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.

Supercritical carbon dioxide solubility measurement and modelling for effective size reduction of nifedipine particles for transdermal application

Nifedipine (NIF) is a Class II drug of the Biopharmaceutical Classification System (BCS) with low oral bioavailability, low dissolution rate and significant hepatic drug metabolism. The transdermal route using supersaturated systems could be considered. For this purpose, physicochemical properties of NIF such as its dissolution rate, may be a limiting factor and must be improved. Crystallization processes assisted by supercritical carbon dioxide (scCO2) and particularly the Rapid Expansion of Supercritical Solution (RESS) process may improve drug bioavailability by reducing particle size and consequently increasing surface area. This study addresses the reduction of NIF particle size using scCO2-RESS as crystallization process. Experimental solubility studies were performed at different temperature (308 and 318 K) and pressure ranges (9–24 MPa). Solubility data were correlated with two thermodynamic models in order to predict NIF solubility in scCO2. Optimized operating conditions, identified by thermodynamic modelling, allowed the production of thinner NIF particles and a size reduction up to ten fold. Particle size reduction improved NIF dissolution kinetics in aqueous medium: after 90 min, 42 % of raw NIF was released against 80 % for crystallized NIF. The scCO2-RESS process is a solvent free process, that can produce micronized or nanosized crystals able to improve physicochemical properties of poorly water-soluble drugs.

UV–visible absorption spectroscopy for in-line API concentration measurement in nanoparticle production process using controlled expansion of supercritical solutions (CESS®)

Most new small drug molecules in pharmaceutical development require improvement of solubility. The controlled expansion of supercritical solutions (CESS®) process is a nanoparticle production technology, dedicated to enhancing the dissolution rate of active pharmaceutical ingredients (APIs) suffering from poor solubility and enabling novel drug delivery opportunities. In this process, the API is dissolved in supercritical carbon dioxide (scCO2) and nanoparticles are formed through controlled pressure reduction. To improve process visibility and control, ultraviolet-visible (UV-Vis) spectroscopy was incorporated into CESS® process as a process analytical technology (PAT) tool. The tool quantifies the amount of API dissolved in scCO2 during the solubilization phase of the process. Sample interfacing of the UV-Vis spectrometer was done with a custom-made pressure and temperature rated transmission flow-through cell. In-process calibration was developed to correlate the UV-Vis absorption spectra to the API concentration. Due to the density-dependent molar absorption coefficient of API in scCO2, the calibration was done for each combination of temperature and pressure. The developed PAT tool provides insight into the process enabling real-time API quantity estimation. It also facilitates process development through Quality by Design (QbD) and offers a system for enhanced process control and troubleshooting. For instance, the in-line API concentration data allows one to study the solubilization behavior of the API in the process and to optimize the process parameters in order to maximize throughput.

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.

Particle size design of acetaminophen using supercritical carbon dioxide to improve drug delivery: Experimental and modeling

In this communication, micronized acetaminophen particles are investigated using the rapid expansion of the supercritical solution (RESS) process. According to the obtained results, the largest acetaminophen particle size was ≤ 40 nm with spherical and quasi-spherical morphology in comparison with unprocessed particles with needle shape and mean particle size of 80.32 µm. The effect of extraction pressure and temperature, pre-expansion temperature, and spaying distance on the acetaminophen particle size and morphology were studied. The results indicated that increases in the extraction pressure and temperature led to decreases acetaminophen particle size but increasing pre-expansion temperature and spaying distance had opposite effects. To investigate particle formation through the RESS process with more details, velocity, pressure, density, and temperature behavior of the supercritical solution and acetaminophen solubility in supercritical CO2 was modeled. Ultimately, the population balance equation was solved based on the moment method and acetaminophen particle size distribution was predicted and the influence of coagulation phenomenon as a remarkable mechanism on particle size distribution was investigated.

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.

Numerical solution of particle size distribution equation: Rapid expansion of supercritical solution (RESS) process

The present study aimed to numerically simulate the rapid expansion of the supercritical solution (RESS) process including particle generation, hydrodynamics, and solving the population balance equation (PBE) to predict the particle-size distribution (PSD) of solid-supercritical carbon dioxide binary systems. Energy, momentum, and mass equations, in addition to the extended generalized Bender equation of state (EoS), were applied to predict the hydrodynamic behavior of a supercritical solution under several operating conditions using a nozzle and expansion vessel. The tetraphenylporphyrin (TBTPP) solubility in supercritical carbon dioxide was calculated using the Peng–Robinson EoS/Kwak–Mansoori as a mixing rule. Subsequently, TBTPP, aspirin, ibuprofen, and salicylic acid nucleation as well as the supersaturation rate were calculated. Finally, we solved the time dependence of the parameters of the size distribution numerically. The established models are compared over a wide parameter range using a reference model that refers to the method of moment log-normal size distribution functions through the RESS process to predict a solid PSD. The results obtained are presented with and without coagulation phenomena. The average absolute percent deviation of solubility of TBTPP was 3.98, and the hydrodynamic behavior of supercritical carbon dioxide showed a similar trend as the results presented in the published research work. Furthermore, a particle size distribution prediction using coagulation showed acceptable agreement with the experimental PSDs.

