Pre-expansion Temperature Research Articles

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.

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.

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.

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.

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.

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.

Investigation on hydrodynamic and formation of nano particle by RESS process: The numerical study

The particle formation by supercritical technology is an active research field. Rapid expansion of supercritical fluid (RESS) is a promising new technology for particle formation using supercritical fluids. In this study, numerical modeling of particle formation of TBTPP (5, 10, 15, 20-tetrakis (3, 5-bis (trifluoromethyl) phenyl) porphyrin) through RESS process is investigated. The RESS process contains two pre-expansion (nozzle part) and expansion vessel (supersonic free jet) parts. In the first section, mass, momentum and energy balances in addition to extended generalized Bender equation of state (egB-EoS) as accurate equation of state is used to calculate temperature, pressure, density and velocity of supercritical carbon dioxide (SC-CO2) based on mathematical modeling and computational fluid dynamics (CFD) simulation methods. Both models include friction in the nozzle and heat exchange in the expansion vessel and in the nozzle region. Using calculated pressure and temperature, the solubility of TBTPP in the supercritical CO2 is predicted by Peng-Robinson EoS with Kwak-Mansoori mixing rule and the results are compared with experimental data and a semi-empirical correlation. Supersaturation, homogenous nucleation and critical radius of TBTPP based on classical nucleation theory are calculated. The effect of pre-expansion temperature on supersaturation, nucleation and critical radius parameters is also studied. The results of hydrodynamic and particle formation modeling present the same trend as reported in the literature.

Phase equilibrium and micronization for flufenamic acid with supercritical carbon dioxide

Abstract The solubility data of flufenamic acid (FFA, a fluorinated and non-steroidal anti-inflammatory drug) in supercritical carbon dioxide were measured with a semi-flow type phase equilibrium apparatus at temperatures from 313.2 K to 333.2 K and pressures up to 21 MPa. Over the experimental conditions, the solubility values are between 0.8 × 10−6 and 2.13 × 10−4 in mole fraction. These solid–gas equilibrium data were correlated with the Chrastil model, Mendez-Santiago and Teja model, and the Peng–Robinson equation of state to average absolute relative deviations of 11.4%, 21.1%, and 7.8%, respectively. Since the solubility of FFA can be as high as 10−4, rapid expansion of supercritical solution (RESS) method is favorable for preparing ultra-fine FFA particles. The experimental results of the RESS micronization show that extraction pressure, pre-expansion temperature, and dimension of capillary tube are the key factors to govern the morphology and the mean size of the resultant particles. While sticky agglomerates were obtained from lower extraction pressures with larger and/or longer capillary tube, needle-like particles were produced at higher extraction pressures with smaller and/or shorter capillary tube. Moreover, operating at lower pre-expansion temperatures and higher crystallization temperatures yielded longer and thinner needle-like crystals. Under higher extraction pressure (e.g., 21 MPa), the mean size of the generated FFA particles distributed from 0.5 to 5.1 µm and from 0.1 to 1.1 µm for the lengths of major and minor axes, respectively. It is also found that the particulate FFA converts from original form I into form III after the RESS processing.

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.

Effect of rapid expansion of subcritical solutions processing conditions on loading capacity of tetrahydrocurcumin encapsulated in poly(l-lactide) particles

Encapsulation of tetrahydrocurcumin (THC) in poly(l-lactide) (PLLA) was achieved by rapid expansion of subcritical solutions of THC and PLLA into water. A pressurized mixture consisting of ethanol and carbon dioxide (3:2wt/wt) was used as a solvent for THC and PLLA with concentrations up to 2wt%. The influences of pre-expansion conditions (temperature and pressure) and THC:PLLA weight ratio on the size and morphology of THC-loaded PLLA particles, as well as the loading capacity of THC, were systematically investigated. All the obtained particles were spherical in shape with average size and THC loading capacity ranges of ∼80–110nm and ∼13–25%, respectively. The loading capacity increased with (i) increasing pre-expansion temperature and reducing pre-expansion pressure and (ii) increasing THC:PLLA weight ratio at high pre-expansion temperature and low pre-expansion pressure. The antioxidant activity of THC remained unchanged after rapid expansion process, and encapsulation in PLLA prolonged the release of THC.

