The formation of fluorinated tetraphenylporphyrin nanoparticles via rapid expansion processes: RESS vs RESOLV

Organic nanoparticles of a fluorinated tetraphenylporphyrin (TBTPP) were produced by rapid expansion of supercritical CO(2) solutions into both air (RESS) and an aqueous receiving solution containing a stabilizing agent (RESOLV). The effect of processing conditions on both particle size and form was investigated. The size of the porphyrin nanoparticles produced via RESS increased in a well-behaved manner from 40 to 80 nm as the preexpansion temperature increased from 40 to 100 degrees C, independent of porphyrin concentration, degree of saturation, and preexpansion pressure. RESOLV of TBTPP + CO(2) solutions was investigated both for minimizing particle growth in the free jet and for the prevention of particle agglomeration. Anionic, nonionic, and polymeric stabilizing agents for the aqueous receiving solution were considered. Expansion into a 0.05 wt % SDS solution produced nanorods 50-100 nm in diameter with an aspect ratio of 3-5. RESOLV in a 0.025 wt % Pluronic F68 solution produced well-dispersed, individual, spherical nanoparticles averaging 23 +/- 10 to 32 +/- 10 nm in diameter, independent of the rapid expansion processing conditions selected. Furthermore, the resulting nanoparticle suspensions were stable, with particle sizes remaining unchanged after several months. However, some particle agglomeration occurred at higher (i.e., 1 wt % TBTPP in CO(2)) concentrations. Contact-angle measurements on solid TBTPP compacts with the tested receiving solutions indicate that a moderate wetting agent such as Pluronic F68 is most effective for preserving the size and form of the porphyrin nanoparticles produced by RESOLV. Finally, the fact that nanoparticles are produced from RESS of TBTPP, in contrast with other organics for which microparticles are produced, can be explained in terms of the high melting point of TBTPP (388 degrees C), which results in a solid-state diffusion coefficient of TBTPP low enough so that particle coalescence is significantly reduced in the free jet.     

Micronization of phenylbutazone by rapid expansion of supercritical CO2 solution

Rapid expansion of supercritical solutions (RESS) technique was applied for the preparation of phenylbutazone fine particles. The operating temperature and pressure affected the yield of the drug fine particles, which was evaluated by dissolving the sprayed product of drug into ethanol. Effect of pre- and post-expansion conditions on the particle size distribution of phenylbutazone was investigated and the smallest sample (mean particle size: 1.59 microm) was obtained when the RESS method was operated at a pressure of 26 MPa combined with a temperature of 32 degrees C. Physicochemical properties of the fine particles were investigated by powder X-ray diffraction and differential scanning calorimetry. It was found that the phenylbutazone fine particles obtained were meta-stable beta form under the experimental conditions tested, suggesting polymorphic transformation during the RESS process.     

Preparation of Fenofibrate Microparticles Using Top-down and Bottom-up Processes

Micronization of fenofibrate using top-down process via jet mill and bottom-up process via rapid expansion of supercritical solution (RESS) was conducted to investigate their effects on the formation of micronized fenofibrate. Processed fenofibrate retained its crystalline structure and have similar chemical structure with unprocessed fenofibrate. The average particle size of fenofibrate was reduced from its original wherein from 68.779±0.146 μm to 3.050±0.085 μm using jet mill process at SFR 2.7 kg/h; and to 3.044±0.056 μm using RESS under the optimum condition. The results revealed that jet mill and RESS processes were applicable for micronization of fenofibrate.     

