Supercritical Antisolvent Process Research Articles

Controlling particle size of levan in powder form with different technologies

Levan is a fructose polysaccharide with multiple applications in different fields, but its obtaining in powdered form with a narrow particle size distribution is a complicated task. Two techniques, electrospraying and supercritical antisolvent (SAS) precipitation, were used to process levan that was first obtained enzymatically. The SAS process was able to micronize the polymer (at experimental conditions far above the mixture critical point of the solvent-antisolvent system) to obtain spherical particles between 0.30 and 0.50 μm with a proper particle size distribution. In this case, the Peng-Robinson equation of state was used to theoretically determine the mixture critical point. Bigger and elongated particles were obtained with electrospraying (0.60 μm). According to solution properties, mainly rheology, solubility and conductivity, the best solvent for levan electrospraying, in order to avoid problems of solvent evaporation and jet formation, was a mixture of water and ethanol with a polymer concentration of 50 mg·cm−3. Indeed, that solution has a viscous behavior (according to the oscillatory analysis), a low degree of pseudo-plasticity (based on the shear flow analysis), and the highest value of conductivity. Therefore, the particle size distribution of levan in powdered form can be tuned depending on the technique used.

Micro and nanosizing of Tamsulosin drug via supercritical CO2 antisolvent (SAS) process

Supercritical anti-solvent (SAS) method is a solvent-free approach where supercritical carbon dioxide (SC-CO2) is used as anti-solvent and one can control the output particle size without disturbing the nature of the particles. The primary objective of this study is to develop SAS method for the production of Tamsulosin (TML) nanoparticles and investigate the parameters affecting the resultant particle size. In order to optimize the production of nano-sized particles, response surface methodology (RSM) based on Box-Behnken design (BBD (was used. Using dynamic light scattering (DLS) and scanning electron microscopy (SEM) analyses, morphologies and mean diameter ranges were examined. To look into how the SAS process affects TML's chemical and physical characteristics, Fourier-transform infrared spectroscopy (FT–IR), X-ray diffraction analysis (XRD) and differential scanning calorimetry (DSC) were further performed. The acquired results demonstrated that the pressure imposes the largest impact on the TML particle production, with the particle size exhibiting an inverse correlation to the pressure. Observations further indicated an increase in particle size with increasing the temperature from 35 to 50 °C. By increasing the flow rate of the drug solution, the average particle size exhibited an initial decrease followed by an increasing trend. Results of the optimization of the SAS process showed that at a pressure, temperature, and injection rate of 25 MPa, 41.3 °C, and 2.9 mL/min, respectively, the TML particles shrink to an average size of 600 nm.

PVP/aprepitant microcapsules produced by supercritical antisolvent process

The supercritical antisolvent (SAS) process was a green alternative to improve the low bioavailability of insoluble drugs. However, it is difficult for SAS process to industrialize with limited production capacity. A coaxial annular nozzle was used to prepare the microcapsules of aprepitant (APR) and polyvinylpyrrolidone (PVP) by SAS with N, N-Dimethylformamide (DMF) as solvent. Meanwhile, the effects of polymer/drug ratio, operating pressure, operating temperature and overall concentration on particles morphology, mean particle diameter and size distribution were analyzed. Microcapsules with mean diameters ranging from 2.04 μm and 9.84 μm were successfully produced. The morphology, particle size, thermal behavior, crystallinity, drug content, drug dissolution and residual amount of DMF of samples were analyzed. The results revealed that the APR drug dissolution of the microcapsules by SAS process was faster than the unprocessed APR. Furthermore, the drug powder collected every hour is in the kilogram level, verifying the possibility to scale up the production of pharmaceuticals employing the SAS process from an industrial point of view.

