Rapid 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.

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.

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.

Micronization of Three Active Pharmaceutical Ingredients Using the Rapid Expansion of Supercritical Solution Technology

AbstractThe rapid expansion of supercritical solution (RESS) technology was applied to recrystallize and micronize three active pharmaceutical ingredients (APIs) of monobenzone, ethylparaben, and kojic acid. All unprocessed (original) APIs had a large mean particle size over 200 μm with wide particle size distribution. Supercritical carbon dioxide served as the solvent to extract each API in a high‐pressure vessel. The nearly saturated supercritical solution was then expanded through a capillary spray nozzle to ambient pressure state. The APIs were recrystallized in a very short time period. The final API particles with submicron sizes were obtained with much less intensity of crystallinity. The optimal RESS process parameters and the improved result of the in vitro dissolution test for the API of ethylparaben are reported.

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.

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.

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.

Physicochemical Properties of the Inclusion Complex of Moxifloxacin with Hydroxypropyl-β-Cyclodextrin Synthesized by RESS

A new method for the synthesis of guest–host inclusion complex of moxifloxacin (MF) with 2-hydroxypropyl-β-cyclodextrin (HPCD) by supercritical fluid technology in the rapid expansion of supercritical solutions (RESS) mode was suggested for developing new drug formulations with improved bioaccessibility. The MF–HPCD complex was synthesized by this method as particles of 2–4 μm, which is the optimum size for creating the oral and inhalation MF drug forms. According to the scanning electron microscopy data, the morphology of MF–HPCD particles (irregular polyhedra) obtained by RESS processing differs from that of the starting components and from that of unbound MF and HPCD obtained by lyophilization from aqueous solution. According to X-ray diffraction data, the crystallinity of MF decreased from 95% to 20–30% after the formation of the HPCD complex. The IR spectroscopic and equilibrium dialysis data showed that RESS provides higher efficiency of drug inclusion in the complex with HPCD compared with that of conventional methods such as lyophilization or mixing of solid components.

A novel approach to predict drugs solubility in supercritical solvents for RESS process using various cubic EoS-mixing rule

Rapid Expansion of Supercritical Solutions (RESS) is an advantageous process to achieve micronization of poorly water-soluble drug. One of the crucial parameters in RESS is drug solubility in supercritical solvent as it affects the supersaturation and particle size distribution. In this study, five cubic equation of state (EoS) with two mixing rules are used to predict the solubility of Ibuprofen, Aspirin, Salicylic acid and Griseofulvin in supercritical carbon dioxide and trifluoromethane as solvent. The equations of state are van der Waals (vdW), Redlich-Kwong (RK), Riazi-Mansoori (RM), Mohsen-Nia-Moddaress-Mansoori (MMM) and Peng-Robinson (PR) with vdW type I and Kwak-Mansoori (KM) mixing rules. The results are presented for mixing rules with and without interaction parameters. Based on the calculated solubilities, two of the most accurate equations of state are PR-KM and PR-vdW with less average absolute percent deviation (AAPD) than the other EoS for all systems. Consequently, particle size of the drug is determined by all EoSs and compared with experimental data.

Evaluation of the Potential Use of Laminar Extrudates on Stabilizing Micronized Coumarin Particles by Supercritical Fluids (RESS)—Study of Different RESS Processing Variables and Mode of Operation

