Supercritical Antisolvent Research Articles

Formation of Rutin-β-Cyclodextrin Inclusion Complexes by Supercritical Antisolvent Precipitation.

In this work, rutin (RUT)–β-cyclodextrin (β-CD) inclusion complexes are prepared by Supercritical AntiSolvent (SAS) precipitation. Well-defined composite microparticles are obtained at guest:host ratios equal to 1:2 and 1:1 mol:mol. The dimensions of composite particles range between 1.45 ± 0.88 µm and 7.94 ± 2.12 µm. The formation of RUT–β-CD inclusion complexes has been proved by different analyses, including Fourier transform infrared spectroscopy, Differential Scanning Calorimetry, X-ray diffraction, and UV-vis spectroscopy. The dissolution tests reveal a significant improvement in the release rate of RUT from inclusion complexes. Indeed, compared to the unprocessed RUT, the dissolution rate is about 3.9 and 2.4 times faster in the case of the complexes RUT–β-CD 1:2 and 1:1 mol:mol, respectively. From a pharmaceutical/nutraceutical point of view, CD-based inclusion complexes allow the reduction of the polymer amount in the SAS composite formulations.

Micronization of Curcuma xanthorrhiza Extract with Addition of PVP Using Supercritical CO2 as Anti-solvent

Curcuma xanthorrhiza Roxb, known as Temulawak or Javanese ginger, is a plant species. Its rhizomes are used as a medicinal herb. It contains curcumin as an active compound and ethereal oils mainly consisted of sesquiterpenes. In this work, Curcuma xanthorrhiza Roxb ethanolic extract was micronized with an addition of PVP using supercritical antisolvent (SAS) method. The ethanolic extract was obtained from dried Curcuma xanthorrhiza Roxb using soxhletation. For the micronization, the extracted compound solvent was a mixture of acetone and ethanol (90:10 (v/v)), while the supercritical CO2 was used as an antisolvent. The effect of operating conditions on the particle size and morphology was evaluated. Through this method, spherical Curcuma xanthorrhiza/PVP particles with mean diameter ranging from 191 ± 70 nm to 178 ± 57 nm were successfully formed. The particle size not significantly decreased as the pressure increased from 8 12 MPa. The addition of PVP is very effective to reduce the particle size, increase the solubility, and enhance the bioavailability of Curcuma xanthorrhiza extract. This work has the potential to improve the use of Curcuma xanthorrhiza in pharmaceutical and nutraceutical applications.

Production of curcumin/β-cyclodextrin inclusion complexes by supercritical antisolvent process

In this work, β-cyclodextrin (β-CD) based inclusion complexes containing curcumin (CURC), a yellow pigment from Curcuma longa plants, were obtained through the Supercritical AntiSolvent (SAS) process. Curcumin has been widely used for its antioxidant, antimicrobial, antibiotic and antiviral properties. Recently, curcumin has been proposed as a potential treatment option for patients with coronavirus disease (CoVID-19). In order to protect the active compound, the supercritical antisolvent process was used, to induce the formation of inclusion complexes using β-CD as the carrier. The effect of different parameters, such as pressure, overall concentration of solutes in the liquid solution, and CURC/β-CD molar ratio, on the morphology and size of the composite particles, was investigated. Well-defined microparticles at 1/1 and 1/2 CURC/β-CD molar ratios were produced. The dissolution rate curve of the obtained inclusion complexes was compared to the one of the unprocessed CURC. Copyright © 2021, AIDIC Servizi S.r.l.

Complete drying and micronization of ecamsule using supercritical CO2 as the antisolvent

The supercritical antisolvent (SAS) process has been used to produce micronized organic powders with excellent properties. In this study, the SAS process was used to produce fine ecamsule powder (1.8–2.8 µm) using supercritical carbon dioxide (scCO2) as the antisolvent. The effects of different process parameters, such as temperature (303–333 K), pressure (10–20 MPa), ecamsule solution flow rate (0.5–2.0 mL min–1), and solute (ecamsule) feed concentration (2.5–10 wt%), on the process yield, particle size and size distribution, and properties of ecamsule were evaluated. To elucidate the ecamsule precipitation mechanism during the SAS process, the Hansen solubility parameters (HSPs) and relative energy differences were used to analyze the solubility of ecamsule in scCO2–ethanol mixtures under the studied conditions. We obtained a yield of micron-sized (1.8 ± 0.8 µm) ecamsule particles of approximately 91% at 323 K, 14 MPa, and a solution flow rate of 1 mL min−1 for an ecamsule feed concentration of 5 wt%. In addition, the ethanol content of the obtained ecamsule microparticles was lower than the detectable limit (<12.5 mg L–1) and they possessed low crystalline structure with improved chemical properties compared with those of their oven-dried counterparts.