Preparation of indapamide-HP-β-CD and indapamide-PVP nanoparticles by supercritical antisolvent technology: Experimental and DPD simulations

The poor aqueous solubility of indapamide (INP) limits its applicability in various biomedical applications. To overcome this issue, nanosized INP particles (INP-HP-β-CD NPs and INP-PVP-K30 NPs) were fabricated using the supercritical antisolvent (SAS) approach to improve the bioavailability of INP. The process, formula, and supercritical antisolvent process were optimized using single-factor and orthogonal methods. The tiny INP-HP-β-CD NPs with a particle size of 142.5 nm and INP-PVP-K30 NPs with a particle size of 150.4 nm were obtained under optimum conditions. Further analysis and characterization, such as SEM, FTIR, XRD, DSC, 1H NMR, and dissipative particle dynamics (DPD) simulations, were carried out to verify the formation mechanism of the INP complex nanoparticles. The altered physical state of INP from crystalline to amorphous loaded onto the polymer resulted in a significant improvement in the solubility and dissolution rate and high biocompatibility with cells compared to raw INP. Therefore, we propose that INP nanoparticles processed by a supercritical antisolvent process can be used as an advanced drug delivery system, especially for insoluble drugs.

Atypical crystal growth within the supercritical antisolvent process: Experimental and molecular modeling approach with sodium bicarbonate

This paper presents the recrystallization of sodium bicarbonate (NaHCO3) using the Supercritical AntiSolvent process. The focus is pointed toward crystal habit and its modification induced by varying the solvent nature. The observed habit is uncommon with crystals exhibiting a “zigzag” shape. High Resolution Scanning Electron Microscopy observations refuted that this shape was due to particle attachment: those “zigzag” particles are likely monocrystals grown in a diffusion-limited media. Firstly, a molecular modeling study shed light on organic solvents that can interact strongly with NaHCO3 crystals. Such solvents were found to be ethylene glycol and glycine, in contrast to ethanol or water which likely interact weakly with NaHCO3 crystals. An experimental campaign confirmed the predicted interactions. Ethylene glycol interactions with NaHCO3 crystals led to the production of a different crystal salt. Alternatively, adding glycine as a growth inhibitor led to the initial polymorphic form, although with a modified growth mechanism.

Cocrystal screening of anticancer drug p-toluenesulfonamide and preparation by supercritical antisolvent process

p-Toluenesulfonamide (PTS) is a new anticancer drug in development. Its poor dissolution behavior complicates the design and development of the formulation process. The present study aimed to improve the dissolution profile of PTS by using a cocrystal engineering approach. Cocrystal screening of PTS with commonly used coformers was investigated, including 4,4′-bipyridine, nicotinamide, isonicotinamide, and sulfacetamide. According to the results of PXRD, FTIR, DSC, and elemental analyzer, a cocrystal of PTS with coformer 4,4′-bipyridine in a stoichiometric ratio of 2:1 was first disclosed. The single crystal of this cocrystal was then prepared, and the crystallographic data were identified and reported. In addition, an intensified crystallization technique, the supercritical antisolvent (SAS) process, was applied to produce this cocrystal using CO2 as the antisolvent. The effect of SAS process parameters was studied, including the operating temperature, operating pressure, solution flow rate, and nozzle diameter. Optimized SAS conditions were proposed for cocrystal preparation, yielding a total powder recovery of approximately 70% and a purity level of up to 90%. Furthermore, according to the results of the dissolution rate study, the dissolution rate of SAS-produced cocrystal was enhanced considerably about 375 times compared to the physical mixture.

Synthesis of highly stable encapsulated astaxanthin/β-cyclodextrin microparticles using supercritical CO2 as an antisolvent

Although astaxanthin has promising physiological functions, its practical applications are limited by poor stability. Herein, astaxanthin was encapsulated in β-cyclodextrin (βCD) using CO2 as a supercritical antisolvent (SAS). The effects of process conditions, including temperature (313–333 K), pressure (12–18 MPa), solution concentration (3–5 wt%), solution flow rate (0.8–1.2 mL min−1), and astaxanthin-to-βCD mole ratio (1:50, 1:25, or 1:10), on the encapsulation efficiency, particle morphology, and residual solvent content were investigated. Astaxanthin–βCD complex spheres with an average diameter of 0.44 ± 0.08 µm were produced at 313 K and 15 MPa with a solution concentration and flow rate of 5 wt%, and 1.0 mL min−1, respectively. Under these optimal conditions, almost complete encapsulation (99.6% encapsulation efficiency) and residual organic solvent removal (0.22 ppm in the complex) were achieved. Density functional theory analysis of the configuration of the astaxanthin–βCD complex indicate that the hydroxyl hydrogen atoms on an ionone ring of astaxanthin interact with the oxygen atoms of βCD, but the ionone ring does not fit deeply within the βCD cavity. Notably, the astaxanthin–βCD complex exhibits higher thermal stability and antioxidant activity than free astaxanthin. The findings suggest that βCD encapsulation via the SAS process can produce astaxanthin microparticles with potential utility for food and pharmaceutical applications.

