Antisolvent Recrystallization Research Articles

Solubility Measurement and Stability Study of Sodium Cefuroxime

The stability of sodium cefuroxime has been a major concern since it was invented as a valuable antibiotic. In this study, online attenuated total reflection-fourier transform infrared spectroscopy was applied to monitor the change in supersaturation and optimize the solvent flow rate in antisolvent recrystallization experiments of sodium cefuroxime. The solubility of sodium cefuroxime under various temperatures T, pH values, and solvents was measured and correlated in models. The effect of the antisolvent (79.1 % ethanol) flow rate on crystallinity was examined, and the products were analyzed by X-ray diffraction, scanning electron microscopy, and stability test. The results showed that appropriate mean particle size, uniform particle size distribution, and good crystalline state could improve the stability of sodium cefuroxime. The optimum antisolvent flow rate for this recrystallization process under these operating conditions was found to be 2 mL·min–1.

In vitro dissolution enhancement of micronized l-nimodipine by antisolvent re-crystallization from its crystal form H

In order to enhance solubility and dissolution rate in water, micronized l-nimodipine (NMD) has been successfully prepared by antisolvent re-crystallization process using acetone as solvent and deionized water as antisolvent. The effects of five experimental parameters on the mean particle size (MPS) of NMD nanosuspension were investigated. It was found that the MPS of NMD nanosuspension decreased significantly when the concentration of NMD-acetone solution increased from 50 to 150 mg/mL along with the increase of volume ratio of antisolvent to solvent from 1 to 3, and then increased slightly with the following increase of them. By contrast, the MPS decreased with the increased feed rate of NMD-acetone solution and the amount of surfactant, from 1 to 3 mL/min and 0.025% to 0.2%, respectively. Thereafter, the MPS did not show any obvious change. The precipitation temperature had no significant effects on MPS. The optimum micronization conditions were determined as follows: NMD-acetone solution concentration of 150 mg/mL, the volume ratio of antisolvent to solvent of 3, the flow rate of NMD-acetone solution of 9 mL/min, the preparation temperature of 15°C and the amount of the surfactant of 0.2%. Under optimum conditions, micronized NMD with a MPS of 708.3 nm was obtained. The micronized product was characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), high performance liquid chromatography-mass spectrometry (LC-MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermo gravimetric (TG), to verify the influences of micronization process on the final product. The results showed that the chemical structure of micronized NMD was not changed, but the crystalline structure had undergone transition during precipitation, which changed from form H into L. The dissolution test showed that micronized NMD exhibited enhanced dissolution rate and solubility of 5.22 folds compared to raw H-NMD. These results suggested that micronized NMD may have potential value to become a new oral NMD formulation with high bioavailability.

Preparation and Characterization of Micronized Vitexin by Antisolvent Recrystallization Method

To improve the dissolution rate of vitexin,the micronization of vitexin in an antisolvent recrystallization process using N-methylpyrrolidone(NMP) as solvent and water as antisolvent was studied in this paper.The effects of operating parameters including concentrations of vitexin solution,system temperatures,stirring rates and kinds of surfactants(PVP,Tween80,SDS) on the particle size of micronized vitexin were investigated.Particles of micronized vitexin with a mean particle size of 291.1 nm were obtained under the optimized process conditions(vitexin solution concentration 20 mg·mL-1,volume ratio of antisolvent to solvent 10∶ 1,stirring rate 1 500 r·min-1 and concentration of PVP 8 mg·mL-1).The processed vitexin particles and the unprocessed one were characterized by scanning electron microscopy(SEM),X-ray diffraction(XRD),differential scanning calorimetry(DSC),Fourier-transform infrared spectroscopy(FT-IR).The results showed that antisolvent recrystallization process did not induce degradation of vitexin and the micronized vitexin had lower crystallinity.The chemical properties of the processed vitexin did not change when compared with the original drug,and there was a significant increase of the dissolution rate of the processed vitexin comparing with the unprocessed vitexin.