Size-Controlled Synthesis of CuO Nanoparticles by the Supercritical Antisolvent Method in SBA-15

Herein, we describe a facile method to control the size and dispersion of CuO nanoparticles (NPs) in SBA-15 by the supercritical antisolvent (SAS) method during the depressurization process of supercritical fluid deposition (SCFD), describing the mass transfer between supercritical carbon dioxide (scCO2) and a cosolvent. On reducing the concentration of the cupric nitrate precursor, the size of CuO NPs was decreased from 3.5 ± 1.0 to 1.0 ± 0.4 nm (Cu loading 14.2–12.1 wt %) under the depressurized rate of ∼20 MPa/min. Based on the size distribution and nucleation theory, the nucleation rate of the precursor could reach 1025 cm–3·s–1, and the calculated interface energy of cupric nitrate was less than 0.1 J/m2, indicating that scCO2 as an antisolvent caused the heterogeneous nucleation of the precursor on the surface of SBA-15 channels. Hence, the nucleation rate and growth of cupric nitrate were regulated under a given scCO2 depressurized rate, and then the CuO NPs’ size distribution and Cu loading were controlled subsequent to calcination.

Preparation of non-steroidal anti-inflammatory drug/β-cyclodextrin inclusion complexes by supercritical antisolvent process

In this work, β-cyclodextrin (β-CD) was used as a carrier to produce inclusion complexes containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), namely nimesulide (NIM) and ketoprofen (KET), by Supercritical AntiSolvent (SAS) process. The effect of different parameters, such as pressure, overall concentration of solutes in the liquid solution, and NSAID/β-CD molar ratio, on the morphology and size of the composite particles, was investigated. Well-defined microparticles at different NSAID/β-CD molar ratios were produced, managing to increase this ratio up to 2/1 mol/mol. The formation of NIM/β-CD and KET/β-CD inclusion complexes was demonstrated through different analytic techniques, such as Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The attainment of inclusion complexes induced the enhancement of the NSAID dissolution rate up to about 21 and 7 times in the case of SAS NSAID/β-CD 2/1 mol/mol if compared to unprocessed NIM and KET, respectively. SAS process was proved to be effective in the preparation of inclusion complexes by using β-CD for an accelerated drug release.

Formulation of açaí (E. oleracea Mart.) Pulp and seeds extracts by co-precipitation in Supercritical Antisolvent (SAS) technology

Açaí (Euterpe oleracea Mart.) is a black-purple berry, typically found in Amazon Rainforest, and a natural phytochemical source, which shows a high content of polyphenols and flavonoids, with remarkable properties as an antioxidant, anti-inflammatory, antimicrobial, and natural dye. The precipitation and encapsulation of Açaí extracts with biopolymers by Supercritical Anti-Solvent (SAS) process were investigated and proposed as primary formulation to protect the active compounds from early degradation and its application in pharmaceutical, cosmetic, and alimentary products. The extractives were obtained from pulp and seeds by Pressurized Microwave assisted Energy (PMAE)(300 W,1.5 bar) using acidified ethanol/water (1:1v/v) as a solvent. The extracts were characterized in terms of total polyphenols content (TPC). The SAS process was carried out by semi-continuous batch at constant conditions (40 °C,100 bar). Particle morphology was studied by SEM, TGA and FTIR. The best results were obtained when ethanol and PVP were applied, obtaining a particle size reduction and an increment of TPC.