Photocatalytic Systems Based on ZnO Produced by Supercritical Antisolvent for Ceftriaxone Degradation

Emerging contaminants are a significant issue in the environment. Photocatalysis is proposed as a solution for the degradation of pollutants contained in wastewater. In this work, ZnO-based photocatalysts have been produced and tested for the photocatalytic degradation of an antibiotic; specifically, ceftriaxone has been used as a model contaminant. Moreover, there is particular interest in combining small-size ZnO particles and β-cyclodextrin (β-CD), creating a hybrid photocatalyst. Zinc acetate (ZnAc) (subsequently calcinated into ZnO) and β-CD particles with a mean diameter of 0.086 and 0.38 µm, respectively, were obtained using the supercritical antisolvent process (SAS). The produced photocatalysts include combinations of commercial and micronized particles of ZnO and β-CD and commercial and micronized ZnO. All the samples were characterized through UV–Vis diffuse reflectance spectroscopy (DRS), and the band gap values were calculated. Raman and FT-IR measurements confirmed the presence of ZnO and the existence of functional groups due to the β-cyclodextrin and ZnO combination in the hybrid photocatalysts. Wide-angle X-ray diffraction patterns proved that wurtzite is the main crystalline phase for all hybrid photocatalytic systems. In the photocatalytic degradation tests, it was observed that all the photocatalytic systems exhibited 100% removal efficiency within a few minutes. However, the commercial ZnO/micronized β-CD hybrid system is the photocatalyst that shows the best performance; in fact, when using this hybrid system, ceftriaxone was entirely degraded in 1 min.

Solubility of famotidine in supercritical carbon dioxide: Experimental measurement and thermodynamic modeling

In the current study, the solubility of famotidine (FAM) in supercritical carbon dioxide (scCO₂) was experimentally determined for the first time. The FAM solubility in scCO₂, expressed as mole fraction, at different temperatures (308 − 338 K) and pressures (12 − 30 MPa) was found to be in the range of 1.40 × 10−6 to 1.11 × 10−4. Due to the low solubility of FAM in scCO₂, the gas anti-solvent and supercritical anti-solvent processes can be a good option to generate the nano/micro size particles of this drug. The experimental solubility data were correlated by the density-based models of Bartle et al., Méndez-Santiago and Teja (MST), Jouyban et al. and Hozhabr et al., by the non-cubic equation of state PC-SAFT, and by the two versions of the Estévez et al. model (ECM-PR and ECM-RK). According to the modeling results, the Estévez et al. model showed the highest accuracy with AARD values of 9.92 (ECM-PR) and 10.70 (ECM-RK). The empirical models also yielded satisfactory outcomes to the correlation of the solubility of FAM in scCO₂.

Photocatalytic performance assessment of Fe-N co-doped TiO2/β-cyclodextrin hybrid systems prepared by supercritical antisolvent micronization for organic dyes removal