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.

Sub-micronization of disulfiram and disulfiram-copper complexes by Rapid expansion of supercritical solution toward augmented anticancer effect

Despite the success in exploring and repurposing of its various biological efficacies such as antitumor and others, disulfiram (DSF), a copper-dependent antitumor drug, suffers from multiple shortcomings of poor aqueous solubility and instability in the physiological environment, which often hinder its clinical applicability. Moreover, the limited availability of copper in the body also hampered the therapeutic ability of DSF. Initially, the determined experimental solubility values of DSF (7.89 × 10−5 to 6.71 × 10-4 mole fraction) in supercritical carbon dioxide (SC−CO2) at different critical conditions are subsequently correlated using various empirical models. Further, the sub-micronized products of DSF (with mean diameters ranging from 1.53 ± 0.45 to 0.62 ± 0.11 μm) and its subsequent DSF-copper complexes (CuET) (with mean diameters ranging from 1.45 ± 0.45 to 0.27 ± 0.06 μm) are fabricated using the rapid expansion of supercritical solutions (RESS) process. Further, the suspension ability of these complexes is improved by coating with polyvinylpyrrolidone (PVP) and methoxy b-poly(L-lactide) 2000- poly(ethylene glycol) 2000 (mPLLA-PEG) solution using the RESS-based processes that with the different receiving mediums. The physicochemical properties and dissolution profiles of these composites are systematically recorded. in vitro anti-proliferation studies confirmed the substantial augmentation of bioefficacy of micronized DSF in the presence of copper. Moreover, the polymer-coated DSF or CuET nanoparticles significantly enhanced the toxicity of DSF, attributing to their relatively smaller sizes and excellent dispersibility in the aqueous environment. Thus, our findings showed that the altered dissolution rate of drugs and the synergistic effect of the metal species in CuET complex significantly amplified the antitumor efficacy of DSF, indicating the potential of RESS process in enhancing the dissolution rate as well as substantial antitumor efficiency of nano-sized drugs and their complexes.

Solid Solubilities of Sulfonamides and Use of Rapid Expansion of Supercritical Solutions for Microparticle Production

AbstractThe solubility of solid active pharmaceutical ingredients in supercritical fluids is a major thermodynamic criterion for selection and screening of microparticle generation processes. To develop an efficient method for solubility prediction, a solution model was adopted to establish the correlations of the solid solubilities of six sulfonamides in supercritical CO2. The model was capable of determining solubility correlations. Accordingly, it was attempted to simplify and generalize the model, yielding a predictive solution model, which provided order‐consistent solubility predictions. A case study for model extrapolation was conducted. After understanding the mechanisms underlying the solubility of sulfonamides, the rapid expansion of supercritical solutions (RESS) process was applied to produce microparticles of p‐toluenesulfonamide, an anticancer drug. The effects of RESS process parameters were investigated.

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.

Application of Box-Behnken Design to Investigate the Effect of Process Parameters on the Microparticle Production of Ethenzamide through the Rapid Expansion of the Supercritical Solutions Process.

In this study, the rapid expansion of the supercritical solutions (RESS) process was used to produce microparticles of a commonly used anti-inflammatory drug, ethenzamide. The effects of process parameters in RESS including the extraction temperature, pre-expansion temperature, and post-expansion temperature were investigated using the Box–Behnken design. According to the results of the analysis of variance (ANOVA), the effect of pre-expansion temperature is the most significant parameter on the mean size of RESS-produced ethenzamide. A higher pre-expansion temperature benefits the production of smaller crystals. In addition, a quadratic effect of the post-expansion temperature was also identified. Through RESS, ethenzamide microparticles with a mean size of 1.6 μm were successfully produced. The solid-state properties including the crystal habit, crystal form, thermal behavior, and spectrometric property were characterized by scanning electron microscopy (SEM), Fourier-transform infrared spectrometer (FTIR), differential scanning calorimeter (DSC), and powder X-ray diffraction (PXRD). These analytical results show that the rod-like crystals were generated through RESS, and the crystal form, thermal behavior, and spectrometric property of RESS-produced crystals are consistent with the unprocessed ethenzamide.

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.