Preparation and characterization of cyclo-1,3,5-trimethylene-2,4,6-trinitramine (RDX) powder: Comparison of microscopy, dynamic light scattering and field-flow fractionation for size characterization

Abstract RDX powder was prepared using a supercritical anti-solvent (SAS) recrystallization. Then the physicochemical properties of the RDX powder were analyzed by using differential scanning calorimetry (DSC), electrophoretic light scattering (ELS), X-ray diffraction (XRD), and scanning electron microscopy (SEM). The size distribution of the RDX powder was studied by dynamic light scattering (DLS) and optical microscopy (OM). Asymmetrical flow field-flow fractionation (AsFlFFF) was tested for determination of size distribution. Results from FFF were compared with those from DLS and OM, and then the merits and limitations of the sizing techniques were discussed. It was found that DLS is not suitable for the size analysis of samples having broad size distributions, such as the RDX powder prepared in this work. The mean sizes of the RDX powder obtained by OM and FFF were in reasonable agreement. For FFF analysis, combination of FL-70, a surfactant, with regenerated cellulose (RC) membrane was found to provide the best performance with good resolution and minimized particle-membrane interaction, resulting in reliable size distribution. The FFF technique showed higher reproducibility in measuring the particle size than OM or DLS with relative standard deviation of 6%. FFF is a useful tool for size-based separation and size characterization of the RDX powder with a particle size distribution from about 1 μm to 25 μm.

Supercritical carbon dioxide anti-solvent purification of anti-oxidative compounds from Lycium barbarum fruits by using response surface methodology

This study employed ultrasonic extraction, column elution fractionation and supercritical anti-solvent (SAS) recrystallization in purifying and in preparing micro-sized particles containing zeaxanthin dipalmitate (ZDP) from the Lycium barbarum fruits. Column fractionation of the ultrasonic acetone extract coupled with the SAS process of the ZDP-laden ethyl-acetate solution enhanced the amount of ZDP to 931.5mg/g in the SAS precipitates (about 64.9% recovery) compared to 72.25mg/g from the ultrasonic extract alone. A two-factor experimental design by response surface method showed that feed concentration and feed flow rate were important for SAS in obtaining the highest purity and the smallest mean size of the ZDP particles. The purest ZDP compound (98.3%) also led to the proliferation of anti-hydrogen peroxide oxidation of human adult retinal pigment epithelial cells.

Asymmetrical Flow Field-Flow Fractionation for Characterization of Cyclotrimethylene Trinitramine (RDX) Particles Prepared by Supercritical Anti-Solvent Recrystallization

In this work, asymmetrical flow field-flow fractionation (AsFlFFF) was employed to determine the mean diameters and size distributions of cyclotrimethylene trinitramine (RDX) particles. The micro-particles of RDX were prepared using a supercritical anti-solvent recrystallization process. The influence of the spraying method, i.e., the pressure drop generated during the spraying of the RDX solution into the supercritical carbon dioxide (CO2) phase, on the size and shape of the recrystallized RDX particles, was investigated. It was found that the mean diameter of the recrystallized RDX particles decreased as the pressure drop increased, mainly due to the reduction in the population of larger particles. Also, the size distribution tended to become narrower with increasing pressure drop for the same reason. Near-spherical RDX particles with a relatively narrow size distribution were obtained at a pressure drop of 11 MPa. The mean diameters of the RDX particles determined by AsFlFFF were in reasonable agreement with those obtained by optical microscopy (OM). The AsFlFFF seems to be a useful tool for the separation and characterization of RDX particles.

Microalgae cultivation and purification of carotenoids using supercritical anti-solvent recrystallization of CO2+ acetone solution

Abstract Zeaxanthin is a type of xanthophyll found in carotenoids, which is produced as a food supplement frequently used for human retinal protection. These works investigated growth rate and harvest of the sea water algal species of Nannochloropsis oculata (N. oculata) by in-door and out-door cultivations; stirred ultrasonic acetone extraction of zeaxanthin from; employed column fractionation to obtain zeaxanthin-rich elution; and then coupled it with supercritical carbon dioxide anti-solvent (SAS) precipitation to generate the highly pure submicron-sized zeaxanthin. The ultrasonic extract contained 38.2 mg/g of zeaxanthin and then the column elution fractionation increased the zeaxanthin content to 41% (410.3 mg/g) with a recovery of 82.3%. The SAS precipitation at 215 bar, 50 °C for 24 min of injection time enhanced the zeaxanthin content to 58% (582.4 mg/g) with a recovery of 67.2%. Experimental results showed that the amount of zeaxanthin increased with total SAS time and feed concentration had an effect of enlarging the precipitates due to agglomeration and accumulation. The SAS precipitation of the column purified algal solution demonstrated a production of micro/nano-sized lamellar particulates that contained high amounts of zeaxanthin.

