Expansion Of Supercritical Solution Process Research Articles

Application of Box-Behnken Design in microparticle production of p-Toluenesulfonamide through the rapid expansion of supercritical solutions process

p-Toluenesulfonamide (PTS) is a developing small molecular anticancer agent with good lipophilic ability. Microparticle production of PTS is an approach to enhance the dissolution profile and explore the potential for novel drug delivery system design. This study employed the rapid expansion of supercritical solutions (RESS) process to produce microparticles of PTS using supercritical carbon dioxide as the solvent. To meet the concept of quality by design in the pharmaceutical industry, the effects of process parameters in RESS operation were investigated and optimized by a design of experiments approach, the Box-Behnken Design (BBD). The design space for microparticle production of PTS was shown, and the analysis of variance (ANOVA) confirmed the significance of process parameters. According to the BBD study, at the optimal operating condition, PTS microparticles were successfully generated from the unprocessed mean size of 240.3 μm to 1.3 μm. The solid-state property of the unprocessed and micronized PTS powders was compared and confirmed consistent through the PXRD, DSC, and FTIR analysis. Finally, the dissolution profiles of PTS before and after the RESS process were determined, and the dissolution rate of RESS-produced PTS microparticles was enhanced 1500 times compared with the unprocessed PTS.

Solid solubility measurement of haloperidol in supercritical carbon dioxide and nanonization using the rapid expansion of supercritical solutions process

Haloperidol is a poorly water-soluble drug, and its efficacy was limited by dissolution behavior. This study aimed to improve haloperidol’s dissolution rate by nanonization using rapid expansion of supercritical solution (RESS) process. To design RESS, the solubility data of haloperidol in supercritical CO2 were measured and reported from 3.4 × 10−7 to 1.4 × 10−5 in mole fraction at temperatures from 313.2 K to 333.2 K and pressure up to 22 MPa. The measured solubility data were then correlated using semi-empirical equations with average absolute relative deviations less than 5%. For RESS study, the effects of operating parameters were compared and discussed. The crystal habit of haloperidol was modified from irregular to spherical, and the mean particle size was reduced to 300 nm. Improvement of the dissolution rate was finally verified, and the dissolution rate of haloperidol was enhanced 74 times after the RESS processing.

Supercritical carbon dioxide utilization in drug delivery: Experimental study and modeling of paracetamol solubility

In the present study, the solubility of paracetamol in supercritical CO2 is measured at temperatures between 311 and 358 K and pressures between 95 and 265 bar. It was shown that the solubility of paracetamol through a static solubility measurement method was between 0.3055 × 10−6 to 16.3582 × 10−6 based on mole fraction. The obtained experimental solubility data revealed the direct effect of pressure on the paracetamol experimental data, while the temperature has a dual effect of both increasing and decreasing effect considering the shifting point known as crossover pressure which was measured to be around 110 bar for paracetamol. Besides, two theoretical approaches were applied to predict the paracetamol experimental results. The experimental data were modeled with two various equations of state (EoSs) i.e. Peng-Robinson EoS and the simplified perturbed chain statistical associating fluid theory (sPC-SAFT) EoS, which their binary interaction parameters were optimized by using genetic algorithm. The obtained results demonstrated the sPC-SAFT EoS predicted the solubility of paracetamol with more accuracy (the average percent deviation was equal to 2.5215), especially at higher pressures. Furthermore, four well-known semi-empirical density-based correlations namely Mendez-Santiago and Teja (MST), Kumar-Johnston (KJ), Bartle et al., and Garlapati and Madras models were applied for modeling the solubility of paracetamol experimental data. According to self-consistency test, KJ model presented more accurate correlative capability with average percent deviation about 4.09%. As a final point, the rapid expansion of supercritical solution process was performed to reduce particle size of paracetamol and mean particle size of paracetamol was calculated based on EoSs and mathematical modeling.

