Interactions of phase equilibria,jet fluid dynamics and mass transfer during supercritical antisolvent micronization

Supercritical antisolvent (SAS) precipitation has been successfully used in the micronization of several compounds. Nevertheless, the role of high-pressure vapor–liquid equilibria, jet fluid dynamics and mass transfer in determining particle size and morphology is still debated. In this work, CO₂ has been adopted as supercritical antisolvent and elastic light has been used to acquire information on jet fluid dynamics using thin wall injectors for the investigation of the liquid solvents acetone and DMSO at operating conditions of 40 °C in the pressure range between 6 and 16 MPa. The results show that two-phase mixing after jet break-up is the phenomenon that characterizes the jet fluid dynamics at subcritical conditions. When SAS is performed at supercritical conditions a transition between multi-phase and single-phase mixing is observed by increasing the operating pressure. Single-phase mixing is due to the very fast disappearance of the interfacial tension between the liquid solvent and the fluid phase in the precipitator. The transition between these two phenomena depends on the operating pressure, but also on the viscosity and the surface tension of the solvent. Indeed, single-phase mixing has been observed for acetone very near the mixture critical point, whereas DMSO showed a progressive transition for pressures of about 12 MPa.In the second part of the work, a solute was added to DMSO to study the morphology of the microparticles formed during SAS precipitation at the different process conditions, to find a correlation between particle morphology and the observed jet. Expanded microparticles were obtained working at subcritical conditions; whereas spherical microparticles were obtained operating at supercritical conditions up to the pressure where the transition between multi- and single-phase mixing was observed. Nanoparticles were obtained operating far above the mixture critical pressure. The observed particle morphologies have been explained considering the interplay among high-pressure phase equilibria, fluid dynamics and mass transfer during the precipitation process.     

Particle formation in supercritical fluids—Scale-up problem

The process of antisolvent precipitation of particles, termed solution enhanced dispersion by supercritical fluids (SEDS™), is applied to precipitate the model drug, paracetamol, from ethanol solutions. In the SEDS process the substrate solution is quickly mixed in a mixing chamber of the coaxial two-component nozzle with an antisolvent, represented in this case by the supercritical CO₂. Resulting partially mixed, highly supersaturated solution is introduced into the precipitation vessel as a jet, which generates intensive circulation of residual fluids that dilute the fresh supersaturated solution. Nucleation starts in the nozzle chamber, whereas particle growth completes the process in the precipitation vessel. The process is carried out above the mixture critical pressure; the antisolvent is thus completely miscible with the solvent. Under such conditions the macro-, meso-, and micro-mixing processes can affect the particle size distribution (PSD) and should be considered when the process is scaled up. Scaling up considerations of the precipitation process are based on scale-up rules, CFD simulations and experimental data for paracetamol precipitation. In simulations the model presented earlier (Ba?dyga et al., 2004) that is based on the population balance equation and CFD modelling of compressible flow processes is applied. Results of experimental investigations and numerical simulations are applied to verify scale-up strategies for the SEDS processes.     

Preparation and Physicochemical Properties of Vinblastine Microparticles by Supercritical Antisolvent Process

The objective of the study was to prepare vinblastine microparticles by supercritical antisolvent process using N-methyl-2-pyrrolidone as solvent and carbon dioxide as antisolvent and evaluate its physicochemical properties. The effects of four process variables, pressure, temperature, drug concentration and drug solution flow rate, on drug particle formation during the supercritical antisolvent process, were investigated. Particles with a mean particle size of 121 ± 5.3 nm were obtained under the optimized process conditions (precipitation temperature 60 °C, precipitation pressure 25 MPa, vinblastine concentration 2.50 mg/mL and vinblastine solution flow rate 6.7 mL/min). The vinblastine was characterized by scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, mass spectrometry and dissolution test. It was concluded that physicochemical properties of crystalline vinblastine could be improved by physical modification, such as particle size reduction and generation of amorphous state using the supercritical antisolvent process. Furthermore, the supercritical antisolvent process was a powerful methodology for improving the physicochemical properties of vinblastine.     