Fabrication of Micron Level Particles of Amoxicillin by Rapid Expansion of Supercritical Solution

In this study, the rapid expansion of supercritical solution (RESS) process was used to precipitate fine solid particles of amoxiccilin where supercritical carbon dioxide was used as a solvent. The process has been done by changing the RESS parameters, including extraction pressure (150–210 bar), extraction temperature (313–333 K), nozzle length (2–15 mm), effective nozzle diameter (450–1700 µm), and spraying distance (1–10 cm), to investigate the effect of these parameters on the size and morphology of the precipitated amoxicillin particles. The characterization (size and morphology) of the particles was examined using scanning electron microscopy (SEM). Based on the different experimental conditions, the mean particle size of the fabricated particles were between 1.08 and 5.72 µm, while the intact particles of amoxicillin were about 41.46 µm. Also, no regular changes in the morphology of the processed particles were observed.     

Micronization of tolbutamide using rapid expansion of supercritical solution with solid co-solvent (RESS-SC) process

Micronization of a sulfonylurea antidiabetic agent, tolbutamide, using rapid expansion of supercritical solution with solid co-solvent (RESS-SC) process was investigated in this study. Menthol was selected as the solid co-solvent in the RESS-SC process owing to its high vapor pressure and ease of removal by sublimation. The tolbutamide particles were micronized successfully from its original mean size of 89.4 ??m to the smallest mean size of 2.1 ??m through the RESS-SC process. The use of solid co-solvent in this process enhanced the saturated solubility of tolbutamide in supercritical carbon dioxide and inhibited the particle growth during pressure expansion after the nozzle. In addition, polymorph conversion from form I to form II after the RESS-SC process was confirmed by XRD and DSC analyses. Measurements of the dissolution rate profiles before and after the RESS-SC process were also investigated. It is shown that the micronized tolbutamide by the RESS-SC process had novelty in dissolution behavior compared to that of the original compound. Its dissolution rate was enhanced by 8.8 times after the RESS-SC process.     

Micronization of Iron Oxide Particles Using Gas Antisolvent Process

Iron oxide particles were micronized by supercritical carbon dioxide (CO₂) as an antisolvent in a batch gas antisolvent (GAS) process. In the present study, the feasibility of GAS process to micronize the iron oxide particles using dimethyl sulfoxide (DMSO) as a solvent was investigated. In this direction, particle size and morphology changes were investigated with changing solution pressure (80–150 bar), temperature (308.15–328.15 K), and concentration (1.5–6 g/l). Based on the different experimental conditions, the particle size of the original iron oxide was decreased in the range of 17.25 to 4.23 µm, which shows a the success of the GAS process to reduce the particle size of the intact iron oxide particles. Simultaneously, morphology changes were observed starting from the irregular morphology for synthesized particles to more regular shapes that included fused and spherical-fused particles.     

Polymeric nanoparticles from rapid expansion of supercritical fluid solution

In this concept paper we highlight applications of supercritical fluid technology in particle formation and production, especially some recent advances in the rapid expansion of supercritical solutions (RESS) processing technique. We also highlight the simple but significant modification to the traditional RESS by using a liquid solvent or solution at the receiving end of the supercritical solution expansion, or the rapid expansion of a supercritical solution into a liquid solvent (RESOLV), and applications of the technique to the preparation of nanoparticles. In particular, successes and challenges in the use of RESOLV for nanoscale (<100 nm) polymeric particles and the subsequent protection of the suspended nanoparticles from agglomeration are discussed.     

Path integral calculation of free energies: quantum effects on the melting temperature of neon

The path integral formulation has been combined with several methods to determine free energies of quantum many-body systems, such as adiabatic switching and reversible scaling. These techniques are alternatives to the standard thermodynamic integration method. A quantum Einstein crystal is used as a model to demonstrate the accuracy and reliability of these free energy methods in quantum simulations. Our main interest focuses on the calculation of the melting temperature of Ne at ambient pressure, taking into account quantum effects in the atomic dynamics. The free energy of the solid was calculated by considering a quantum Einstein crystal as reference state, while for the liquid, the reference state was defined by the classical limit of the fluid. Our findings indicate that, while quantum effects in the melting temperature of this system are small, they still amount to about 6% of the melting temperature, and are therefore not negligible. The particle density as well as the melting enthalpy and entropy of the solid and liquid phases at coexistence is compared to results obtained in the classical limit and also to available experimental data.     