This work aims to demonstrate that micronized β-cyclodextrin (β-CD) improves the photocatalytic activity of Fe-N-TiO2. Fe-N-TiO2/β-CD hybrid systems were employed in the photocatalytic removal of Acid Orange7 (AO7) and Methylene Blue (MB). The supercritical antisolvent process (SAS) was used to micronize β-CD at different pressures. The chemical-physical properties of the hybrid photocatalysts were detected through various characterization methods. Wide angle X-ray diffraction patterns evidenced the anatase as the typical TiO2 crystalline phase. FT-IR spectra showed interactions between β-CD and Fe-N-TiO2. The activity of photocatalysts in the degradation of AO7 and MB dyes was analyzed under UV and visible light irradiation. Fe-N-TiO2/β-CD120 photocatalyst led to the total UV light-driven discoloration of the AO7 aqueous solution. Instead, the Fe-N-TiO2/β-CD120 system allowed for achieving an MB discoloration kinetic constant under visible light higher than the AO7 discoloration kinetic constant. Reuse cycle tests proved that the Fe-N-TiO2/β-CD120 sample is a stable photocatalytic material.

Non-Isothermal Compressible Flow Model for Analyzing the Effect of High CO<sub>2</sub> Inlet Flow Rate on Particle Size in a Supercritical Antisolvent Process

In this work with CFD simulations, the evaluation of the supercritical anti-solvent (SAS) process for producing nanoparticles from an expanded solution of ethanol/solute in carbon dioxide is reported. The influence of the solution and antisolvent flow rates on mean particle size, the flow dynamic, and the supercritical mixture's jet velocity must be well established in the literature and analyzed. The high flow rate of the anti-solvent resulted in increased mean particle sizes for all studied cases. At the lowest flow rate of CO<sub>2</sub> examined, an increase in the solvent flow rate [0.3-1.0] ml/min initially led to a decrease of 11.2% in the mean particle diameter (MPD); however, further increasing the solvent flow rate [1.0-2.0]ml/min was an increase of 33% in this parameter. At the highest CO<sub>2</sub> flow rate, the behavior of MPS was the opposite; it had a rise de 13.5% in MPD with an increase in solvent flow rate; further increasing the flow rate of the solvent, there was a drop of 8.6% in MPD. Significant variations in the temperature lead to large fluctuations in the particle diameters. At last, the contact zones between CO<sub>2</sub> and ethanol were delimited, favoring the understanding of the influence of the flow patterns generated by the variation of the flow rates in the mean particle diameters.

Novel crystal morphology for sodium bicarbonate obtained by using the supercritical anti-solvent process

Novel crystal morphology for sodium bicarbonate obtained by using the supercritical anti-solvent process

Generation of high-porosity cerium oxide nanoparticles and their functionalization with caryophyllene oxide using supercritical carbon dioxide

Oral diseases affect to millions people worldwide. Metallic nanoparticles are used as novel treatment due to its antimicrobial, antifungal, anti-inflammatory properties. Supercritical anti-solvent process and supercritical solvent impregnation process have been used to create cerium oxide nanoparticles and impregnate them with caryophyllene oxide, an antifungical and anti-microbial compound. High porosity nanoparticles, between 70 and 450 times higher than the raw cerium material were precipitated and impregnated successfully. The antimicrobial activity of impregnated nanoparticles investigated in vitro showed promising results against Staphylococcus aureus.

Preparation of inhalable quercetin-β-cyclodextrin inclusion complexes using the supercritical antisolvent process for the prevention of smoke inhalation-induced acute lung injury

Quercetin (Que) is a natural flavonoid with good anti-inflammatory and anti-apoptosis activities, but its poor water solubility and low bioavailability restrict its clinical application. Cyclodextrin inclusion is one effective method to improve the solubility of Que. In this study, Que-β-cyclodextrin inclusion complexes (Que-β-CD) were prepared using the supercritical antisolvent (SAS) process with supercritical carbon dioxide (SCCO2) and the grinding method, called S-Que-β-CD and G-Que-β-CD, respectively. Que-β-CD was identified with Fourier transform infrared spectroscopy and the X-ray diffraction method. S-Que-β-CD powders had a higher loading efficiency (19.81%) and drug release (71.76%), the smaller mass median aerodynamic diameter (2.83 µm), and the larger fine particle fraction (48.74%) than G-Que-β-CD powders, indicating the SAS process suitable for the preparation of Que-β-CD and S-Que-β-CD suitable for pulmonary inhalation. Pulmonary delivery of S-Que-β-CD showed good protection of the mouse lung from smoke inhalation-induced acute lung injury (SI-ALI), which was indicated by reduced pulmonary edema, high percutaneous oxygen saturation, weak inflammation and apoptosis, and the recovery of body weight. The SAS process is the optimal preparation method to obtain inhalable S-Que-β-CD powders with accelerated drug release, high lung deposition and enhanced therapeutic efficiency.