Use of solvent mixtures in supercritical antisolvent process to modify precipitates morphology: Cellulose acetate microparticles

In the supercritical antisolvent precipitation (SAS), the jet fluid dynamics is characterized by two-phase mixing at subcritical conditions, and by one-phase mixing at completely developed supercritical conditions. The amplitude of the pressure range, in which binary systems organic solvent/scCO₂ exhibit the transition between two-phase to one-phase mixing, depends on the organic solvent that is in contact with supercritical carbon dioxide (scCO₂) and conditions the morphology of the microparticles produced by SAS. When this pressure range is wide, as in the case of dimethylsulfoxide (DMSO), solutes solubilized in the organic solvent can be precipitated as microparticles by atomization, droplets formation and drying; when this pressure range is narrow, as for acetone, gas mixing prevails and only nanoparticles are generally observed. Therefore, generally speaking, solutes that are soluble only in solvents exhibiting gas mixing in scCO₂, do not exhibit microparticles morphology and this fact is a limitation for several industrial applications.In this work, a model compound, cellulose acetate (CA), that is slightly soluble in DMSO and freely soluble in acetone, was processed by SAS using mixtures of the two solvents that exhibit intermediate behaviors between the two pure solvents, to extend two phase mixing and produce CA microparticles. Using different DMSO/acetone mixture percentages, the effects of the polymer concentration in the liquid solution and of the pressure were studied. A mixture of DMSO/Acetone 50/50 (v/v), at a pressure of 85 bar and a concentration of the liquid solution equal to 40 mg/mL, efficiently produced non-coalescing CA microparticles with a mean diameter of 0.42 μm and a standard deviation of about 0.15 μm, demonstrating that this SAS strategy can be successful.     

Nanoparticle formation of lycopene/β-cyclodextrin inclusion complex using supercritical antisolvent precipitation

With a view to promoting dispersion of lycopene in water, the precipitation of an inclusion complex of lycopene and β-cyclodextrin was investigated using the solution-enhanced dispersion by supercritical fluids (SEDS) process. The inclusion complex, which was prepared in N,N-dimethylformamide (DMF), was dissolved in the same solvent and then micronized by SEDS, using carbon dioxide (CO₂) as a supercritical antisolvent. The effects of the initial concentrations of lycopene and β-cyclodextrin, the CO₂ flow rate, the solution flow rate, and the pressure and temperature at which the process was conducted were examined. The morphologies of the resulting particles were observed by scanning electron microscopy (SEM) and field emission-scanning electron microscopy (FE-SEM). Small spherical particles were obtained at all operating conditions. At high pressure, high temperature, high CO₂ flow rate and low solution flow rate, particles with an average particle size of about 40 nm were obtained.     

A new approach to select solvents and operating conditions for supercritical antisolvent precipitation processes by using solubility parameter and group contribution methods

A new approach is proposed to select operating temperature and pressure for supercritical antisolvent particle precipitation based on solubility parameter calculated by group contribution methods and using only the critical properties of the solvent. Solubility parameters are also used to choose the most suitable organic solvent for a given application. Supercritical antisolvent precipitation operating conditions of 36 systems are investigated including 8 organic solvents (methanol, ethanol, acetone, DMSO, DCM, chloroform, NMP and acetic acid) and 6 solid solutes (atenolol, tartaric acid, flunisolide, paracetamol, amoxicillin and cholesterol) in the temperature and pressure ranges of 25⿿85 °C and 50⿿250 bar. The results show a good agreement between the experimental and calculated data for these systems. Although particle precipitation depends on several parameters such as mass-transfer rates and hydrodynamics, the focus of this work is on the role of thermodynamics to indicate the preliminary conditions for a successful antisolvent precipitation process. Validation and results of this new approach suggest that it can be a useful tool for a qualitative and completely predictive evaluation of supercritical antisolvent particle precipitation in a cheaper way than carrying out experimental runs.     

Micronization of taxifolin by supercritical antisolvent process and evaluation of radical scavenging activity

The aim of this study was to prepare micronized taxifolin powder using the supercritical antisolvent precipitation process to improve the dissolution rate of taxifolin. Ethanol was used as solvent and carbon dioxide was used as an antisolvent. The effects of process parameters, such as temperature (35-65 °C), pressure (10-25 MPa), solution flow rate (3-6 mL/min) and concentration of the liquid solution (5-20 mg/mL) on the precipitate crystals were investigated. With a lower temperature, a stronger pressure and a lower concentration of the liquid solution, the size of crystals decreased. The precipitation temperature, pressure and concentration of taxifolin solution had a significant effect. However, the solution flow rate had a negligible effect. It was concluded that the physicochemical properties and dissolution rate of crystalline taxifolin could be improved by physical modification such as particle size reduction using the supercritical antisolvent (SAS) process. Further, the SAS process was a powerful methodology for improving the physicochemical properties and radical scavenging activity of taxifolin.     