Production of elastin-like recombinamer-based nanoparticles for docetaxel encapsulation and use as smart drug-delivery systems using a supercritical anti-solvent process

This study presents a new groundbreaking methodology for integrating innovative concepts to develop novel drug-delivery strategies. This methodology combines genetically engineered elastin-like recombinamers (ELRs) with supercritical fluid (SCF) techniques to encapsulate a poorly water-soluble drug in a one-step process. The chemotherapeutic agent docetaxel (DTX) is encapsulated with a block copolymer ELR containing the RGD peptide, a specific target sequence for cancer cells, using the supercritical anti-solvent (SAS) technique in a high process yield of up to 70%. SEM studies show spherical microparticles of 10μm after encapsulation. After dispersion under physiological conditions, microparticles disaggregate into stable monodisperse nanoparticles of 40nm size and −30mV ζ-potential. This protects the drug, as confirmed by NMR analysis, thereby increasing the water solubility of DTX up to fifty orders of magnitude. The delivery process is governed by the Fick diffusion mechanism and indicates that the presence of DTX on the particles surface is practically negligible. Cellular assays showed that, due to the presence of the cancer target sequence RGD, breast cancer cells were more affected than human endothelial cells, thus meaning that the strategy developed in this work opens the way to new controlled release systems more precise than non-selective chemotherapeutic drugs.

Advanced green approaches for the synthesis of NiCu-containing catalysts for the hydrodeoxygenation of anisole

NiCu-containing catalysts stabilized by SiO2 with a different metals ratio are prepared via the «green» supercritical antisolvent (SAS) precipitation method. Obtained catalysts are characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and CO adsorption. The addition of water and a silica sol into precursor solution allows us to obtain highly loaded (70 wt. % of metals) dispersed metal catalysts with a Ni1-xCux solid solution structure without phase separation into individual metals. These heterogeneous catalysts are used for hydrodeoxygenation of anisole – a model compound of pyrolysis liquid. The main product of the hydrodeoxygenation process over prepared catalysts was cyclohexane.

Optimization of the supercritical fluidized bed process for sirolimus coating and drug release.

Directly coating an active pharmaceutical ingredient (API) onto excipient granules has been a common approach to prepare solid dosage forms. The combination of supercritical anti-solvent (SAS) and fluidized bed (FB) coating technology (SAS-FB) has the advantages of preventing nanoparticles aggregation, oxidation and light exposure. However individual operating parameters and factors which contribute to the overall coating efficiency remain to be defined. Sirolimus is an immunosuppressive agent for preventing the rejection of organ transplants and this drug is sensitive to light exposure and high temperature. Our study used sirolimus as the model API to evaluate parameters including temperature, pressure, drug concentration, mass, material and diameter of carrier, CO2 flow rate and solvent in the SAS-FB process. By optimizing these parameters, we achieved a 3.5-fold enhancement of the coating efficiency over the standard condition. A series of characterizations of the sirolimus coated particles were performed from which scanning electron microscopy and Raman mapping confirmed that the sirolimus particles were uniformly coated on carriers as cuboid particles; X-ray powder diffraction showed that processed sirolimus is crystalline but has lower crystallinity than the API, and fourier transform infrared spectroscopy and differential scanning calorimeter confirmed that there is no chemical interaction between sirolimus and carriers after SAS-FB processing. Finally compared to sirolimus alone, sirolimus coated particles displayed a faster dissolution and higher bioavailability. Collectively, our optimized operation parameters for SAS-FB coating technique provide a useful guidance for achieving higher efficiency of drug coating and faster release rate of sirolimus pellets, which has the potential to apply to other APIs.

Prediction of Crystal–Solvent Interactions in a Supercritical Medium: A Possible Way to Control Crystal Habit at High Supersaturations with Molecular Modeling

The purpose of this work is to contribute to a better control of the crystallization process which occurs in a supercritical medium, especially during the Supercritical AntiSolvent (SAS) process. I...

Effect of solvent selection and nozzle geometry on Curcuma mangga micronization process using supercritical antisolvent: Experiment and CFD simulation

In this study, ethanolic extracts of Curcuma mangga (C. mangga) were micronized using the supercritical antisolvent (SAS) method. Acetone, ethyl acetate, and dichloromethane were used as solvents to study the effects of solvent selection on the obtained particles. Supercritical carbon dioxide (CO2) was used as the antisolvent. The effects of nozzle geometry (cross nozzle and T-nozzle) on particle size and morphology were also evaluated. Microparticles and submicron particles were successfully produced with particle sizes ranging from 0.202 ± 0.05 μm to 1.653 ± 0.89 μm. Of the three solvents, ethyl acetate produced smaller particle sizes with a narrow particle size distribution. For all the types of solvents used, micronized particles prepared with the cross-nozzle had smaller average particle sizes than with the T-nozzle. The smallest particles of mean size 0.202 ± 0.05 μm were achieved at 16 MPa and 313 K using ethyl acetate as the solvent and a cross-nozzle. Computational fluid dynamics simulations were successfully performed on the internal flow to study the turbulent flow and volume fraction inside the nozzle. The results of this are expected to help improve the applications of the active ingredients of C. mangga rhizomes in the pharmaceutical industry.