Preparation of liposomes composed of supercritical carbon dioxide-philic phospholipids using the rapid expansion of supercritical solution process

The synthesis of supercritical carbon dioxide-philic phospholipids allowed the vitamin E acetate (VEA) liposomes composed of them to be successfully prepared using the rapid expansion of supercritical solution (RESS) process without any organic solvent. The single-factor analysis and the response surface methodology combined with Box–Behnken design were used to optimize the operation conditions. The results indicated that pressure was the most important factor to the encapsulation efficiency of the liposomes, which was increased with a higher pressure. Temperature and mass ratio also had some effects, while the interaction of the three factors was not significant. The liposomes prepared under the optimal conditions (i.e., temperature of 55.45 °C, pressure of 25.00 MPa, and mass ratio of 6.35:1) showed good stability as well as the slow and continuous release behavior. The encapsulation efficiency, average particle size, PDI, and zeta-potential of the prepared liposomes were 92.84 ± 0.98%, 247.4 ± 6.5 nm, 0.295 ± 0.012, and −42.55 ± 0.64 mV, respectively.

Response Surface Optimization of Catechin Liposomes Preparation Using the Rapid Expansion of Supercritical Solution Process.

Phospholipid liposomes are a promising drug delivery system. Catechin, a hydrophilic drug, was used to prepare catechin liposomes through a modified rapid expansion of supercritical solution (RESS) process in this study. The influences of operation parameters (i.e., temperature, pressure, and mass ratio of liposomal materials to catechin) on the properties of the prepared liposomes were determined using the single-factor analysis. The process was further optimized by response surface methodology (RSM) based on the Box-Behnken design (BBD). The encapsulation efficiency (EE) values can be adequately predicted using the obtained equation. The maximum EE value can reach 61.36±0.68% under the optimal parameters (i.e., the expansion temperature, pressure, and p/c mass ratio were 56.34 °C, 19.99 MPa, and 5.99, respectively). The prepared liposomes can effectively protect and stabilize the loaded catechin effectively. In addition, the in vitro release study showed the slow and sustained release behavior of the catechin liposomes.

Investigation of process parameters by using a two-level factorial design for microparticle production of ipriflavone through rapid expansion of supercritical solution process

This study investigated the significance of process parameters in the rapid expansion of supercritical solution (RESS) for microparticle production of ipriflavone by using a two-level (2k) factorial design. Four process parameters, namely the extraction temperature (A), extraction pressure (B), pre-expansion temperature (C), and postexpansion temperature (D), of RESS were studied. The mean particle size data and results of analysis of variance revealed that the effect of C and the cross-interaction effect of AD and BD were significant in the process. The trends of these significant effects were evaluated through crystallization kinetics. After the RESS was performed, ipriflavone exhibited a considerably reduced mean size of 3 μm and a flake-like habit. In addition, differential scanning calorimetry and powder X-ray diffraction revealed that the crystal form of ipriflavone remained unchanged after RESS.

Solid solubility measurement of ipriflavone in supercritical carbon dioxide and microparticle production through the rapid expansion of supercritical solutions process

In this study, the solid solubilities of ipriflavone in supercritical CO2 were measured by using a semi-flow apparatus. The Chrastil equation, Mendez-Santiago and Teja equation, and a solution model developed from the regular solution model and Flory–Huggins equation were adopted to correlate the measured solubility data. Because the solubility in mole fraction of ipriflavone can be as high as 10−4, the rapid expansion of supercritical solutions (RESS) process was adopted to produce ipriflavone microparticles. The effects of the operating parameters of the RESS process on the mean particle size of ipriflavone were evaluated and discussed. In addition, based on the results of powder X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectrometry analysis, particulate ipriflavone exhibited consistency with the unprocessed sample in terms of crystal structure, melting temperature, and spectrometric properties.

Trends on the Rapid Expansion of Supercritical Solutions Process Applied to Food and Non-food Industries.

The supercritical fluids applied to particle engineering over the last years have received growing interest from the food and non-food industries, in terms of processing, packaging, and preservation of several products. The rapid expansion of supercritical solutions (RESS) process has been recently reported as an efficient technique for the production of free-solvent particles with controlled morphology and size distribution. In this review, we report technological aspects of the application of the RESS process applied to the food and non-food industry, considering recent data and patent survey registered in literature. The effect of process parameters cosolvent addition, temperature, pressure, nozzle size among others, during RESS on the size, structure and morphology of the resulted particles, and the main differences about recent patented RESS processes are reviewed. Most of the experimental works intend to optimize their processes through investigation of process parameters. RESS is a feasible alternative for the production of particles with a high yield of bioactive constituents of interest to the food industry. On the other hand, patents developed using this type of process for food products are very scarce, less attention being given to the potential of this technique to develop particles from plant extracts with bioactive substances.