Preparation and Characterization of Tripterygium wilfordii Multi-Glycoside Nanoparticle Using Supercritical Anti-Solvent Process

The aim of this study was to prepare nanosized Tripterygium wilfordii multi-glycoside (GTW) powders by the supercritical antisolvent precipitation process (SAS), and to evaluate the anti-inflammatory effects. Ethanol was used as solvent and carbon dioxide was used as an antisolvent. The effects of process parameters such as precipitation pressure (15–35 MPa), precipitation temperature (45–65 °C), drug solution flow rates (3–7 mL/min) and drug concentrations (10–30 mg/mL) were investigated. The nanospheres obtained with mean diameters ranged from 77.5 to 131.8 nm. The processed and unprocessed GTW were characterized by scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy and thermal gravimetric analysis. The present study was designed to investigate the beneficial effect of the GTW nanoparticles on adjuvant-induced arthritis in albino rats. The processed and unprocessed GTW were tested against Freund’s complete adjuvant-induced arthritis in rats. Blood samples were collected for the estimation of interleukins (IL-1α, IL-1β) and tumor necrosis factor-α (TNF-α). It was concluded that physicochemical properties and anti-inflammatory activity of GTW nanoparticles could be improved by physical modification, such as particle size reduction using supercritical antisolvent (SAS) process. Further, SAS process was a powerful methodology for improving the physicochemical properties and anti-inflammatory activity of GTW.     

Enhancing the solubility and bioavailability of isoflavone by particle size reduction using a supercritical carbon dioxide-based precipitation process

Isoflavones are a group of small molecular compounds found in many plants. Genistein is the most well studied isoflavones because of its beneficial effects in reducing menopausal symptoms, anti-oxidant and anti-cancer. The major difficulty in developing isoflavone-based healthcare products is their low water solubility. In this study, the solubility and oral bioavailability of genistein were increased by reducing its particle size using supercritical CO₂ as an antisolvent in the precipitation process. The effects of various process parameters including type of solvent, pressure of precipitation, and concentration of genistein solution on particle formation were evaluated. We found that under optimized conditions: dissolving 4 mg/mL genistein in acetone and precipitating them with supercritical CO₂ under 100 bar at 40 °C, the size of genistein particles was reduced from its original width of 10–50 μm to ∼254 nm. The reduction of genistein particle size not only increased its water solubility by 2 fold but more importantly increased its 24 h-plasma concentration by 2.6 fold after orally administrated to rats. These results proof the concept of using supercritical CO₂ as an antisolvent in the precipitation process to reduce particle size of water insoluble compounds such as genistein and to improve its oral bioavailability.     

Crystallization of silibinin from organic solutions using supercritical and aqueous antisolvents

Silibinin, an anticancer drug, was crystallized from organic solutions using supercritical and aqueous antisolvents. Silibinin was dissolved in acetone and ethanol at concentration range of 0.01–0.04 g/mL, and the drug solutions were placed in contact with two different antisolvents, carbon dioxide and water. The mixing of the drug solutions and antisolvents led to the prompt precipitation of silibinin in a solid crystal form. The experimental variables, such as temperature, solution concentration, mixing rate and solution/antisolvent volume ratio were manipulated. When the experiments were conducted with a supercritical antisolvent, the effects of external additives on the crystal habit were examined. α-d-Glucose penta acetate, triton X-100 and urea were added to the solution at concentration range of 0.001–0.003 g/mL as external additives. The temperature increase of 20 °C induced 25% increase in particle size. As the solution concentration was increased from 0.01 to 0.04 g/mL, the average particle size decreased from 35.5 to 22.0 μm in supercritical antisolvent experiments, while the particle size increased from 8.9 to 30.4 μm in aqueous antisolvent experiments. The use of different kinds of external additives resulted in different modifications of the particle shape and structures.     

Controlled liquid antisolvent precipitation using a rapid mixing device

Particle formation by the liquid antisolvent (LAS) process involves two steps: mixing of solution–antisolvent streams to generate supersaturation and precipitation (which includes nucleation and growth by coagulation and condensation) of particles. Uniform mixing conditions ensure rapid and uniform supersaturation, making it a precipitation controlled process where the particle size is not further affected by mixing conditions and results in precipitation of ultra-fine particles with narrow particle size distribution (PSD). In this work, we demonstrate that the use of an ultrasonically driven T-shaped mixing device significantly improves mixing of solution and antisolvent streams for precipitation of ultra-fine particles in a continuous operation mode. LAS precipitation of ultra-fine particles of multiple active pharmaceutical ingredients (APIs) such as itraconazole (ITZ), ascorbyl palmitate (ASC), fenofibrate (FNB), griseofulvin (GF), and sulfamethoxazole (SFMZ) in the size range 0.1–30 μm has been carried out from their organic solutions in acetone, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and ethanol (EtOH). Classical theory of homogeneous nucleation has been used to analyze the result, which suggests that higher nucleation rate results in finer particle size. Interestingly, experimental determination of degree of supersaturation indicates that higher supersaturation does not necessarily result in higher nucleation rate and nucleation rates can be correlated to solvent polarity.     