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.

Production of ultrafine clobetasol propionate via rapid expansion of supercritical solution (RESS): Full factorial approach

In this study, ultrafine clobetasol propionate (CP) particles were produced by rapid expansion of supercritical solution (RESS). Particle size and morphology of CP were examined using eleven experiments based on 2 level full factorial design and the effects of extraction pressure (200–260bar), pre-expansion temperature (70–110°C) and menthol (co-solvent) weight fraction (3–7wt.%) were evaluated. The size was measured by Nanosizer® and processed particles were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared analysis (FT-IR) and differential scanning calorimetry (DSC). The mean particle size of processed CP was between 95nm and 318.8nm. According to the statistical analysis, pressure had the most significant effect on the particles size with the lowest probability value (0.001) and highest Fischer value (53.1).

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.

Recrystallization of adefovir dipivoxil particles using the rapid expansion of supercritical solutions (RESS) process

In this study, recrystallization of adefovir dipivoxil particles was carried out by the rapid expansion of supercritical solutions (RESS) process. Supercritical carbon dioxide, which is a green solvent, was selected as a solvent. The effect of process parameters such as extraction temperature and pressure, pre-expansion temperature, spray distance, and nozzle configuration on the particle size of adefovir dipivoxil was evaluated and it was found that the process parameters did influence the particles size. The solubility of adefovir dipivoxil in CO2 was measured for the purpose of setting proper experimental conditions. Increasing the extraction temperature (308.15–328.15K) caused the particle size of adefovir dipivoxil to increase. Particle size decreased with increasing extraction pressure (20–30MPa). The particle size of adefovir dipivoxil increased with increasing pre-expansion temperature. An increase in the spray distance (8, 16, 32cm) resulted in a decrease in the average size of particles. The effect of the internal nozzle diameter on the size and shape of the precipitated particles was examined using different nozzle internal diameters (152, 500, 762μm). When the internal nozzle diameter size was larger, the particle size did not show significant change. The adefovir dipivoxil particles that underwent RESS process were analyzed by SEM, XRD, DSC and FT-IR spectra.

Encapsulation of Lavandin Essential Oil in Poly‐(ϵ‐caprolactones) by PGSS Process

AbstractLavandin essential oil has been encapsulated in poly‐(ϵ‐caprolactone) (MW: 4000 g mol–1) by means of the particles from gas saturated solutions (PGSS) process. The influence of process conditions, i.e., pre‐expansion temperature and pressure, and oil/polymer mass ratio, on the morphology of particles and the efficiency of encapsulation has been analyzed. Spherical particles with particle sizes of 100–700 μm were obtained, with increasing particle sizes and more agglomeration as the oil/polymer ratio was increased. The efficiency of encapsulation was increased by conditions that favored a fast solidification of the polymer shell, including high pre‐expansion pressures, reaching efficiencies up to 50 % with oil loads up to 120 mg oil/g particles.

Effect of concentration and degree of saturation on co-precipitation of catechin and poly(l-lactide) by the RESOLV process

