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.     

Supercritical CO2 precipitation of poly(l-lactic acid) in a wide range of miscibility

Polymer microparticles are useful for numerous applications such as stationary phases in chromatography, adsorbents and catalyst supports, as well as for drug delivery systems. In recent decades the application of supercritical fluids for microparticle precipitation has been developed to a point where it is an ideal alternative to conventional processes. In this work poly(l-lactic acid) (PLLA), a biodegradable and biocompatible thermoplastic aliphatic polyester, has been processed using supercritical fluids, particularly by rapid expansion of supercritical solutions (RESS) and supercritical antisolvent (SAS) processes over a wide miscibility range. Particle morphology was greatly improved from irregular blocks to spherical microparticles on applying the SAS process. The effects of changes in polymer concentration, liquid flow rate, nozzle diameter, solvent, pressure and temperature have also been evaluated on the particle size of PLLA in the SAS precipitation. A higher concentration of the initial solution led to a decrease in particle size. Dichloromethane was the best of the chlorinated solvents investigated. The nozzle diameter had a negligible effect on particle size and the highest liquid flow rate gave the largest particle size. A larger particle size was also obtained on increasing the operating temperature. In contrast, the particle size decreased on increasing the operating pressure.     

Preparation and Physicochemical Properties of 10-Hydroxycamptothecin (HCPT) Nanoparticles by Supercritical Antisolvent (SAS) Process

The goal of the present work was to study the feasibility of 10-hydroxycamptothecin (HCPT) nanoparticle preparation using supercritical antisolvent (SAS) precipitation. The influences of various experimental factors on the mean particle size (MPS) of HCPT nanoparticles were investigated. The optimum micronization conditions are determined as follows: HCPT solution concentration 0.5 mg/mL, the flow rate ratio of CO(2) and HCPT solution 19.55, precipitation temperature 35 °C and precipitation pressure 20 MPa. Under the optimum conditions, HCPT nanoparticles with a MPS of 180 ± 20.3 nm were obtained. Moreover, the HCPT nanoparticles obtained were characterized by Scanning electron microscopy, Dynamic light scattering, Fourier-transform infrared spectroscopy, High performance liquid chromatography-mass spectrometry, X-ray diffraction and Differential scanning calorimetry analyses. The physicochemical characterization results showed that the SAS process had not induced degradation of HCPT. Finally, the dissolution rates of HCPT nanoparticles were investigated and the results proved that there is a significant increase in dissolution rate compared to unprocessed HCPT.     

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.     

Synthesis of 5-Fluorouracil nanoparticles via supercritical gas antisolvent process

The micronization of an anticancer compound (5-Fluorouracil) by supercritical gas antisolvent (GAS) process was investigated. 5-Fluorouracil was dissolved in dimethyl sulfoxide (DMSO) and subsequently carbon dioxide as an antisolvent was injected into this solution thus, the solution was supersaturated and nanoparticles were precipitated. The influence of antisolvent flow rate (1.6, 2 and 2.4 mL/min), temperature (34, 40 and 46), solute concentration (20, 60 and 100 mg/mL) and pressure (9, 12 and 15 MPa) on particle size and particle size distribution were studied. Particle analyses were performed by scanning electron microscopy (SEM) and Zetasizer Nano ZS. The mean particle size of 5-Fluorouracil was obtained in the range of 260–600 nm by varying the GAS effective parameters. The High performance liquid chromatography (HPLC) and Fourier transforms infrared spectroscopy (FTIR) analyses indicated that the 5-Fluorouracil nanoparticles were pure and the nature of the component did not change. The experimental results indicated that increasing the antisolvent flow rate and pressure, while decreasing the temperature and initial solute concentration, led to a decrease in 5-Fluorouracil particle size.     

New Insights into Acrylic Polymer Precipitation by Supercritical Fluids

Nanosystems based on polymers have attracted much attention due to the almost infinite diversity. In the past decades, the application of supercritical fluids for polymeric particle precipitation has been developed as an alternative to conventional processes. Here, precipitation of an acrylic copolymer was attempted by the rapid expansion of supercritical solutions (RESS) and successful by supercritical antisolvent (SAS) processes. In addition, the nanoparticles were characterized with different techniques. The polymer concentration, pressure, temperature, liquid solution flow rate and nozzle diameter effects were also evaluated with regard to particle size and the particle size distribution of this polymer.     