Effects of dye particle size and dissolution rate on the overall dye uptake in supercritical dyeing process

Supercritical dyeing proceeds in a sequence of multiple phenomena such as dissolution, adsorption, and diffusion involving different timescales. The aim of this work is to highlight the significant role of the dissolution rates of dyes into the supercritical solution. For this purpose, the dissolution rates of different-sized dyestuffs in the supercritical solutions were measured with a newly proposed methodology utilizing in-situ UV/Vis absorption. It was found that the dissolution rate of disperse dyes is enhanced by micronizing the particles with the rapid expansion of supercritical solution process. The dye uptakes of micronized particles in polyester fiber were increased compared to that of the raw particles. This correlation underscores the sensitivity of the final product quality towards the instantaneous dye concentration surrounding the fibers.

Preparation of vitamin C liposomes by rapid expansion of supercritical solution process: Experiments and optimization

Vitamin C (VC) liposomes were prepared by the rapid expansion of supercritical solution process (RESS) in this study. The combined effects of temperature, pressure, and feeding ratio of VC against phosphatidylcholine (PC) on the drug loading content of the prepared liposomes were determined and discussed using response surface analysis. The results revealed that these conditions showed a very complicated influence, but the experimental data could be well predicted by the model obtained in this study. Under the optimal operating conditions (the pressure of 25 MPa, the temperature of 48 °C, and the feed ratio of VC against PC of 0.25) calculated by the present model, the VC loaded liposomes were successfully prepared with the loading content of 75.38 ± 1.03%. The particle size, PDI and Zeta-potential of the prepared samples was 270.4 ± 5.2 nm, 0.254 ± 0.010 and −41.7 ± 0.9 mv, respectively. The experimental loading content value was in accordance with the predicted one, indicating that the present model could be used to predict the loading content of the prepared VC liposomes using RESS.

Preparation of Curcuma Longa L. Extract Nanoparticles Using Supercritical Solution Expansion

Nanoparticles of Curcuma longa Linn (turmeric) rhizome extract were prepared using supercritical carbon dioxide (SC-CO2). The SC-CO2 was used for sample pre-treatment, including lipophilic compounds removal and extraction, as well as particle production. The particle formation process was based on the expansion of supercritical solution of plant extract into a secondary chamber. In the course of the expansion of supercritical solution process, the herbal extract changed from dissolved mode at higher pressures to precipitated mode at lower pressures, as long as the pressures were higher than the critical pressure. The particle growth via coagulation was limited by a large number of unsuccessful collisions between CO2 molecules and primary nuclei due to the presence of pressurized CO2 molecules where the particle formation occurs. The presence of curcumin derivatives in nanoparticles was confirmed by liquid chromatography-mass spectrometry results. Irregular to quasi-spherical particles with average diameter of 47 ± 20 nm (n = 300) were prepared at a pre-expansion pressure of 35 MPa, pressure drop of 24 MPa, temperature of 50°C, equilibration time of 30 min, collection time of 60 min, extract volume of 30 μL, and feeding solution concentration of 2 mg mL−1.

Continuous nanonization of lonidamine by modified-rapid expansion of supercritical solution process

Despite the significant advancements in the pharmaceutical manufacturing process, the aqueous solubility of most of the potent drugs has remained as an unresolved problem during the formulation development and drug delivery processes. To address this critical issue, we modified the continuous-rapid expansion of supercritical solution (RESS-C) process, which is incessant, stable and well-regulated. Initially, the solubility of lonidamine (LND) in supercritical carbon dioxide (SC-CO2) was tested using a static analytical method at altered critical conditions (T: 308.15-328.15K, P: 10.0-30.0MPa). Under optimized conditions (LND conc.- 0.5% (w/v), flow rate- 1.0mL/min, T- 328.15K, P- 20.0MPa and CO2 flow rate- 30.0g/min), the modified RESS-C process resulted in nano-sized spheres with a smooth surface and a narrow particle size distribution. Further, the crystal properties of the samples and their molecular interactions were elucidated. The altered physical state of RESS-C processed LND from crystalline to amorphous resulted in the solubility improvement and also enhanced the in vitro antiproliferative effects compared to the unprocessed LND, demonstrating the potential of the modified RESS-C process in improving the bioavailability of poorly water-soluble drugs.