Crosslinked microparticle preparation in supercritical carbon dioxide with photopolymerization

An antisolvent processing technique by simultaneous compressed antisolvent precipitation and photopolymerization for cross-linked polymer microparticles formation was presented in this paper. In this process, photopolymerization of the homogeneous solution composed of methylene chloride, poly(ethylene glycol)600 diacrylate (PEG600DA) as monomer and diphenyl-(2,4,6-trimethylbenzoyl)-phosphine oxide (TPO) or 2,2-dimethoxy-2-phenylacetophenone (DMPA) as photoinitiator resulted to microparticle when it was sprayed into supercritical carbon dioxide (scCO₂) and simultaneously exposed to initiating light. High miscibility of the solvent in scCO₂ made methylene chloride quickly extracted from the dispersion phase, leaving very high concentrations of monomer (PEG600DA) dispersed in scCO₂. The high monomer concentration combined with photo initiating polymerization facilitates rapid reaction rates and ultimately lead to polymer precipitation. Particle size and morphology were adjustable by changing the processing conditions, such as temperature and pressure. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Polymeric microparticles prepared by supercritical antisolvent precipitation

This work has as main objective the development of a model process to obtain microparticles of an acrylate-methacrylate copolymer (Eudragit L100^® and Eudragit EPO^®) using supercritical carbon dioxide (SC-CO₂) as antisolvent (GAS). After studying the behaviour of the copolymers in SC-CO₂ at different operation conditions (pressure, temperature and presence of ethanol (EtOH)), efforts were invested in the optimization of Eudragit EPO^® precipitation from an organic solution using carbon dioxide as antisolvent in batch mode. After loading the precipitation vessel with a fixed quantity of the copolymer dissolution, the SC-CO₂ has been added until the pressure of operation has been reached. Three process parameters, namely, solution nature, presence of surfactants and organic solvent removal step, have been evaluated. Microparticles with mean diameter from about 2 to 12 μm are obtained.     

Role of hydrodynamics in supercritical antisolvent processes

An experimental study of hydrodynamics role in the supercritical antisolvent (SAS) process is here presented. Jet dispersion and atomization of a liquid phase into a dense one have been characterized for miscible systems and for commonly used conditions in SAS processes. The critical atomization jet velocity tends to the same value for all the systems studied. The dispersion has also been studied in the case of an organic solution containing the solute to be precipitated. The presence of sulfathiazole in a concentration up to 10 wt% does not influence the liquid jet dispersion. The nucleation zone has been located: crystals are not formed in the plain jet but in the entities resulting from the jet break-up. The observation of the crystals formed shows that the key-point is the mixing state more than the atomization state to form fine particles. However, atomization conditions lead to more homogeneous powder characteristics.     

Supercritical antisolvent precipitation of andrographolide from Andrographis paniculata extracts: Effect of pressure, temperature and CO2 flow rate

Andrographis paniculata extracts were precipitated using the so-called supercritical antisolvent (SAS) technique. Ethanol was used as the solvent and compressed CO₂ as the antisolvent. The effects of process operating conditions (pressure: 5-24 MPa, temperature: 308-328 K and CO₂ flow rate: 0.5-1.5 g/min) on particle size and morphology of precipitated andrographolide were evaluated. X-ray diffraction (XRD) patterns showed significant changes in andrographolide morphology depending on process operating conditions; both column-like and slice-like crystals were observed depending on operating conditions. Crystals with mean diameters of 3.30-228.35 μm were produced, smaller crystals were obtained at high pressure, low temperature and high CO₂ flow rate and vice versa for large crystals. In addition, SAS process also produced high precipitation yields, since solubility of andrographolide is small in the supercritical CO₂ plus ethanol. When operating under subcritical conditions, amorphous particles were produced.     