Supercritical Antisolvent Process for Pharmaceutical Applications: A Review

The supercritical antisolvent (SAS) technique has been widely employed in the biomedical field, including drug delivery, to obtain drug particles or polymer-based systems of nanometric or micrometric size. The primary purpose of producing SAS particles is to improve the treatment of different pathologies and to better the patient’s compliance. In this context, many active compounds have been micronized to enhance their dissolution rate and bioavailability. Aiming for more effective treatments with reduced side effects caused by drug overdose, the SAS polymer/active principle coprecipitation has mainly been proposed to offer an adequate drug release for specific therapy. The demand for new formulations with reduced side effects on the patient’s health is still growing; in this context, the SAS technique is a promising tool to solve existing issues in the biomedical field. This updated review on the use of the SAS process for clinical applications provides useful information about the achievements, the most effective polymeric carriers, and parameters, as well as future perspectives.

Optimization of process parameters for preparation of polystyrene PM2.5 particles by supercritical antisolvent method using BBD-RSM

The objective of this study is to optimize the process parameters for preparing polystyrene (PS) PM2.5 particles by supercritical antisolvent (SAS) method. Toluene was selected as the solvent and supercritical carbon dioxide (SC-CO2) was used as the antisolvent. The Box–Behnken design-response surface method was applied to investigate the effect of crystallizer pressure, PS massic concentration, flow ratio of CO2/solution and crystallizer temperature on the size and the distribution of PS particles, systematically. It is found that crystallizer temperature is the most significant variable on the size and the distribution of PS particles, followed by flow ratio of CO2/solution and PS massic concentration, and crystallizer pressure is the slightest significant factor. The particle size increases with the increase of crystallizer temperature. The optimum conditions are obtained as crystallizer pressure 9.8 MPa, PS massic concentration 1.6 wt%, flow ratio of CO2/solution 140 g/g and crystallizer temperature 309 K. Under these conditions, the PS particle with the size of 2.78 μm and a narrow size distribution has been prepared, meeting PM2.5 standard aerosols. The results suggest that it is feasible to produce PM2.5 standard aerosols by SAS.

Development of nimesulide amorphous solid dispersions via supercritical anti-solvent process for dissolution enhancement

Formulating amorphous solid dispersions (ASDs) is one of the most promising strategies to overcome solubility limitations in drug development. In this work, development of nimesulide (NIM) ASDs via supercritical anti-solvent (SAS) process was proposed, where the mixtures of dichloromethane (DCM) and methanol (MeOH) were selected as the liquid solvent, and the mixtures of hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were the dispersing materials. The effects of NIM/HPMC/PVP (w/w/w) ratio and DCM/MeOH (v/v) ratio on particle solid-state properties were investigated to identify successful operating conditions. NIM-ASDs powders were formed by well separated spherical microparticles, where NIM crystals had transformed into amorphous state completely; the production yield was 93.6 ± 1.14%; and the reproducibility was very high. For NIM-ASDs, intermolecular interactions between NIM and dispersing materials were formed; the residual solvent was far below the ICH limit; and the chemical structure of NIM did not be degraded or disrupted. Moreover, NIM-ASDs increased the NIM solubility in PBS (pH=6.8) more than 5-folds; the dissolution of NIM from NIM-ASDs granules was faster and more complete than that from commercial Aulin® granules in PBS (pH=6.8). Also, NIM-ASDs well hindered the aging in the recrystallization of amorphous NIM during 12-month sealed storage. Overall, development of NIM-ASDs via SAS process presents an opportunity that as a modified product to increase the efficacy of NIM.

Directed Synthesis of Ultradisperse Individual and Bimetallic Zirconium and Hafnium Oxides by Supercritical Antisolvent Precipitation

A method for the synthesis of mono- and bimetallic zirconium and/or hafnium oxides by supercritical antisolvent precipitation has been developed. The oxides have been obtained using a laboratory dispersing system, alkoxides (zirconium propoxide, hafnium butoxide) and zirconium acetylacetonate have been used as precursors. A white powder of amorphous phase with composition MO2 · mH2O · nCxHyOz (M = Zr, Hf) has been obtained in all experiments. Differential thermal and X-ray powder diffraction analysis have been used to study the obtained phases and their thermolysis products (mono- and bimetallic zirconium and/or hafnium dioxides). Particle size and their morphology have been studied by optical and electron microscopy and dynamic light scattering. It has been shown that the particles of prepared oxides have spherical shape, while their size is dependent on the molar ratio of initial solution components. According to electron microscopy data, annealed samples have smaller particle size as compared with the initial samples.