Rapid expansion of subcritical solutions into liquid solvents (RESOLV) was able to consistently produce catechin (CTC)-loaded poly(l-lactide) (PLLA) nanoparticles. The effects of CTC concentration and processing conditions – pre-expansion temperature and pressure, and degree of saturation – on the size and morphology of CTC-loaded PLLA nanoparticles were investigated, as well as the loading capacity (LC), entrapment efficiency (EE), and release of CTC. RESOLV experiments were carried out with 0.1wt% CTC+0.2wt% PLLA and 0.2wt% CTC+0.2wt% PLLA solutions in mixtures of EtOH and CO2 (3:2, wt/wt) with pre-expansion temperature and pressure of 60–100°C and 265–325bar, respectively. The obtained CTC-loaded PLLA nanoparticles were spherical, with average sizes, LC, and EE ranges of ∼30–40nm, 2.4–7.3%, and 4.7–22.0%, respectively. CTC concentration, pre-expansion temperature, and degree of saturation had significant effects on LC and EE of CTC, without affecting the size of composite nanoparticles. The LC and EE of CTC increased with increasing pre-expansion temperature and degree of saturation, and with decreasing CTC concentration. The release profiles of CTC from the nanoparticles exhibited an initial stage of burst release (first 8h) followed by a sustained release (∼1–9 days). Furthermore, the fraction of CTC being released from the nanoparticles decreased with increasing the degree of saturation of subcritical solutions prior to rapid expansion and with increasing the LC of CTC.

Micronization of ethosuximide using the rapid expansion of supercritical solution (RESS) process

Ethosuximide is a succinimide anticonvulsant active pharmaceutical ingredient (API). It was used in our rapid expansion of supercritical solution (RESS) experiments with supercritical carbon dioxide as the solvent. Effects of four process parameters on the particle formation of ethosuximide were investigated. These parameters include the extraction pressure (Pext), orifice nozzle diameter (Dn), pre-expansion temperature (Tpre) and post-expansion temperature (Tpost). It is observed that an operation at a higher extraction pressure, lower post-expansion temperature and smaller orifice nozzle diameter is favorable for the production of smaller ethosuximide particles while the effect of pre-expansion temperature is insignificant. This API was micronized from its original mean size of 175.5μm to the smallest average size of 1.5μm at the optimal RESS process conditions. A polymorph conversion of ethosuximide was observed after the RESS process by physical properties characterization using the X-ray diffractometer (XRD) and differential scanning calorimetry (DSC). Measurements of the dissolution profiles for ethosuximide before and after the RESS process were also conducted. The micronized ethosuximide product shows novel dissolution behavior and significantly enhanced dissolution rate after the RESS treatment.

Investigation of different particle sizes on superhydrophobic surfaces made by rapid expansion of supercritical solution with in situ laser diffraction (RESS-LD)

In situ laser diffraction, scanning electron microscopy (SEM) imaging, and thermography have been used to investigate particle formation and particle size distribution of alkyl ketene dimer (AKD) produced by rapid expansion of supercritical solution (RESS). The investigated RESS process is based on an earlier reported method to prepare superhydrophobic coatings. Spray distance, pre-expansion temperature and pressure have been varied and the results from the methods have been compared. SEM images and light scattering data correlate well, and show that the mean particle size increased and the size distribution became significantly broader with increasing spray distance. Mean particle diameters of above 5μm were only observed for pre-expansion temperatures at 50°C or below. Furthermore, results show that by placing the surface to be coated within the cold expansion zone of carbon dioxide (CO2), i.e. in this study at 55mm or shorter for a pre-expansion temperature (Tpe) and pressure (Ppe) of 57°C and 180bar, respectively, will produce a surface evenly covered by 3-μm crystalline AKD flake-like particles. Obtained results also indicated, but did not prove, that agglomerates of AKD particles were carried to the surface by liquid CO2 droplets in the jet.

L-Menthol crystal micronized by rapid expansion of supercritical carbon dioxide

Rapid expansion of supercritical solutions (RESS) is a promising alternative for micronizing various materials including l-menthol of which dissolution would be mainly controlled by its particle size and morphology. The aim of this work is to study the effect of ethanol co-solvent, pre-expansion temperature and pre-expansion pressure on the size and morphology of l-menthol crystals micronized by rapid expansion of supercritical CO2 in prior to their microencapsulation. Calculation of l-menthol dissolution in supercritical CO2 (SC-CO2) was conducted, suggesting that the appropriate pre-expansion temperature would be below 50°C. Verification based on FT-IR analysis suggested that the fine particles of l-menthol crystals with controlled size and morphology could be prepared by rapid expansion of supercritical CO2 without any structural change.