The study evaluates the ability of extrudates to deliver coumarin particles micronized by the rapid expansion of supercritical solutions (RESS). The RESS parameters were drug load (2-50g), pressure (15-42MPa) and temperature (40-60°C) in the extraction and pressure in the expansion (0.1-5MPa) chambers in batch or continuous and CO2 flow rate in the continuous mode of operation. Particles were characterized for size (laser diffractometry, optical and electronic microscopies-19-61μm), surface area (BET-0.282-0.423m2/g), density (pycnometry-1.273-1.358g/cm3) and yield (2-70%). Extrudates were characterized for the force of extrusion (4kN), release of coumarin (100%/24h) and mechanical properties (bending strength and stiffness increased, whereas elasticity decreased in storage) and X-ray diffractometry (micronized particles and extrudates have shown identical patterns) and calorimetry (DSC, enthalpies increased on storage). In the discontinuous mode of operation, increased loads in the extraction or increased pressure in the expansion chambers led to larger particles, whereas increased temperature and pressure in the extraction chamber led to smaller particles. In the continuous mode of operation, a decrease on the expansion pressure, load and CO2 flow rate led to increased yields. An increase on the flow rate led to a decrease on the particles' diameter, but an increase on coumarin load in the extraction chamber led to an increase in diameter. The study has identified the key parameters in RESS continuous and discontinuous modes of operation affecting the properties of the micronized coumarin particles and has proved the ability of extrudates with a laminar shape on delivering micronized particles.

Polymorphic properties of micronized mefenamic acid, nabumetone, paracetamol and tolbutamide produced by rapid expansion of supercritical solutions (RESS)

The rapid expansion of a supercritical solution (RESS) process was used to produce submicron Paracetamol (=Acetaminophen), Mefenamic acid, Nabumetone and Tolbutamide particles. These model drugs have been chosen since different numbers of polymorphs (I & II, I–III and I–V) have been reported in literature. Thus, the aim of this investigation was twofold: to examine the possibility of using the RESS process to produce submicron drug particles and to control the polymorphic properties of drug micro-particles. The unprocessed and micronized particles are characterized by scanning electron microscopy, X-ray diffraction and differential scanning calorimetry.A significant reduction was observed in the particle size and size distribution of the particles produced by RESS. The mean particle size of the processed particles increased in the following order: Mefenamic acid (0.08μm≤x50≤0.16μm)<Paracetamol (0.16μm≤x50≤0.34μm)<Tolbutamide (0.34μm≤x50≤0.45μm)<Nabumetone (0.75μm≤x50≤0.81μm).Under certain temperature (333 and 353K) and pressure (15, 20, 25 and 30MPa) conditions, it was possible to form the favorable Tolbutamide polymorphic form II. Thus, this study demonstrates that the polymorphic characteristics of submicron Tolbutamide particles produced by RESS can be controlled by varying the pre-expansion conditions while the simple static treatment with supercritical CO2 does not induce polymorphic conversion of the drugs investigated.

Formation and Characterization of Beclomethasone Dipropionate Nanoparticles Using Rapid Expansion of Supercritical Solution.

Particle size of Beclometasone Dipropionate (BDP) was reduced by the rapid expansion of supercritical solution (RESS) process, using CO2 as supercritical solvent. Also, the effect of RESS parameters such as extraction pressure, pre-expansion temperature, and weight fraction of co-solvent on the size and distribution of BDP particles were investigated. The effects of extraction pressure (200-260 bar), pre-expansion temperature (70-110 °C) and weight fraction of menthol as a co-solvent on mean particle size (MPS) of BDP were investigated by design of experiment (DOE). Particles were characterized using Scanning Electron Microscopy (SEM) and Dynamic Light Scattering (DLS). The average sizes of precipitated BDP were between 64.1 and 294 nm. Analysis of variance (ANOVA) showed that extraction pressure was the most significant parameter and a higher extraction pressure caused production of smaller particles. Also, it was found that higher temperature and weight fraction of co-solvent increased the MPS. The interaction effects of extraction pressure-pre-expansion temperature and pre-expansion temperature-co-solvent ratio were significant through the analysis of variance. It was observed that the MPS of precipitated particles was mostly influenced by pressure. The smallest MPS of BDP obtained from the RESS process was 65 nm that revealed a significant size reduction from its original MPS of 9 μm. Moreover, a slight change was observed for precipitated particles of BDP into spherical form while the original particles were irregular in shape. RESS process showed as a promising method for production of BDP nanoparticles that may results in improvement of drug's physicochemical properties.

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.