Solubility of probenecid in supercritical carbon dioxide and composite particles prepared using supercritical antisolvent process

The solubilities of probenecid in supercritical carbon dioxide (CO2) were measured in terms of mole fraction ranging from 0.13 × 10−5 to 1.45 × 10−5 at temperatures from 313.2 K to 353.2 K and pressures from 15 MPa to 31 MPa. The solubility data were correlated with the dimensionally consistent Chrastil equation, Garlapati and Madras equation, Mendez-Santiago and Teja equation, Kumar and Johnston equation, and the Peng-Robinson equation of state to deviations of 12.3 %, 6.7 %, 9.7 %, 8.1 %, and 16.2 %, respectively. Due to the low solubility nature, supercritical antisolvent (SAS) process was used for designing composite particles of probenecid and poly(lactide-co-glycolide) (PLGA). The effects of operating parameters on particle morphology, recovery and drug loading were studied. Through SAS, PLGA coated probenecid particles were successfully obtained. The recovery could be higher than 80 %, and the probenecid concentration could be up to 75 mg/mL. Moreover, results of dissolution studies reveal the PLGA coated composite particles can accelerate the dissolution rate by about 10 and 2.4 times, comparing with the unprocessed probenecid and SAS-processed probenecid without PLGA.

Particle preparation of pharmaceutical compounds using supercritical antisolvent process: current status and future perspectives.

The low aqueous solubility and subsequently slow dissolution rate, as well as the poor bioavailability of several active pharmaceutical ingredients (APIs), are major challenges in the pharmaceutical industry. In this review, the particle engineering approaches using supercritical carbon dioxide (SC CO2) as an antisolvent are critically reviewed. The different SC CO2-based antisolvent processes, such as the gas antisolvent process (GAS), supercritical antisolvent process (SAS), and a solution-enhanced dispersion system (SEDS), are described. The effect of process parameters such as temperature, pressure, solute concentration, nozzle diameter, SC CO2 flow rate, solvent type, and solution flow rate on the average particle size, particle size distribution, and particle morphology is discussed from the fundamental perspective of the SAS process. The applications of the SAS process in different formulation approaches such as solid dispersion, polymorphs, cocrystallization, inclusion complexation, and encapsulation to enhance the dissolution rate, solubility, and bioavailability are critically reviewed. This review highlights some areas where the SAS process has not been adequately explored yet. This review will be helpful to researchers working in this area or planning to explore SAS process to particle engineering approaches to tackle the challenge of low solubility and subsequently slow dissolution rate and poor bioavailability.

Vapor–Liquid Equilibria of Quaternary Systems of Interest for the Supercritical Antisolvent Process

In the Supercritical Antisolvent process (SAS), the thermodynamic behavior of complex multicomponent systems can influence the particles’ morphology. However, due to the limited thermodynamic data for multicomponent systems, the effect of solutes is often neglected, and the system is considered as pseudo-binary. It has been demonstrated that the presence of a solute can significantly influence the thermodynamic behavior of the system. In particular, when the SAS process is adopted for the production of drug/polymer coprecipitated microparticles, the effect of both the drug and the polymer in the solvent/CO2 mixture should be considered. In this work, the effect of polyvinylpyrrolidone (PVP), used as the carrier, and of the liposoluble vitamins menadione (MEN) and α-tocopherol (TOC), as model drugs, was investigated as a deviation from the fundamental thermodynamic behavior of the DMSO/CO2 binary system. Vapor–liquid equilibria (VLE) were evaluated at 313 K, with a PVP concentration in the organic solution equal to 20 mg/mL. The effect of the presence of PVP, MEN, and TOC on DMSO/CO2 VLE at 313 K was studied; furthermore, the effect of PVP/MEN and PVP/TOC, at a polymer/drug ratio of 5/1 and 3/1, was determined. Moreover, SAS precipitation experiments were performed at the same polymer/drug ratios using a pressure of 90 bar. Thermodynamic studies revealed significant changes in phase behavior for DMSO/CO2/PVP/TOC and DMSO/CO2/PVP/MEN systems compared to the binary DMSO/CO2 system. From the analysis of the effect of the presence of a single compound on the binary system VLE, it was noted that PVP slightly affected the thermodynamic behavior of the system. In contrast, these effects were more evident for the DMSO/CO2/TOC and DMSO/CO2/MEN systems. SAS precipitation experiments produced PVP/MEN and PVP/TOC microparticles, and the obtained morphology was justified considering the quaternary systems VLE.

