Supercritical Antisolvent Process Process Research Articles

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.

Co-precipitation of fluorescein with extracts of mango leaves by supercritical antisolvent process

Fluorescein was coprecipitated together antioxidant compounds from mango leaves by the supercritical antisolvent process (SAE). The ethanol extract rich in antioxidant compounds was previously obtained by enhanced extraction. The influence of temperature (35–55 °C), pressure (150–200 bar) and CO2 flow rate (10–30 g/min) on the SAE process were investigated. The decrease in pressure contributed to a decrease in particle size, while an increase in temperature and the flow rate of CO2 contributed, in general, to the production of smaller particles diameter. SEM images revealed the formation of coprecipitates composed by a mixture of spherical (extract of mango leaves) and irregular (fluorescein) particles confirming the presence of both precipitates. The analysis with DPPH showed that the SAE technique is valid to obtain particles of high antioxidant activity even though the fluorescein is present in the process. By using the fluorimeter assay it was demonstrated that the coprecipitates could be detected by UV-Vis due to the presence of fluorescein.

PVP/flavonoid coprecipitation by supercritical antisolvent process

To date, various delivery systems have been developed to improve chemical stability and increase the bioavailability of polyphenolic compounds. In the present study, the micronization of two flavonoids, quercetin and rutin, and their coprecipitation with polyvinylpyrrolidone (PVP) were studied using the supercritical antisolvent process (SAS). SAS process parameters were optimized with the aim of obtaining composite microspheres with controlled mean size and particle size distribution. Spherical microparticles (with mean diameters in the range between 0.47 and 9.52 μm for PVP/quercetin and in the range 0.84–8.17 μm for PVP/rutin) were precipitated, depending on the operating conditions. In correspondence of the best operating conditions, the entrapment efficiency in PVP, for both flavonoids, was 99.8% and the dissolution rate from the coprecipitated powders was 10 and 3.19 times faster compared to the dissolution rates of unprocessed flavonoids for quercetin and rutin, respectively.

Coprecipitation of curcumin/PVP with enhanced dissolution properties by the supercritical antisolvent process

The poor solubility of curcumin (CURC) in aqueous media leads to a low bioavailability, which prevents its application in pharmaceutical formulations. In this work, the Supercritical Antisolvent process (SAS) was used to produce coprecipitates of CURC and poly (vinyl pyrrolidone) (PVP) from mixtures of ethanol and acetone. The effects of operating parameters: pressure, temperature, solution concentration, drug/polymer mass ratio and solution flow rate were analysed for a 70–30 (v/v) acetone-ethanol mixture. It was found that the composition of acetone in the solvent mixture is the parameter that affects particle size and curcumin recovery the most. The thermal behaviour, crystallinity, molecular interactions, apparent solubility, release profile of the coprecipitates and possible degradation of curcumin were investigated. The results showed that the SAS process is effective in preparing amorphous formulations of CURC/PVP with an apparent solubility of more than 600 times higher than that of the physical mixture of the raw compounds.

Co-precipitation of anthocyanins of the extract obtained from blackberry residues by pressurized antisolvent process

An ethanolic anthocyanin-rich extract was obtained from blackberry residues through ultrasound assisted extraction, and extracts were co-precipitated with the biodegradable polymer polyvinylpyrrolidone (PVP) through the supercritical antisolvent process (SAS), using carbon dioxide as antisolvent. The influence of temperature (30–45 °C), PVP concentration in the extract (0.5–4.0%) and solution flow rate (1–10 mL/min) on the SAS process were investigated. The decrease of these three parameters contributed to produce particles with smaller diameter, residual ethanol, humidity and water activity, although with higher hygroscopicity. Moreover, the increase of these parameters intensified the agglomeration of the particles. SEM images revealed co-precipitates with irregular shapes obtained at high temperatures, flow rates and PVP concentrations. FTIR analysis showed that neither extract nor PVP properties were modified in the SAS process. Good precipitation yields were achieved, indicating that the SAS process is effective and selective in the co-precipitation of anthocyanins.

Precipitation of submicron particles of rutin using supercritical antisolvent process

Spherical submicron particles of rutin were prepared by a supercritical antisolvent process (SAS). Selection of the appropriate solvent determined the success of the precipitation process. A mixture of acetone and DMSO in a 9:1 ratio was selected in order to study the main parameters that influence the SAS process in terms of particle size, size distribution and particle morphology. Smaller particles were produced at higher temperature and pressure, and with a lower initial concentration of the solution. A lower liquid solution flow rate is recommended to obtain submicron particles but the CO2 flow rate and nozzle diameter had a negligible effect on particle size, at least at the levels evaluated. The precipitated powders were analysed by Scanning Electron Microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-Ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC). The SAS process contributed to the dehydration of rutin, thus conferring higher added value. Moreover, amorphization of the processed samples was produced during the process. Processed rutin particles dissolved more rapidly than commercial rutin in simulated fluids and this is related to the particle size reduction and the loss of crystallinity due to amorphization. This effect was more pronounced in simulated intestinal fluids than in gastric fluids.