Recrystallization and Micronization of p-Toluenesulfonamide Using the Rapid Expansion of Supercritical Solution (RESS) Process

This study is focused on the micronization of p-toluenesulfonamide (p-TSA) using the rapid expansion of supercritical solution (RESS) process. Taguchi’s experimental design method was applied to determine the optimum operating conditions. L9(34) orthogonal array with four control factors and three levels of each control factor was used to design nine experimental conditions. Four control factors were selected, including extraction temperature, extraction pressure, pre-expansion temperature, and post-expansion temperature. The particle size and morphology of the prepared samples were observed by scanning electron microscopy (SEM). In addition, Fourier transform infrared spectrometer (FTIR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) were employed to compare the differences between the raw and micronized p-TSA particles. The experimental and analytical results indicated that the extraction temperature was the most significant factor for the micronization of p-TSA in the RESS process, and the optimal operating conditions were at an extraction temperature of 50 °C, an extraction pressure of 220 MPa, a pre-expansion temperature of 220 °C, and a post-expansion temperature of 30 °C. The p-TSA particles were micronized from the original average size of 294.8 μm to the smallest average size of 1.1 μm at the optimal RESS process conditions. Furthermore, the physicochemical characteristics of p-TSA did not differ significantly before and after recrystallization.

Preparation and optimization of Vitamin E acetate liposomes using a modified RESS process combined with response surface methodology

Liposomes have attracted much attention in the pharmaceutical and cosmetic industries. In this study, the Vitamin E acetate (VEA) liposomes are prepared using a modified rapid expansion of supercritical solution (RESS) process. The effects of operation conditions (e.g., temperature, pressure, and the mass ratio of ethanol to CO2) on encapsulation efficiency (EE), polydispersity index (PDI), and Zeta-potential of the liposomes are investigated. Additionally, the response surface methodology (RSM) based on Box–Behnken design (BBD) is employed to reveal the interaction between the operation conditions and optimize the VEA liposomes preparation process. The high encapsulation efficiency of 98.63 ± 0.42% is obtained at the temperature of 59.55 °C, the pressure of 23.45 MPa, and the mass ratio of ethanol to CO2 of 0.36%. The particle size distribution and morphology of VEA liposomes indicate that liposomes prepared by this technology can meet the requirements of the Chinese Pharmacopeia Commission (2010). Eventually, the stability and in vitro release behaviors of VEA liposomes are determined. The results show that the prepared liposomes have good stability, and the slow and sustained release is observed during the in vitro release experiment.

Population balance modeling: application in nanoparticle formation through rapid expansion of supercritical solution

The rapid expansion of supercritical solution (RESS) process is a novel method to produce free-solvent particles with narrow particle size distribution (PSD), and it is offered to replace conventional particle formation methods. The present study is aimed to investigate the numerical simulation of the RESS process comprising hydrodynamic and particle formation and solving population balance equation to compute PSD of solute-supercritical CO2 (SC-CO2) systems. Mass, momentum and energy balances in addition to an accurate equation of state are used to calculate hydrodynamic behavior of SC-CO2 at various conditions through a nozzle and supersonic free jet with considering heat exchange in the nozzle. The solubility of TBTPP (5, 10, 15, 20-tetrakis (3, 5-bis (trifluoromethyl) phenyl) porphyrin) in SC-CO2 is calculated using the Soave–Redlich–Kwong equation of state with van der Waals mixing rule. After that, supersaturation and nucleation of TBTPP and three other drugs, i.e., aspirin, salicylic acid and ibuprofen, are investigated. Eventually, the method of moments is used to solve the population balance equations to determine PSD of the solutes. The results are presented with and without coagulation. Furthermore, the effect of nozzle length and pre-expansion temperature on PSD is studied. Furthermore, to improve the results of coagulation model on PSD, collision frequency and lognormal function are modified. The modifications improve the coagulation results. The average absolute percent deviation of TBTPP solubility is 1.86. The CO2 hydrodynamic behavior shows the same trend as reported in the literature. Moreover, results of PSD calculation with coagulation indicated there is a good agreement with the experimental ones.

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.

Production and characterization of ultrafine aspirin particles by rapid expansion of supercritical solution with solid co-solvent (RESS-SC): expansion parameters effects

Micronization of polar drugs by the rapid expansion of supercritical solution (RESS) process is not successful in near critical pressure due to the extremely low solubility of the drugs in near-critical CO2. In this study, for the first time, micronization of aspirin was successfully performed by the rapid expansion of supercritical solution with solid co-solvent (RESS-SC) process in near-critical pressure by using menthol as solid co-solvent. To achieve this aim, some experiments were conducted to study the influences of expansion pressure ranging from 1 to 8 bar, pre-expansion temperature ranging from 30 to 70 °C, spray distance ranging from 2 to 6 cm, nozzle diameter ranging from 300 to 700 µm, and nozzle types (orifice - capillary) on the morphology and size of aspirin particles. The obtained particles were characterized by x-ray diffraction (XRD) and scanning electron microscope (SEM) analysis. Utilizing RESS-SC process in near-critical condition, aspirin particles in the range of 0.17–6.61 µm were obtained.