Measurement and modelling of binary (solid + liquid + vapour) equilibria involving lipids and CO2

The development of solid lipid nanoparticles (SLN) using supercritical fluid at room temperature is an innovative alternative compared to traditional pharmaceutical methods and the safety and drug efficacy of SLN made using supercritical CO₂ is increased. One of the micronization techniques which have provided the best results in the production of SLN is particles from gas-saturated solution (PGSS). The solid–liquid–vapour coexistence curve of a solid in a compressed gas is of primary importance in assessing the feasibility of PGSS and the selection of appropriate operating conditions. The objectives of this work are to perform experimental measurements using a high pressure differential scanning calorimeter (DSC) to obtain melting properties as a function of composition and develop a simplified approach to model multiphase equilibria of lipids in compressed CO₂. The selected lipid was tristearin. Before assessment of triestearin and CO₂ phase equilibrium, the performance of this thermodynamic model was evaluated in two other lipids which provided results with high accuracy.     

Novel Semiconducting Polymer Particles by Supercritical Fluid Process

Summary: A simple method to prepare surfactant‐free and solvent‐free semiconducting polymer particles by using an environmentally benign supercritical carbon dioxide (scCO₂) process is reported. The process of the rapid expansion of supercritical solutions (RESS) is used to produce spherical particles of poly[2‐(3‐thienyl)acetyl 3,3,4,4,5,5,6,6,7,7,8,8,8‐tridecafluorooctanoate] (PSFTE), 50–500 nm in size, from 0.1–0.5 wt.‐% PSFTE solutions in CO₂ at pre‐expansion temperatures of 40 °C and pre‐expansion pressures of 276 bar.

An FESEM image of PSFTE particles produced by the RESS process with CO₂.     

Interaction of pharmaceutical hydrates with supercritical CO2

The aim of this work was to study the solubility in supercritical CO₂ of the hydrated phase of three model drugs, namely theophylline, carbamazepine, and diclofenac sodium, in comparison with the respective anhydrous form. Possible solid-state modifications, stemming from the interaction with supercritical CO₂, were investigated by differential scanning calorimetry, thermogravimetric analysis, hot stage microscopy, Fourier Transform infrared spectroscopy and Karl-Fischer titrimetry. It was found that all three pharmaceutical hydrates exhibited higher solubility in supercritical CO₂ than the relevant anhydrous phases. In the case of theophylline monohydrate, the instability of the crystal phase at the experimental temperature adopted has been evidenced. Diclofenac sodium tetrahydrate represents a peculiar case of chemical interaction with the acid supercritical fluid, mediated by crystal water. This revised version was published online in July 2006 with corrections to the Cover Date.     

Joint processing of experimental data on melting,evaporation, and sublimation processes

A technique and computational program for estimating thermodynamic parameters are developed for the joint processing of experimental data on the saturated vapor pressure in melting, evaporation, and sublimation processes. Computation is based on the equality of pressures over the solid and liquid phases at a melting temperature. The efficiency of the proposed technique is demonstrated by processing experimental data on the phase transitions of Sc(thd)₃.     

Effect of supercritical CO2 plasticization on the degradation and residual crystallinity of melt‐extruded spironolactone