Dynamic Simulation and Optimization of Population Balance Model for Gas Anti-solvent Recrystallization Process

Crystallization processes are widely used in various applications such as polymers, dyes, pharmaceuticals, and explosives. Novel crystallization processes using supercritical fluids have recently attracted much attention due to the environmental advantage of using environmentally benign carbon dioxide as a solvent. Gas anti-solvent (GAS) process is one of the most common supercritical processes, which utilize the low solubility of the anti-solvent to produce particles. In this work, a mathematical model from a population balance model (PBM) is developed to describe the particle size distribution (PSD) of GAS process and it is numerically solved. The developed PBM involves a set of partial differentials equation with algebraic constraints, which requires effective numerical approaches. A solution scheme based on a high resolution method is proposed to solve the dynamic problem using MATLAB. In addition, the effect of the supercritical CO2 addition rate is investigated. At last, we present the results of open-loop test for the system and propose a nonlinear model predictive control (NMPC) strategy to control the particle size distribution of the GAS process.

Preparation of highly pure zeaxanthin particles from sea water-cultivated microalgae using supercritical anti-solvent recrystallization

Xanthophylls, including zeaxanthin, are considered dietary supplements with a potentially positive impact on age-related macular degeneration. Using pilot-scale column fractionation coupled with supercritical anti-solvent (SAS) recrystallization, highly pure zeaxanthin particulates were prepared from ultrasonic extracts of the microalgae, Nannochloropsis oculata, grown in sea water. Column partition chromatography increased the concentration of zeaxanthin from 36.2mg/g of the ultrasonic extracts to 425.6mg/g of the collected column fractions. A response surface methodology was systematically designed for the SAS process by changing feed concentration, CO2 flow rate and anti-solvent pressure. Zeaxanthin-rich particles with a purity of 84.2% and a recovery of 85.3% were produced using supercritical anti-solvent recrystallization from the column eluate at a feed concentration of 1.5mg/mL, CO2 flow rate of 48.6g/min and pressure of 135bar.

Enhanced bioavailability after oral and pulmonary administration of baicalein nanocrystal

The aim of the study was to investigate the potential of oral and pulmonary nanocrystal to enhance the bioavailability of baicalein, a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi. So far, the nano-sized delivery system of baicalein and its pulmonary delivery have received no exploration. In the present investigation, the baicalein nanocrystal was prepared by anti-solvent recrystallization followed by high pressure homogenization. In vitro characterization was performed including particle size and distribution, Zeta potential, dissolution, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffractometry. It was indicated that no crystalline change was observed after nanocrystal preparation. The baicalein nanocrystal containing only trace of stabilizer exhibited a significantly enhanced dissolution of baicalein. In vivo test was also carried out in rats and pharmacokinetic parameters of the baicalein crystal and the baicalein nanocrystal after gavage and pulmonary administration were compared, based on the simultaneous determination of baicalein and baicalin by high performance liquid chromatography. The mean relative bioavailability of oral baicalein nanocrystal was 1.67-fold that of oral baicalein crystal. The pulmonary baicalein nanocrystal had rapid and extensive absorption and had almost identical pharmacokinetic parameters to intravenous baicalein injection.