Rapid Expansion of Supercritical Fluids for Particle Formation from Pharmaceutical Compounds: A Review

The rapid expansion of supercritical solution (RESS) is a promising method for particle formation. In this paper, general review of fundamental and available results from studies of particle formation by RESS process using carbon dioxide as a solvent for pharmaceutical compounds.

Characterization of Carbamazepine-Loaded Solid Lipid Nanoparticles Prepared by Rapid Expansion of Supercritical Solution

Purpose: To prepare carbamazepine-loaded solid lipid nanoparticles (CBZ-SLN) for prolonged release of CBZ in oral drug delivery.Methods: CBZ-loaded SLNs were prepared by rapid expansion of supercritical solution (RESS). SLNs were formulated using stearic acid as the lipid component. Initially, lipid and drug were separately micronized by RESS process separately. This was followed by co-precipitation of the components with the two solutes using RESS to produce drug-loaded SLNs. The formulations were characterized by infrared spectroscopy (IR), scanning electron microscopy (SEM) and ultraviolet spectrophotometry (UV).Results: Application of RESS to pure stearic acid yielded spherical particles in the range 40 to 200 nm which was about 600 times smaller than the unprocessed powder based on SEM observation. Similarly, RESS processing of carbamazepine produced nanoparticles with rod shape. FT-IR analysis showed that no chemical structure change occurred during RESS processing of both components. Coprecipitation of drug and lipid using RESS produced SLNs with drug loading capacity of 2.2 %. RESS yielded ultrafine spherical particles (100 nm) of CBZ-SLNs.Conclusion: The successful preparation and characterization of carbamazepine-loaded solid lipid nanoparticles by RESS as well as their characterization has been achieved in this study.Keywords: Rapid expansion of supercritical fluid, Stearic acid, Solid lipid nanoparticles, Carbamazepine, Co-precipitation

Simultaneous formation and micronization of pharmaceutical cocrystals by rapid expansion of supercritical solutions (RESS).

We investigated the RESS process as a means of simultaneous micronization and cocrystallization of a model drug with poor aqueous solubility. 1:1 cocrystals of ibuprofen (IBU) and nicotinamide (NA) were produced with a pilot scale unit for RESS processing.IBU and NA were dissolved in scCO2 at 30 MPa and 50°C. After 24 h, the supercritical solution was expanded at a medium CO2 flow rate of 3.8 kg/h during 60 min into an expansion vessel kept at ambient conditions. Cocrystals were identified with DSC, XRD and confocal Raman microscopy (CRM) and further characterized by SEM, specific surface area, wetting ability, solubility and dissolution testing. Judging by DSC, XRD and CRM, cocrystals with high purity could be produced with the RESS technique. Micronization via RESS was successful, since the specific surface area of RESS cocrystals was increased almost tenfold in comparison to cocrystals produced by slow solvent evaporation. Due to the additional micronization, the mean dissolution time of IBU from RESS cocrystals was decreased. RESS cocrystallization offers the advantage of combining micronization and cocrystallization in a single production step. For drugs with dissolution-limited bioavailability, RESS cocrystallization may therefore be a superior approach in comparison to established cocrystallization techniques.

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, 60:40wt/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 (Ppre, Tpre) 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 30nm to several microns, depending on processing parameters. Rapid expansion of fluoropolymer solutions (0.3–1.0wt%) with Ppre of 331bar initiated from unsaturated conditions produced nanoparticles with a narrow size distribution of ∼30–70nm; whereas larger particles with broader size distributions and a lower degree of agglomeration were obtained when supersaturated solutions were expanded with Ppre of 172bar, especially at Tpre (80°C) – higher than the glass transition temperature (73°C) of poly(TFEMA). The surface coverage by the fluoropolymer increased with increasing Ppre and poly(TFEMA) concentration, but decreased with increasing Tpre. In addition, the hydrophobicity of the coated substrate, determined by water contact angle and water vapor transmission rate measurements, increased with increasing surface coverage.