Screening design of experiment applied to the supercritical antisolvent precipitation of quercetin

A fractional factorial design of experiment at two levels has been applied to the micro- and nanoprecipitation of quercetin by a supercritical antisolvent process (SAS) in order to identify the factors that are important and their appropriate ranges with the mean particle size used as a response. The model was successfully fitted by multiple linear regressions. In general, higher pressures and temperatures, a lower initial concentration of the solution, and high CO2/liquid solution flow rate ratios favored the precipitation of smaller particles. The use of a smaller nozzle diameter led to smaller particle sizes in the assayed range but washing time had a negligible effect. The morphologies of the precipitates were analyzed by scanning electron microscopy (SEM). X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were employed to evaluate the possible loss of crystallinity and activity of the precipitates. Dynamic light scattering (DLS) and image analysis software were used to measure the particle size and particle size distribution. The particle size range of the precipitates was 0.15–1.24μm and the formation of nanoparticles or microparticles was dependent on the operating conditions of the SAS process. The dynamic light scattering measurements gave higher than expected particle sizes due to possible agglomeration.

Selection of Solvent in Supercritical Antisolvent Process

Supercritical antisolvent process (SAS) is widely being used to micronize the pharmaceutical compounds. The advantage of SAS process is that thermal degradation does not occur in the pharmaceutical compounds as the operating temperature is near to room temperature. This process starts with the atomization of a solution, a mixture of pharmaceutical compound and solvent, in the supercritical carbon dioxide environment. The transfer of carbon dioxide (antisolvent) to the droplet decreases the solubility of solute in the solution causing precipitation of solute in micro to nano-particle size range. In this work, four solvents: dimethyl sulfoxide, ethanol, acetone and dichloromethane have been considered to study the effect of solvent on droplet diameter, solvent mass transfer rate into supercritical carbon dioxide environment and velocity profile. The atomized droplet moves downward and mass transfer takes place. Two film theory of mass transfer has been used to calculate the molar flow rate of solvent into supercritical environment and carbon dioxide into droplet. Due to this two way mass transfer, composition of the droplet and thus size is changing continuously. The size of the droplet is calculated assuming that the droplet remains spherical during its downward movement. The size depends on the total number of moles in the droplet and molar density. Peng-Robinson equation of state has been used to calculate the molar density. The velocity profile of droplet is calculated using force balance equation on a moving body in a medium. Result shows that dichloromethane is the best solvent as it has small initial droplet diameter and less residence time compare to other solvents.

Polymer encapsulation of amoxicillin microparticles by SAS process

Encapsulation of amoxicillin (AMC) with ethyl cellulose (EC) by a supercritical antisolvent process (SAS) was investigated. AMC microparticles obtained previously by an SAS process were used as host particles and EC, a biodegradable polymer used for the controlled release of drugs, was chosen as the coating material. In this work, a suspension of AMC microparticles in a solution of ethyl cellulose in dichloromethane (DCM) was sprayed through a nozzle into supercritical CO2. Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and HPLC analyses were carried out. The effects of AMC:EC ratio, the initial polymer concentration of the solution, temperature and pressure on the encapsulation process were investigated. Although all the experiments led to powder precipitation, the AMC encapsulation was achieved in only half of the cases, particularly when the lower drug:polymer ratios were assayed. In general, it was observed that the percentages of AMC present in the precipitates were higher on increasing the AMC:EC ratio. In these cases composites rather than encapsulates were obtained. The in vitro release profiles of the resulting materials were evaluated in order to ascertain whether composites can be used as encapsulated systems for drug delivery systems.