Micronization of vanillin by rapid expansion of supercritical solutions process

Uniform microparticles of vanillin were precipitated by the Rapid Expansion of Supercritical Solution (RESS) process and this reduced the commercial particle size by a factor of one hundred. A design of experiments full factorial at two levels was performed. The effects that pressure, temperature, contact time and nozzle diameter had on the particle size and yield of the RESS precipitation were evaluated. Pressure and temperature were the factors that had the most marked effects on particle size and yield. The use of higher pressure and temperature is recommended to obtain the smallest particle size and the highest yield. However, at lower pressure the temperature is a crucial factor in that the use of a lower temperature led to considerably smaller particles and good yields whereas a higher temperature gave the highest particle size and the lowest yield. A higher contact time and smaller nozzle diameter led to slight improvements in the vanillin particle size and yield according to the results of the design. The crystallinity of the RESS-processed vanillin was unaltered when compared to the unprocessed material.

Impact of rapid expansion of supercritical solution process conditions on the crystallinity of poly(vinylidene fluoride) nanoparticles

The rapid expansion of supercritical solution (RESS) process was used to produce poly(vinylidene fluoride) (PVDF) nanoparticles. PVDF was chosen since five different crystal phases (α, β, γ, δ, ε) have been reported in literature. The experiments were performed with a low molar mass polymer (Mn=1500gmol−1) that consists exclusively of α phase. The main objectives of this study were to examine the influence of process parameters, i.e. inner nozzle diameter, pre-expansion temperature and pressure on polymer crystallinity and crystal phase properties. Before and after micronization, the polymer was characterized by scanning electron microscopy, size-exclusion chromatography, differential scanning calorimetry and X-ray diffraction.The findings of our investigations clearly show that RESS enables the formation of submicron particles. Furthermore, under certain process conditions, i.e. higher expansion and cooling rates and thus small nozzle diameters, RESS induces a crystal phase transformation from α to the desired β phase. In opposite thereto, simple static treatment with scCO2 does not induce crystal phase transformation. Furthermore, average molar mass, dispersity and crystallinity of the RESS product was reduced due to the preferred extraction of low molar mass fractions.

Measurement of solid solubilities of diuron in supercritical carbon dioxide and analysis of recrystallization by using the rapid expansion of supercritical solutions process

A semi-flow type apparatus was used to measure the solid solubilities of diuron, an herbicide, in supercritical carbon dioxide (CO2) from 10 to 20MPa at 308.2, 318.2, and 328.2K. The mole fraction of solid diuron dissolved in supercritical CO2 was between 8.72×10−7 and 1.63×10−5. The measured solubility data were correlated using three thermodynamic models: the Chrastil equation, Mendez-Santiago and Teja equation, and regular solution model coupled with the Flory–Huggins equation. These models yielded satisfactory results with the average relative deviations being less than 6%. Furthermore, an analysis using the rapid expansion of supercritical solutions (RESS) process was conducted to determine the effects of three operating temperatures on recrystallization of diuron. Three extraction temperatures (Text) (308, 318, and 328K), three pre-expansion temperatures (Tpre) (433, 453, and 473K), and three post-expansion temperatures (Tpost) (273, 293, and 313K) were used to determine the effect of operating temperatures. A lower post-expansion temperature of 273K and higher pre-expansion temperature of 473K were associated with the production of smaller diuron particles with a narrower size distribution. The effect of extraction temperature remained insignificant. The mean particle size of diuron could be successfully reduced to approximately 6μm by using the RESS process.

Numerical simulation of particle formation in the rapid expansion of supercritical solution process

In this paper, we numerically study particle formation in the rapid expansion of supercritical solution (RESS) process in a two dimensional, axisymmetric geometry, for a benzoic acid+CO2 system. The fluid is described by the classical Navier–Stokes equation, with the thermodynamic pressure being replaced by a generalized pressure tensor. Homogenous particle nucleation, transport, condensation and coagulation are described by a general dynamic equation, which is solved using the method of moments. The results show that the maximal nucleation rate and number density occurs near the nozzle exit, and particle precipitation inside the nozzle might not be ignored. Particles grow mainly across the shocks. Fluid in the shear layer of the jet shows a relatively low temperature, high nucleation rate, and carries particles with small sizes. On the plate, particles within the jet have smaller average size and higher geometric mean, while particles outside the jet shows a larger average size and a lower geometric mean. Increasing the preexpansion temperature will increase both the average particle size and standard deviation. The preexpansion pressure does not show a monotonic dependency with the average particle size. Increasing the distance between the plate and the nozzle exit might decrease the particle size. For all the cases in this paper, the average particle size on the plate is on the order of tens of nanometers.