Immediate‐release solid dispersions of a slowly dissolving active pharmaceutical ingredient, spironolactone, were prepared by supercritical‐CO₂‐assisted melt extrusion (a solvent‐free and continuous manufacturing technology) using Eudragit E as matrix. Through optimizing process parameters (i.e. temperature, melt throughput, pressure and CO₂ flow), stable foams with high porosity, homogeneous structure and thin (even submicronic) walls could be prepared, as revealed by scanning electron microscopy. The samples were found to be rigid enough to mill, enabling further processing, as is necessary to formulate tablets. The influence of extrusion temperature and melt throughput on residual drug crystallinity was measured using non‐invasive confocal Raman mapping coupled with chemometric analysis, while the influence on the degree of drug degradation was determined using high performance liquid chromatography. The plasticizing effect of supercritical CO₂ was shown to reasonably improve the purity of the prepared solid dispersions by enabling high‐yield production at lower temperature ranges. At the same time, shorter residence time and lower temperature slightly increased residual drug crystallinity. The obtained foamy structures ensured immediate drug dissolution in an acidic medium. Copyright © 2014 John Wiley & Sons, Ltd.     

Grafting of glycidyl methacrylate onto polypropylene using supercritical carbon dioxide

Free-radical grafting of glycidyl methacrylate (GMA) onto polypropylene (PP) films has been studied using supercritical carbon dioxide (SC-CO₂) as a solvent and a swelling agent. As the reaction temperature was below the melting point, PP was modified in the solid phase. The PP film was first soaked with the monomer GMA and benzoyl peroxide (BPO) as an initiator using SC-CO₂ at different experimental conditions of pressure, temperature, and thermal treatment time. After releasing CO₂, film GMA molecules were grafted onto PP in different times. Using this method, the degree of grafting and the morphology could be controlled through the combination of pressure, temperature, and soaking time. FTIR spectra confirmed that GMA had been grafted onto PP and that polypropylene-graft-glycidyl methacrylate (PP-g-GMA) presented a high surface reactivity for conductive polyaniline anchoring. DSC measurements and TG analyses showed that the thermal profiles of the graft copolymer and virgin PP are quite similar and that the graft PP does not exhibit changes in terms of thermal degradation profile and melting temperature, respectively. X-ray data showed that a high degree of grafting leads to a lower degree of crystallinity of polypropylene.     

Mathematical modelling for extraction of oil from Dracocephalum kotschyi seeds in supercritical carbon dioxide

Extraction of oil from Dracocephalum kotschyi Boiss seeds using supercritical carbon dioxide was designed using central composite design to evaluate the effect of various operating parameters including pressure, temperature, particle size and extraction time on the oil yield. Maximum extraction yield predicted from response surface method was 71.53% under the process conditions with pressure of 220 bar, temperature of 35 °C, particle diameter of 0.61 mm and extraction time of 130 min. Furthermore, broken and intact cells model was utilised to consider mass transfer kinetics of extracted natural materials. The results revealed that the model had a good agreement with the experimental data. The oil samples obtained via supercritical and solvent extraction methods were analysed by gas chromatography. The most abundant acid was linolenic acid. The results analysis showed that there was no significant difference between the fatty acid contents of the oils obtained by the supercritical and solvent extraction techniques.     

On-Line coupling of supercritical fluid extraction with high performance liquid chromatography

Supercritical fluid extraction was coupled directly with high performance liquid chromatograph. The system was evaluated for direct injection of supercritical CO₂ and modified supercritical CO₂ at high pressure and temperature onto a HPLC system with varying mobile phase compositions and flow rates. Injection of 9 μL supercritical CO₂ onto the HPLC using methanol/water mobile phases from 100% methanol to 80% with a flow of 1.0 mL/min did not adversely affect the baseline of UV detector. However at higher percentages of water, CO₂ solubility in the mobile phase decreased and caused baseline interferences on the UV detector. At higher HPLC mobile phase flow rates, supercritical CO₂ was injected to higher percentages of water without any effect on the UV baseline. Also, increasing the extraction pressure or modifier concentration did not change the results. Separations of polynuclear aromatic hydrocarbons and linear alkenebenzene sulfonate test mixtures were obtained using on-line SFE/HPLC interfaced system.     