聚乙二醇SAS微粒化的研究

经SAS微粒化实验研究,确定了聚乙二醇SAS沉析操作的优化条件:温度为25℃、压力为8MPa,反萃取剂CO2的密度为0.778gL-1,聚乙二醇/丙酮溶液的浓度为5~15 gL-1,溶液流量为1~5mLmin-1,过程为连续操作。实验所得聚乙二醇微粒的平均尺寸小于0.1mm,而其尺寸分布为0.033~0.38mm。     

Influence of pressure, temperature and concentration on the mechanisms of particle precipitation in supercritical antisolvent micronization

In this work, supercritical antisolvent micronization (SAS) is used to produce nanoparticles, microparticles and expanded microparticles of a model compound, gadolinium acetate (GdAc), using dimethylsulfoxide (DMSO) as the liquid solvent with the aim of studying the dependence of particles’ diameter and morphology on some process parameters like pressure, temperature and concentration of the starting solution. Experiments are performed varying the precipitation pressure between 90 and 200 bar, the precipitation temperature between 35 and 60 °C and the concentration of GdAc in the liquid solution in the range from 20 to 300 mg/mL. The experimental evidences show that the formation of particles with specific sizes in the micrometric and nanometric range depends on specific values of each one of these parameters. An explanation of the results is proposed in terms of the competition between two characteristic times of the SAS process that can control the precipitation process. The time of jet break-up of the liquid solution that produces liquid droplet formation, and the dynamic surface tension vanishing time, that induces gas mixing with the precipitation of nanoparticles from the gaseous phase. Indeed, GdAc sub-microparticle, or microparticle (diameter in the range 0.23-1.6 μm with mean diameters in the range 0.28-0.52 μm) formation can be attributed to micro-droplet drying, whereas nanoparticles (mean diameter in the range 90-210 nm) are consistently produced when gas mixing is the possible governing process. In conclusion, the precipitation mechanisms can be modulated varying one SAS parameter a time, thus selecting the range of particle diameters required for the specific application.     

Nanostructured cellulose acetate filaments produced by supercritical antisolvent precipitation

The supercritical antisolvent precipitation technique was used to precipitate cellulose acetate in form of nanostructured filaments. Two different solvents were used: acetone, chosen because it is a typical laboratory solvent, and a mixture acetic acid + water, that is industrially used in the cellulose acetylation process. The influence of the operating parameters, such as concentration of the liquid solution, pressure and temperature, on the structure of cellulose acetate filaments was studied. Several centimeter long structures, formed by nanoelements ranging from about 50 to 250 nm, were obtained. Some experiments were replicated on a pilot plant to demonstrate the scalability of the process.     

Preparation and characterization of camptothecin powder micronized by a supercritical antisolvent (SAS) process

Micronized camptothecin (CPT) is prepared with a supercritical antisolvent (SAS) apparatus using dimethyl sulfoxide (DMSO) as solvent and carbon dioxide as antisolvent. Four factors, namely CPT solution concentration and flow rate, precipitation temperature and pressure are optimized by a four-level orthogonal array design (OAD). By analysis of variance (ANOVA), only precipitation pressure has a significant effect on the MPS of micronized CPT. The optimum micronization conditions are determined as follows: CPT solution concentration 1.25 mg/ml, CPT solution flow rate 6.6 ml/min, precipitation temperature 35 °C and precipitation pressure 20 MPa. Under the optimum conditions, micronized CPT with a MPS of 0.25 ± 0.020 μm is obtained. The micronized CPT obtained was characterized by Scanning Electron Microscopy (SEM), Atomic Force Microscope (AFM), High performance liquid chromatography-mass spectrometry (LC-MS), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Differential scanning calorimeters (DSC) and Gas chromatography (GC) analyses. The results showed that the obtained CPT particles have lower crystallinity and SAS micronization process does not induce degradation of CPT. In addition, the residual DMSO is less than the ICH limit for class 3 solvents.     

φ50 mm折流板脉冲萃取柱吹气法测量存留分数

在柱径为50 mm的折流板脉冲萃取柱中,首先利用吹气法研究了硝酸水溶液和30％TRPO-煤油水溶液体系的单相流时均摩擦压降Δp_f特性.实验结果表明当A′ω≠0,且u_c＝0时,Δp_f可以忽略;而当Aω＝0时,Δp_f与u_c满足Noh模型的线性关系.在Noh模型的基础上,给出了计算Aω≠0时单相流时均摩擦压降的模型,实验结果与模型预测相一致.在单相流摩擦压降的基础上,又研究了连续相分别为硝酸溶液和30％TRPO-煤油溶液体系的两相流时均摩擦压降Δp_f特征.实验结果表明：两相流时均摩擦压降Δp_f可用于计算分散相存留分数,其近似由连续相所对应的Noh单相流模型求得,并可用于折流板脉冲萃取柱分散相存留分数的确定.