Colored nanoparticles dispersions as electronic inks for electrophoretic display

Phthalocyanine green (CuPcCl) nanoparticles was successfully prepared by anti-solvent recrystallization method and combined with in situ modification to improve the electrophoretic properties and dispersion ability in organic medium. The produced particles were characterized by SEM, FT-IR and ζ-potential test. It was found that the particles exhibited 120 nm with spherical shape and narrow size distribution when the modifier was mixture of CTAB and PVP. Sedimentation ratio of the prepared CuPcCl particles in tetrachloroethylene was nearly down to zero within 30 days and the ζ-potential was 26.8 mV. In addition, stable TiO 2/C 2Cl 4 dispersion was prepared by coated TiO 2 surface with trimethoxyoctylsilane. The sedimentation ratio of the modified TiO 2 was nearly 7.6% within 30 days, and the ζ-potential value was −28.9 mV. The particle size was about 300 nm with spherical morphology. The results demonstrated that green CuPcCl and white TiO 2 dispersions were suitable as electronic ink and showed potential value in the application of electrophoretic display.

Liquid Antisolvent Recrystallization of Phenylbutazone and the Effect of Process Parameters

Phenylbutazone was crystallized from solutions by the liquid antisolvent recrystallization technique. Acetone was used as a solvent, and distilled water was selected as an antisolvent. The influence of processing parameters, such as drug concentration, temperature, injection rate of drug solution, and mixing method of drug solution with antisolvent, on the particle size distribution were investigated. Furthermore, to examine the variation of resulting particle size in the presence of the ultrasound, the ultrasonic wave was applied to all experiments. Larger crystals were obtained when crystallization took place at higher temperatures. The enhancement of drug concentration favored decreased particle size. Regarding the mixing method of the drug solution and antisolvent, smaller particles were produced when the drug solution was injected into antisolvent, and larger crystals were obtained when the antisolvent was injected into drug solutions. As the injection rate of the drug solution increased, the average particle size decreased. The processed particles consistently exhibited an acicular crystal habit. The presence of ultrasound caused a reduction of particle size under all operational conditions.

Application of continuous supercritical anti-solvents for rapid recrystallization and purification of zeaxanthin dipalmitates from de-glycosides of Lycium barbarum fruits

This study employed column elution fractionation coupled with supercritical anti-solvent recrystallization to isolate the purest zeaxanthin dipalmitates (ZP), one of the eye-protecting compounds in the Lycium barbarum fruits. The amount of ZP increased to 983 mg/g in liquid anti-solvent precipitates with 29.1% recovery and increased to 929 mg/g in supercritical anti-solvent precipitates with 59.6% recovery, respectively from the ultrasonic acetone extract. Experimental data showed that supercritical anti-solvent recrystallization is feasible in producing platelet type precipitates within a few minutes. These ZP compounds exhibit anti-oxidative abilities by proliferating human adult retinal pigment epithelial cells (from 22% to 31%); though it was a meager increase when compared to those of algal 95% zeaxanthin (from 43% to 94%).

Demonstration of continuous supercritical carbon dioxide anti-solvent purification and classification of nano/micro-sized precipitates of algal zeaxanthin from Nannochloropsis oculata

This study examined time dependent continuous supercritical anti-solvent (SAS) recrystallization applied for purifying and generating zeaxanthin rich particulates from micro-algal Nannochloropsis oculata. Feed solutions varied from 0.4 to 1.2 mg/ml subjected into a 250 ml SAS crystallizer to yield a few classifications of nano- or micro-sized purified precipitates corresponding to different recrystallization time zones. The effect of operational conditions on amount, recovery of the zeaxanthin and mean size, morphology of the precipitates was obtained from experimentally designed SAS process. The mean size of particles falls within several hundreds of nanometers and the content of zeaxanthin in the particulates range from 65 to 71%, which relies highly upon the recrystallization time. This work demonstrated an environmental benign process in producing nano- or micro-sized particles containing rich-zeaxanthin from algal solution by using supercritical anti-solvent within minutes.

Determination of Solvent Contamination and Characterization of Ultrafine HNS Particles after Solvent Recrystallization

AbstractSolvent–antisolvent recrystallization employed for size reduction of HNS has been described and the effect of various parameters such as stirring rate, effect of antisolvent type, antisolvent temperature, ultrasonication, etc. was investigated. Purified HNS, produced by hot solvent recrystallization of production grade crude HNS, of mean particle size ∼95 μm was used for preparation of ultrafine particles of HNS. Solvent contamination in terms of residual solvent was determined by 1H NMR and GC‐MS analysis. In addition, ultrafine HNS has been characterized for purity (HPLC, 1H NMR), particle size and shape (PSA and SEM), specific surface area (BET analysis), thermal behavior (TGA, DSC), sensitivity (impact, friction), etc. The results have been compared with C‐HNS. UF‐HNS was >99% pure with mean particle size <1 μm. SEM showed submicrometer size rods like particles of HNS as the final material.

