (Rapid Expansion of Supercritical Solutions) and RESSAS (Rapid Expansion of Supercritical Solution into Aqueous Solution) to produce submicron particles of Naproxen, a poorly water-soluble drug. Thereby the effect of various process conditions on the obtained product properties was investigated. The experimental results show, that the RESS processing of Naproxen leads to particles in the range from 0.56 to 0.82 μm which is about 22 times smaller than the unprocessed powder. RESSAS experiments show, that stabilized Naproxen particles have an average diameter of 0.3 μm for drug concentrations up to 1 g/dm³ in 0.4 wt% PVP solution while expansion into a 0.4 wt% Tween^® 80 solution produced particles 8 μm in diameter. Furthermore, it is shown that the improved dissolution behaviour of the processed powder depends on the particle size and hence increased surface area and on the pH-value of the dissolution media.     

Influence of polydispersity of poly(lactic acid) on particle formation by rapid expansion of supercritical CO2 solutions

Poly(lactic acid) (PLA) particles were generated by rapid expansion of supercritical PLA/CO₂ solutions (RESS). Two different PLA samples, one with high (PDI = 2.4) and the other one with low (PDI = 1.4) polydispersity but similar number average molecular weight, were compared. After micronization, the polymers were analysed by rapid-scan infrared spectroscopy, scanning electron microscopy, size-exclusion chromatography, differential scanning calorimetry, and NMR spectroscopy. Our investigation reveals that the polydispersity of the polymers strongly affects the size but not the shape of the particles. We found larger particles (∼730 nm) for the PLA with high polydispersity than for the PLA with low polydispersity (∼270 nm). In both cases, spherical particles were formed. Moreover, our results clearly show that PLA with high polydispersity is less suitable for RESS processing because the low-molecular weight chains are depleted over time and process conditions are thus not constant.     

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 microcapsules of medicines by the rapid expansion of a supercritical solution with a nonsolvent

The rapid expansion from a supercritical solution with a nonsolvent (RESS‐N) was applied to the formation of polymeric microcapsules containing medicines such as p‐acetamidophenol, acetylsalicylic acid, 1,3‐dimethylxanthine, flavone, and 3‐hydroxyflavone. A suspension of medicine in carbon dioxide (CO₂) containing a cosolvent and dissolved polymer was sprayed through a nozzle to atmospheric pressure. The pre‐expansion pressure was 10–25 MPa, and the temperature was 308–333 K. The polymers were poly(L ‐lactic acid) (molecular weight = 5000), poly(ethylene glycol) (PEG; PEG4000, molecular weight = 3000; PEG6000, molecular weight = 7500; and PEG20000, molecular weight = 20,000), poly(methyl methacrylate) (molecular weight = 15,000), ethyl cellulose (molecular weight = 5000), and PEG–poly(propylene glycol)–PEG triblock copolymer (molecular weight = 13,000). The solubilities of the polymers as coating materials and these medicines as core substance were very low in CO₂. However, the solubilities of these polymers in CO₂ significantly increased with the addition of low molecular weight alcohols as cosolvents. After RESS‐N, polymeric microcapsules were formed according to the precipitation of the polymer caused by a decrease in the solvent power of CO₂. This method offered three advantages: (1) enough of the coating polymers, which were insoluble in pure CO₂, dissolved; (2) the microparticles of the medicine were encapsulated without adhesion between the particles because a nonsolvent was used as a cosolvent and the cosolvent remaining in the mixture was removed by the gasification of CO₂; and (3) the polymer‐coating thickness was controlled with changes in the feed composition of the polymer for drug delivery. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 742–752, 2003     

快速膜乳化法制备粒径均一的PLGA微球和微囊

以聚(乳酸-羟基乙酸)(PLGA)为膜材,采用快速膜乳化结合溶剂萃取法制备了胰高血糖素样肽-1(GLP-1)微囊,研究了PLGA分子量对药物装载率、药物活性和体外释放行为的影响. 制备均一微球的优化条件为过膜压力1000 kPa,过膜次数3次,外水相稳定剂聚乙烯醇浓度19 g/L,油水体积比1:5. 在此条件下,制备了粒径350 nm左右、多分散系数小于0.050的载GLP-1的PLGA微囊,GLP-1包埋率达65%以上,活性保留达85%以上,药物体外释药可达20 d.     

Modeling of the solubility of solid solutes in supercritical CO<Subscript>2</Subscript> with and without cosolvent using solution theory

In this work, regular solution theory was applied to study the solubility of solids in a supercritical fluid (SCF) with and without cosolvent, and a new model for binary and ternary systems was proposed. The activity coefficient can be obtained from the model and the solubility can then be calculated easily. For a binary system there are two adjustable parameters and for a ternary system, four adjustable parameters; the parameters are related to the interactions between molecules in solution. The proposed model was compared with the HSVDW1 and HSVDW2 models. The calculated results show that the proposed model is more accurate, and the AAD for the three models is 4.5%, 7.9% and 18.5%, respectively. The model was further used to correlate the solubility data of 2-naphthol in SC CO₂ with and without cosolvent measured by us before, and the overall AAD is 3.23%.     