Fabrication of betamethasone micro- and nanoparticles using supercritical antisolvent technology: In vitro drug release study and Caco-2 cell cytotoxicity evaluation

Poor solubility limits the pharmacological activities of betamethasone (BM), including its anti-inflammatory and anti-allergic effects. To improve the aqueous solubility and dissolution rate of BM, supercritical antisolvent (SAS) technology was used to prepare BM microparticles and BM–polyvinylpyrrolidone (PVP) solid dispersion nanoparticles. The effects of temperature, pressure, solution feeding rate, and drug concentration on particle formation were investigated using both single-factor and orthogonal experimental methods, and the optimal preparation process was screened. The physicochemical properties of the BM particles were characterized by scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffraction. After the SAS process, the particle size was reduced significantly and the crystalline shape was altered, which considerably increased the solubility and dissolution rate of BM. Furthermore, the toxicity of BM to live cells was reduced because of the BM–PVP solid dispersions.

Development of highly stable ICG-polymeric nanoparticles with ultra-high entrapment efficiency using supercritical antisolvent (SAS)-combined solution casting process

Indocyanine green (ICG), a water-soluble near-infrared (NIR) photosensitizer, has been enormously regarded in tumor diagnosis and phototherapy. Although tremendous progress in establishing the nanocarrier-based delivery systems has been explored, several limitations of low ICG encapsulation and sophisticated fabrication process remain significant challenges in producing nanoplatforms, limiting the theranostic outcomes of ICG. According to the unique advantages of the supercritical antisolvent (SAS) process and solution casting method, a novel combination approach to obtain the ICG-loaded nanoparticles (ICG-PLO NPs) is demonstrated, in which SAS assisted-ICG nanoparticles (ICG NPs) are coated with polypeptide poly-l-ornithine (PLO) using solution casting approach. This unique nanoplatform with ultra-high drug encapsulation efficiency remarkably improved the aqueous and photothermal stability of ICG. Notably, the coating of PLO could improve the internalization level in cells and anticancer effect in vivo, comprehensively augmenting the cancer phototherapy effect of ICG. Together, the findings of novel particle formation by integrated strategy would certainly broaden the applications of supercritical fluid (SCF) technology, potentiating the design of nano-formulations of ICG for clinical translation.

Particle crystallization by supercritical antisolvent processing techniques: the case of Retama raetam powder for pharmaceutical purposes

Abstract In this work, the Supercritical AntiSolvent process has been used to generate micronized crystals of Retama raetam. The process was performed using ethanol and CO2 as solvent and antisolvent, respectively. Recrystallization was made at various temperatures (30–50 °C) and pressures (8–12 MPa) using a constant flow rate of supercritical CO2 (2 kg/h). We have been also varied the solution flow rate and its volume to identify conditions leading to spheroidal powder morphology. Size and morphology have been characterized by scanning electron microscopy and ImageJ software. The spraying of the supercritical solution directing the flow towards the precipitator results in the deposition of fine particles with uniform morphology at the bottom, and of a porous film adhering to the precipitator wall. For that reason, thermodynamic and hydrodynamic aspects are discussed so as to rationalize the powder and spongious film characteristics and provide a new way to control the SAS process applied to plant derivatives.