Molecular imprinting using monomers with solid-state polymerization

Molecular imprinting of two diolefinic compounds with solid-state photopolymerization, 2,5-distyrylpyrazine (DSP) and diethyl p-phenylenediacrylate (EPA), was demonstrated. Solid nanoscale particles of the monomer were produced and deposited onto the surface of a surface acoustic wave (SAW) transducer using the technique known as rapid expansion of supercritical solutions (RESS). The particles were polymerized by UV light in the presence of an alkane template vapor. Both imprinted and non-imprinted devices were tested upon exposure to a variety of alkane vapors in the gas phase. The results demonstrate an enhanced sensitivity to vapors at or below the size of the template. A size exclusion mechanism of recognition is proposed.     

Effect of supercritical carbon dioxide on the crystallization and melting behavior of linear bisphenol A polycarbonate

The crystallization and melting behavior of bisphenol A polycarbonate treated with supercritical carbon dioxide (CO₂) has been investigated with differential scanning calorimetry. Supercritical CO₂ depresses the crystallization temperature (T_c) of polycarbonate (PC). The lower melting point of PC crystals increase nonlinearly with increasing treatment temperature. This indicates that the depression of T_c is not a constant at the same pressure. T_c decreases faster at a higher treatment temperature than at a lower temperature. The leveling off of the depression in T_c at higher pressures is due to the antiplasticization effect of the hydrostatic pressure of CO₂. The melting curves of PC show two melting endotherms. The lower melting peak moves to a higher temperature with increasing treatment temperature, pressure, and time. The higher temperature peak moves toward a higher temperature as the treatment temperature is increased, whereas this peak is independent of the treatment pressure, time, and heating rate. The double melting peaks observed for PC can be attributed to the melting of crystals with different stability mechanisms. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 280–285, 2004     

Organic zeolites from a diolefinic monomer

Submicrometer particles of diethyl p-phenylenediacrylate (EPA) with tunable molecular adsorption characteristics were produced by solid-state photopolymerization in the presence of template molecules. EPA monomer particles were produced by rapid expansion of supercritical solutions (RESS), and deposited directly onto surface acoustic wave (SAW) resonators. The EPA particles were photopolymerized directly on the SAW devices in the presence of molecular templates, and dynamic sorption isotherms of C1- through C9-alkanes were studied to characterize the particle-vapor interaction. The mass increase due to vapor uptake into the particulate coatings was measured by monitoring the SAW resonance frequency during vapor sorption. The vapor selectivity and molecular porosity of the particulate coatings were studied in situ on the piezoelectric substrate by measuring sorption isotherms. A gradual exclusion of smaller alkane molecules from the molecularly imprinted particulate coatings was observed with decreasing template molecule size. The observed selective and reversible adsorption of alkane analytes with different molecular sizes suggest that these imprinted polymers may be categorized as organic analogues of zeolites.     

Effect of cosolvent on solid phase transitions of α‐ to β‐form crystal of syndiotactic polystyrene occurred in supercritical Co2 containing solvent

The solid phase transition mechanism of α‐ to β‐form crystal upon specific treating with supercritical CO₂ + cosolvent on original pure α and mixed (α+β) form syndiotactic polystyrene (sPS) was investigated, using wide angle X‐ray diffraction and differential scanning calorimetry measurements as a function of temperature, pressure, and cosolvent content. As in the supercritical CO₂, sPS in supercritical CO₂ + cosolvent underwent solid phase transitions from α‐ to β‐form, and higher temperature or higher pressure favored this transformation. Due to the higher dipole moment of acetone, small amounts of acetone used as cosolvent with CO₂ made the transition of α‐ to β‐form occur at lower temperature and pressure than in supercritical CO₂, and made the α‐form crystal completely transform to β‐form in the original mixed (α+β) form, whereas ethanol did not. The original β‐form crystal in the original mixed (α+β) form sample acted as the nucleus of new β‐form crystal in the presence of cosolvent as it did in supercritical CO₂, when compared with the original pure α‐form sample. © 2007 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 45: 1625–1636, 2007