Solvent effect on particle morphology in recrystallization of HMX (cyclotetramethylenetetranitramine) using supercritical carbon dioxide as antisolvent

Supercritical fluid processes have gained great attention as a new and environmentally benign method of preparing the microparticles of energetic materials like explosives and propellants. In this work, HMX (cyclotetramethylenetetranitramine) was selected as a target explosive. The microparticle formation of HMX using supercritical antisolvent (SAS) recrystallization process was performed and the effect of organic solvent on the size and morphology of prepared particles was observed. The organic solvents used in this work were dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), cyclohexanone, acetone, and N-methyl pyrrolidone (NMP).

Continuous nanoparticle production by microfluidic-based emulsion, mixing and crystallization

BaSO 4 and 2,2′-dipyridylamine (DPA) nanoparticles were synthesized as reactive crystallization and anti-solvent recrystallization examples, respectively, of using the microfluidic-based emulsion and mixing approach as a new avenue of continuously producing inorganic and organic nanoparticles. BaSO 4 nanoparticles in the size range of 15–100 nm were reactively precipitated within the confinement of an aqueous droplet which was coalesced from two separate aqueous droplets containing BaCl 2 and (NH 4) 2SO 4 using a three T-junction micromixer configuration constructed with commercially available simple tubing and fitting supplies. Also, DPA nanoparticles of about 200 nm were crystallized by combining DPA+ethanol and water droplets using the same micromixer configuration.

Solubility of Simvastatin and Lovastatin in Mixtures of Dichloromethane and Supercritical Carbon Dioxide

The phase behavior of simvastatin and lovastatin drugs, which are well-known to be effective drugs for hypercholesterolemia therapy, in solvent mixtures of dichloromethane (DCM) and supercritical carbon dioxide (CO2) was investigated to present a guideline for establishing operating conditions in the particle formation of the drugs by a supercritical antisolvent recrystallization process utilizing DCM as a solvent and CO2 as an antisolvent. The solubilities of the statin drugs in the DCM + CO2 mixtures were determined as functions of temperature, pressure, and solvent composition by measuring the cloud points of the ternary mixtures of simvastatin + DCM + CO2 and lovastatin + DCM + CO2 at various conditions using a high-pressure phase equilibrium apparatus equipped with a variable-volume view cell. The solubility data of simvastatin and lovastatin are presented in the mixtures of DCM + CO2 with the DCM mole fractions between 0.18 and 0.34 at temperatures from 303.25 K to 333.25 K and at pressures up to ab...

Micronization of Phenanthrene Using the Gas Antisolvent Process. 1. Experimental Study and Use of FTIR

In this study the micronization of phenanthrene from toluene was studied using the gas antisolvent (GAS) recrystallization process. A systematic investigation of the influence of the key GAS process parameters, antisolvent addition rate (1, 20, 50, and 100 mL/min), temperature (25, 45, 55, and 65 °C), solute concentration (25%, 50%, 75%, and 100%), and agitation rate (500, 1000, 2000, and 3500 rpm), was investigated on the particle morphology, size, and size distribution. It was found using laser diffraction that increasing the antisolvent addition rate and the agitation rate, while decreasing the temperature and solute concentration, led to a decrease in the mean particle diameter. Furthermore, a unimodal particle size distribution was obtained at the higher agitation and antisolvent addition rates, but a particle size distribution of a bimodal nature was obtained at the higher temperatures and the lower agitation and antisolvent addition rates. The process parameters could be reproducibly tuned to give ...

Micronization of Phenanthrene Using the Gas Antisolvent Process: Part 2. Theoretical Study

In the second part of our study, a rigorous mathematical model was developed and simulated using Parsival for the gas antisolvent recrystallization process using phenanthrene−toluene−carbon dioxide...