Supercritical fluid technology for solubilization of poorly water soluble drugs via micro- and naonosized particle generation.

Approximately two-third of the compounds in the pharmaceutical industry were developed through combinatorial chemistry and high throughput screening of particulate solids. Poor solubility and bioavailability of these pharmaceuticals are challenging attributes confronted by a formulator during product development. Hence, substantial efforts have been directed into the research on particle generation techniques. Although the conventional methods, such as crushing or milling and crystallization or precipitation, are still used; supercritical fluid technology introduced in the mid-1980s presents a new method of particle generation. Supercritical fluid processes not only produce micro- and nanoparticles with a narrow size distribution, they are also employed for the microencapsulation, cocrystallization, and surface coating with polymer. Recognized as a green technology, it has emerged as successful variants chiefly as Rapid Expansion of supercritical solutions (RESS), Supercritical anti-solvent (SAS) and Particles from Gas Saturated Solution (PGSS) depending upon type of solvent, solute, antisolvent and nebulization techniques. Being economical and eco-friendly, supercritical fluid technolgy has garnered considerable interest both in academia and industry for modification of physicochemical properties such as particle size, shape, density and ultimately solubility. The current manuscript is a comprehensive update on different supercritical fluid processes used for particle generation with the purpose of solubility enhancement of drugs and hence bioavailability.

Particle design of itraconazole by supercritical anti-solvent technology: Processing-microstructure-solubility relationship

Particle design in recent years has attempted to overcome solubility limitations in drug development. In this work, the particle microstructures of itraconazole (ITZ) were designed by a supercritical anti-solvent (SAS) process, with or without hydroxypropyl methylcellulose (HPMC) as the dispersing material, where the processing-microstructure-solubility relationship was investigated. The results showed that ITZ particles with different shapes and crystal forms were obtained, which enhanced the ITZ solubility from 4.4 μg/mL to 108.5 μg/mL. For the optimal sample, ITZ crystal transformed into amorphous state, resulting in high solubility and fast dissolution rate. Moreover, hydrogen bond interaction was formed between HPMC and ITZ, which could hinder the recrystallization of dissolved ITZ, resulting in its complete dissolution. Also, the production efficiency was increased to 38.5 mg ITZ/min, which laid a foundation for the scale-up. These results show the great potential of SAS process on the particle design of poorly soluble drugs for solubility enhancement.

Photocatalytic Degradation of Eriochrome Black-T Azo Dye Using Eu-Doped ZnO Prepared by Supercritical Antisolvent Precipitation Route: A Preliminary Investigation

Photocatalytic Degradation of Eriochrome Black-T Azo Dye Using Eu-Doped ZnO Prepared by Supercritical Antisolvent Precipitation Route: A Preliminary Investigation

Process intensification for the synthesis of ultra-small organic nanoparticles with supercritical CO2 in a microfluidic system

Submicronization of organic compounds is a challenging requirement for applications in the imaging and pharmaceutical fields. A new Supercritical AntiSolvent process with microreactor (µSAS) was developed for nanoparticle (NP) synthesis. Tetrahydrofuran (THF) was used to solubilize a model organic molecule, tetraphenylethylene, and supercritical carbon dioxide (sc-CO2) was used as antisolvent. The solubility of TPE in the THF/CO2 system was first measured by in situ experiments. Then, NPs of TPE were prepared in various experimental conditions and characterized by transmission electron microscopy (TEM). Chosen experimental conditions led to NPs with a mean size of 9 ± 3 nm. Experimental µSAS results were compared with size distributions obtained by simulation, to obtain surface tension values, which are difficult to access by experiment alone. Simulations coupling Computational Fluid Dynamics (CFD) and Population Balance Equation (PBE) were performed under turbulent conditions in the high pressure microreactors. This coupled experimental and theoretical approach allowed a deep understanding of the µSAS process and underlined the superior value of this technique for the preparation of NPs.