Effects of expansion parameters on characteristics of gemfibrozil powder produced by rapid expansion of supercritical solution process

Micronization of gemfibrozil particles was carried out by the rapid expansion of a supercritical solution process with CO2 as the solvent. In this work, effects of spray distance (2.5, 5.5, 10.5 and 15cm), nozzle type (capillary and orifice nozzles), nozzle diameter (0.25 and 0.5cm for orifice diameter) and temperature of expansion vessel (10, 26, 30 and 65°C) on the characteristics of gemfibrozil particles were studied. In addition to traditional sampling methods, an electrostatic precipitation was also carried out as sampling method for collection of the RESS produced particles. Based on our knowledge, this study on the effect of charged plate sampling method (electrostatic sampler) in the RESS process is the first study of this kind. The smallest mean size of gemfibrozil particles produced by orifice nozzle with 0.25mm inner diameter, 10.5cm spray distance and 65°C temperature of expansion vessel was about 0.6μm. The largest mean particle size of gemfibrozil particles was 2.1μm produced by a capillary nozzle with a spray distance of 5.5cm. The results showed that the spray distance and the nozzle type were the efficient parameters on the morphology of precipitated particles but nozzle diameter had little effect on the mean size of precipitated particles.

Exploring High Operating Conditions in the Ibuprofen Precipitation by Rapid Expansion of Supercritical Solutions Process

Micronization of ibuprofen by a rapid expansion of supercritical solutions (RESS) process has been explored for a wide range of operating conditions, including temperatures above the melting point of ibuprofen. Morphologies, particle sizes (PSs), and particle size distributions (PSDs) have been analyzed by scanning electron microscopy and the crystallinity has been evaluated by X-ray diffraction measurements. Possible structural changes in the drug after supercritical fluid processing were evaluated by Fourier transform infrared spectroscopy. The effects of different pressures (100–350 bar), temperatures (308–353 K), and nozzle diameters (100–200 μm) on the drug precipitation have also been investigated. The morphology of the precipitated particles was improved in the majority of cases in comparison to the raw material, and the PS decreased. In general, higher pressures led to smaller particle sizes. The smallest particle sizes were obtained at 318 and 333 K, and precipitated powder was obtained even at temperatures above the melting point of ibuprofen. A larger nozzle diameter led to a larger particle size.

Formation of gemfibrozil with narrow particle size distribution via rapid expansion of supercritical solution process (RESS)

Abstract Micronized gemfibrozil (GEM) particles were produced by the process of rapid expansion of supercritical solutions (RESS). An experimental design was used to investigate the effects of three process parameters including extraction temperature (25 to 55 °C), extraction pressure (100 to 250 bar) and nozzle diameter (150 to 240 μm) on the particle size distribution (PSD) and morphology of the produced particles. The characterization of the particles was carried out using scanning electron microscopy (SEM) and X-ray diffraction (XRD) measurements to evaluate the produced particles. The average particle size of the unprocessed material was 30 μm ± (2.5). The average particle size of GEM after processing via the RESS process was between the minimum of 0.8 μm ± (0.03) and the maximum of 2.2 μm ± (0.057) depending upon the process parameters. The results showed that both increasing the temperature from 25 to 55 °C and increasing the nozzle diameter from 0.15 to 0.24 mm caused an increasing effect on the average particle size, whereas increasing the extraction pressure (100–250 bar) led a decrease in the average particle size.

Precipitation of Micronized Piroxicam Particles via RESS

In this study, the rapid expansion of supercritical solutions process was used to micronize the intact particles of piroxicam. Experiments were carried out to investigate the effect of extraction pressure (160–220 bar), extraction temperature (308–333 K), spraying distance (1–10 cm), and nozzle configuration (length and effective diameter) on the size and morphology of the precipitated piroxicam particle. The characterization of the particles was determined by scanning electron microscopy (SEM). The particle size of the original piroxicam particles was (39.2 µm) while depending upon the different experimental conditions, smaller particles of piroxicam (1.52–8.78 µm) were obtained.