Drug recrystallization using supercritical anti-solvent (SAS) process with impinging jets: Effect of process parameters

The aim of this study is to improve mixing in supercritical anti-solvent process (SAS) with impinging jets in order to form finer particles of sulfathiazole, a poorly water-soluble drug. The influence of several process parameters upon the powder characteristics is studied. Parameters are jets' velocity (0.25ms−1 to 25.92ms−1), molar ratio solvent/CO2 (2.5% to 20%), temperature (313K to 343K), pressure (10MPa to 20MPa) and sulfathiazole concentration in the organic solution (0.5% to 1.8%). Two solvents are used: acetone and methanol. Smaller particles with a more homogeneous morphology are obtained from acetone solutions. For the smallest jets' velocity, corresponding to a non-atomized jet, the stable polymorphic form is obtained, pure or in mixture. At this velocity, pressure is the most influential parameter controlling the polymorphic nature of the powder formed. The pure stable polymorph is formed at 20MPa. Concerning the particle size, the most influential parameters are temperature and sulfathiazole concentration.The use of impinging jets with different process parameters allows the crystallization of four polymorphs among the five known, and particle sizes are varied. This work demonstrates the studied device ability of the polymorph and the size control. A comparison with the classical SAS process shows that particle size, size distribution and morphology of particles crystallized with impinging jets are different from the ones obtained with classical SAS introduction device in similar operating conditions. Mean particle sizes are significantly smaller and size distributions are narrower with impinging jets device.

Co-precipitation of amoxicillin and ethyl cellulose microparticles by supercritical antisolvent process

Microparticles of ethyl cellulose (EC) and amoxicillin (AMC) have been precipitated by a supercritical antisolvent process (SAS) using CO 2 as the antisolvent and a mixture of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) as solvents. Combinations of three temperatures (308, 323 and 333 K) and four pressures (100, 150, 200 and 250 bar) were assessed in the vessel and the rest of the variables were held constant (i.e. CO 2 flow rate, sample flow rate, washing time, nozzle diameter and the amoxicillin:ethyl cellulose ratio). Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and elemental analysis (EA) were used to determine the particle size and shape and to confirm the presence of both compounds in the resulting precipitates. In most cases, mixed amoxicillin and ethyl cellulose particles were produced with sizes in the micrometer range. Pressure and temperature effects on the co-precipitation were investigated. The release behaviour of the microparticles precipitated by the SAS process was evaluated in two biological fluids – simulated gastric and simulated intestinal fluids. Co-precipitated materials allowed a slower drug release rate than pure drug.

Production of Ursolic Acid Nanoparticles by Supercritical Antisolvent Precipitation

The aim of this study was to obtain nanoparticles and improve solubility of ursolic acid (UA), using supercritical antisolvent process (SAS). The four effects of process variables on drug particle formation during SAS process were investigated. Particles with mean particle size ranging from 139.4 ± 19.4 to 1039.8 ± 65.2 nm were obtained. The UA was characterized by scanning electron microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy, specific surface area and dissolution test. The XRD analyses showed that the processed UA was amorphous. The processed UA had solubility 4.4 times higher than the unprocessed UA.

In situ optical monitoring of the solution concentration influence on supercritical particle precipitation

We report a novel approach for the measurement of the location of particle formation in the supercritical antisolvent process (SAS). The measurement strategy is based on in situ Raman and elastic light scattering. In the SAS process, paracetamol was used as the solute, ethanol as the solvent and carbon dioxide as the antisolvent. Experiments were performed under miscible conditions for the binary system ethanol and carbon dioxide at 313 K and pressures between 10 MPa and 17.5 MPa. For high paracetamol concentrations in the injected ethanol solution, particles were found to start precipitating after jet breakup in a multi-phase flow. For low paracetamol concentrations, precipitation starts later in a one-phase flow, when the transient interface (phase boundary) between the injected solution and the supercritical carbon dioxide has diminished.

A new system for particle formation using the principle of the SAS process: The Concentric Tube Antisolvent Reactor (CTAR)

This paper presents a new system to produce micrometric narrow size distribution particles. The principle is the same as for a conventional supercritical antisolvent process (SAS), with the contact of the organic solution containing the solute to be precipitated and the supercritical CO 2 playing the role of an antisolvent. This paper exposes the functioning of the system used for the contact of the two phases. It is constituted by two concentric tubes; an external one partially for the CO 2 and an internal one for the organic solution. Its name is the Concentric Tube Antisolvent Reactor (CTAR). This system is a compacted and simple one. It has been tested with a usual polymer ( l-poly lactic acid) often processed by the use of the SAS methods. Different experiments have shown that this system is convenient for the production of particles, leading to almost equivalent results as in other processes with identical operating conditions. There are still remaining problems for the recovery of the powder formed, which is usual for this kind of process. This system could be very useful for the scaling up of the process, by multiplying the number of tubes with an easy permanent control on the operating conditions. Some improvements have been made for operating parameters, as the concentration of LPLA in the organic solution and the molar ratio solvent/supercritical CO 2 that can be processed.