Micronization of cilostazol using supercritical antisolvent (SAS) process: Effect of process parameters

The aim of this study was to improve dissolution rate of poorly water-soluble drug, cilostazol, using supercritical antisolvent (SAS) process. The effect of process variables, such as pressure, temperature, drug concentration, type of solvents, feed rate ratio of CO₂/drug solution, on drug particle formation during SAS process was investigated. Particles with mean particle size ranging between 0.90 and 4.52 μm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration, solvent type, feed rate ratio of CO₂/drug solution. In particular, mean particle size and distribution were markedly influenced by drug solution concentration during SAS process. Moreover, the drug did not change its crystal form and the operating parameters might control the ‘crystal texture’ due to the change in crystallinity and preferred orientation during SAS process, as confirmed by differential scanning calorimetry and powder X-ray diffraction study. In addition, the dissolution rate of drug precipitated using SAS process was highly increased in comparison with unprocessed drug. Therefore, it is concluded that the dissolution rate of drug is significantly increased by micronization of cilostazol, leading to the reduction in particle size and increased specific surface area after SAS process.     

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。     

T型微通道内丙酸倍氯米松纳米颗粒的制备

引言 干粉吸入剂是将一种或多种药物制成一定范围的微小颗粒,经特殊的给药装置使药物以粉雾状进入呼吸道和肺部,发挥局部或全身的作用.影响吸人的因素主要有粒径大小、形态、分散性和吸湿性等特性,其中药物的粒径大小和分布是影响DPI肺部沉积率的重要因素[1-2].因此,药物纳米化是干粉吸入剂取得成功的一大关键.目前,多采用的药物纳米化技术为机械粉碎(如球磨、气流粉碎),制备的产品粒度分布宽、能耗大、效率低、易使热不稳定药物的结构破坏或降解等[3].而相对于传统的机械纳米化过程,液相沉淀法显示了更好的可控性,并且由于其操作简单、弹性大、设备投资小,而成为制备纳米药物颗粒的主要方法之一[4].     

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.     

Formation of biodegradable polymeric fine particles by supercritical antisolvent precipitation process

The supercritical antisolvent (SAS) precipitation process as a “green” alternative to specialty particles recrystallization was successfully used to generate poly(L ‐lactide) acid (L‐PLA) from dichloromethane (DCM) solution using CO₂ as antisolvent. The influence of main operating parameters on the synthesis of L‐PLA particles in the SAS process was methodically examined. In particular, antisolvent addition rate (30, 40, 50, and 60 g/min), temperature (35, 40°C, 45°C, and 50°C), solute concentration (50, 75, 100, and 150 mg/10 ml), and solution addition rate (1, 2.5, 5, and 7.5 ml/min). These parameters could be tuned to give a mean particle diameter of 0.62 μm. It was found using scanning electron microscopy and laser diffraction that increasing the antisolvent addition rate and the solution addition rate, while decreasing the temperature and solute concentration, led to a decrease in the L‐PLA mean particle diameter. Furthermore, a unimodal particle size distribution was obtained at the higher solution and antisolvent addition rates. Spherical‐like primary particles have been obtained in all the experimental runs; thus, no change of particle morphology with the process parameters has been noticed. These results manifested that SAS recrystallization process is a valuable technique to generate reproducibly polymer particles with controlled size and size distribution. POLYM. ENG. SCI. 2013. © 2012 Society of Plastics Engineers     

Antisolvent crystallization of carbamazepine from organic solutions

Carbamazepine was crystallized from organic solutions using an antisolvent crystallization technique. Ethanol was used as a solvent for the carbamazepine and distilled water was used as an antisolvent. The carbamazepine was dissolved in the solvent, and the drug solution was injected into the antisolvent causing the particle precipitation. During the crystallization experiments, the effects of the process parameters such as solution concentration, temperature, injection rate of the solution, and the presence of ultrasound, were investigated. An analysis of the produced particles showed that external characteristics such as particle size and its distribution were a strong function of the process parameters, while the internal structures such as crystallinity and thermal stability were nearly unaffected. Smaller particles were obtained when solutions with high drug concentrations were used. Higher temperature resulted in larger crystals. Particle size was also influenced by the injection rate of the drug solutions. Carbamazepine particle size was significantly reduced when the ultrasonic wave was selectively applied.     