Highly interconnected macroporous MBG/PLGA scaffolds with enhanced mechanical and biological properties via green foaming strategy

In this study, mesoporous bioactive glass particles (MBGs) are incorporated into poly(lactic-co-glycolic acid) (PLGA) to fabricate highly interconnected macroporous composite scaffolds with enhanced mechanical and biological properties via a developed supercritical carbon dioxide (scCO₂) foaming method. Scaffolds show favorable highly interconnected and macroporous structure through a high foaming pressure and long venting time foaming strategy. Specifically, scaffolds with porosity from 73% to 85%, pore size from 120 μm to 320 μm and interconnectivity of over 95% are controllably fabricated at MBG content from 0 wt% to 20 wt%. In comparison with neat PLGA scaffolds, composite scaffolds perform improved strength (up to 1.5 folds) and Young's modulus (up to 3 folds). The interconnected macroporous structure is beneficial to the ingrowth of cells. More importantly, composite scaffolds also provide a more promising microenvironment for cellular proliferation and adhesion with the release of bioactive ions. Hopefully, MBG/PLGA scaffolds developed by the green foaming strategy in this work show promising morphological, mechanical and biological features for tissue regeneration.     

快速膜乳化法制备载醋酸曲普瑞林PLGA微球

以生物可降解聚合物聚(乳酸?羟基乙酸)(PLGA)为载体,以160 g/L明胶水溶液为内水相、含500 g/L PLGA的二氯甲烷为油相,采用快速膜乳化和溶剂蒸发法制备了粒径均一的载醋酸曲普瑞林PLGA微球,微球粒径约30 mm,粒径分布系数Span<0.8,醋酸曲普瑞林包埋率达80.12%,药物在磷酸盐缓冲液中释放36 d的释放率为72.60%,体外释放行为良好.     

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.     

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.     

快速膜乳化法制备胸腺法新长效缓释微球

采用快速膜乳化技术结合溶剂蒸发法制备以生物可降解聚乳酸-羟基乙酸(PLGA)为载体的胸腺法新载药微球,考察了PLGA分子量、油相中PLGA和乳化剂浓度、外水相pH值和内水相体积等对微球包埋率和粒径的影响. 结果表明,制备粒径均一的PLGA载药微球的优化条件为：PLGA分子量51 kDa,油相中PLGA和乳化剂浓度为100和10 g/L,内水相体积0.5 mL,外水相pH值为3.5. 该条件下所制载药微球粒径均一性好(Span<0.7),药物包埋率高达80%以上,突释率24 h内低于20%,线性持续稳定释药时间长达30 d.     

Morphologies of blends of isotactic polypropylene and ethylene copolymer by rapid expansion of supercritical solution and isobaric crystallization from supercritical solution

Isotactic polypropylene (iPP) and ethylene‐butene (EB) copolymers were dissolved in supercritical propane and precipitated by rapid expansion of supercritical solution (RESS) and isobaric crystallization from SS (ICSS). The cloud‐point pressures of the ternary solutions were found to increase as the immiscibility of PP and EB copolymer increased (i.e., as the number of ethyl branches in the EB copolymers decreased). The RESS process resulted in microfibers and a trace of microparticles, and the EB copolymer domains in the blends decreased in size as the ethyl branch content in the EB copolymers increased. The thermal stability of the copolymer domains was improved by synthesizing thermoplastic vulcanizate (TPV) from PP and ethylene‐propylene‐diene terpolymer in a supercritical propane solution followed by RESS. The ICSS process produced microcellular polymeric foamlike materials, but the two polymers were precipitated independently by thermally induced phase separation. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 1478–1487, 2000     

Swelling and morphological properties of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) hydrogels in solution with high salt concentration

Understanding the swelling properties of hydrogels and how they affect the hydrogel's morphology is of fundamental importance in the development of hydrogel-based artificial muscles, bio-actuators, sensors and other devices. In this paper, the swelling behavior of PVA-PAA hydrogel films in saline water and in buffer solutions of different pH values was investigated. It was observed that the swelling factor of the hydrogel decreases when the ionic strength of the solvent solution increases. Scanning Electron Microscopy (SEM) revealed structures with different pore shapes and sizes depending on the type of solution used for hydration. In saline water, Energy Dispersive X-Ray (EDS) analysis indicated the formation of NaCl crystals within the polymeric network. Finally, the PVA-PAA hydrogel was used as an actuator to strain a fiber Bragg grating sensor, thus providing an indirect measurement of the pH value of the surrounding solution.     

High yield preparation of all-organic raspberry-like particles by heterocoagulation via hydrogen bonding interaction

We describe here a straightforward strategy towards the high yield preparation of raspberry-like all-organic particles. Poly(acrylic acid)-b-poly(butyl acrylate) core–shell nanoparticles (D ∼ 80 nm) and larger poly(ethylene oxide)-b-poly(butyl acrylate) core–shell (D ∼ 230 nm), synthesized by RAFT emulsion polymerization, were mixed at high solids content (23 wt%) at room temperature without any particular precaution (no dropwise addition, no pH adjustment). Raspberry-like particles constituted of one central PEO-b-PBA particle surrounded by about thirty PAA-b-PBA particles were successfully obtained, with no coagulum formation. The heteroaggregation process is probably driven by the hydrogen-bond interactions between the PAA and the PEO shells of the particles. The raspberry-like particles were characterized using electron microscopy (TEM and cryo-TEM), dynamic light scattering (DLS), chromatography (HDC) and calorimetry (ITC), demonstrating the selectivity of the process.