Kinetics modeling of ampicillin nanoparticles synthesis via supercritical gas antisolvent process

Modeling of supercritical gas antisolvent (GAS) process was carried out for ampicillin nanoparticles synthesis. The particle size distribution of ampicillin limits bioavailability. Therefore, the kinetic data are essential for the control of particle size. Volume expansion and phase equilibrium modeling was studied to determine optimal operating conditions for experimental ampicillin production. Experimental ampicillin precipitations with GAS process at various antisolvent addition flow rates were investigated. The process model was then studied for the determination of nucleation and growth rate parameters. Equation of state, material and population balance equations were used for this modeling. A combination of the Crank-Nicholson and Lax-Wendroff methods was utilized to solve the population balance equation. Comparison of the experimental and modeling data showed that the model successfully predicted the particle size distribution. The effect of antisolvent addition rate on nucleation indicated that nucleation was enhanced via higher antisolvent addition rate and consequently smaller particle size was obtained. The mean particle sizes of ampicillin were obtained to be 357.09, 337.04 and 356.68 nm at antisolvent flow rates of 1.6, 2 and 2.4 mL/min, respectively.     

过程参数对超临界抗溶剂法共沉淀紫杉醇-PLLA的影响(英文)

Paclitaxel(PTX) is an effective anticancer drug with poor solubility in water.Recently,much effort has been devoted into alternative formulations of PTX for improving its aqueous solubility.In this study,PTX and poly(L-lactic acid)(PLLA) were co-precipitated by a supercritical antisolvent(SAS) process using dichloromethane(DCM) and the mixtures of DCM/ethanol(EtOH) or DCM/dimethyl sulfoxide(DMSO) as the solvent,with super-critical carbon dioxide as the antisolvent.The effects of solvent,solvent ratio,temperature,pressure,polymer con-centration and solution flow rate on particle morphology,mass median diameter(Dp50) and PTX loading were in-vestigated using single-factor method.The particle samples were characterized using X-ray diffraction(XRD),scanning electron microscopy(SEM),laser diffraction particle size analyzer and high pressure liquid chromatogra-phy(HPLC).XRD results indicate that the micronized PTX is dispersed into the PLLA matrix in an amorphous form.SEM indicates that the solvent and the solvent ratio have great effect on the particle morphologies,and particle morphology is good at the volume ratio of DCM/EtOH of 50/50.For the mixed DCM/EtOH solvent,Dp50 increases with the increase of the temperature,pressure,PLLA concentration and solution flow rate,and PTX loading in-creases with pressure.Suitable operating conditions for the experimental system are as follows:DCM/EtOH 50/50(by volume),35 ℃,10-12 MPa,PLLA concentration of 5 g·L-1 and solution flow rate of 0.5 ml·min-1.     

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.     

Recrystallization of erlotinib hydrochloride and fulvestrant using supercritical antisolvent process

Recrystallization of two anti-cancer active pharmaceutical ingredients (APIs), erlotinib hydrochloride (erlotinib HCl) and fulvestrant, using supercritical antisolvent (SAS) process was investigated in this study. The most commonly used supercritical carbon dioxide was employed as the antisolvent. Effect of three process parameters including the operating temperature, pressure and solution flow rate have been studied. Analyses of the recrystallized erlotinib HCl and fulvestrant were examined by SEM, XRD and DSC. Erlotinib HCl was recrystallized from its mean particle size of 20 μm to 2 μm with different crystal habits. Different polymorphs of erlotinib HCl were obtained and confirmed from the XRD and DSC results. The prior art polymorph form A of erlotinib HCl showed enhanced dissolution rate by 3.6 times to its original polymorph form B. Significant particle size reduction was also obtained for fulvestrant. The mean particle size was reduced from its original value of 22 μm to 2 μm with much narrower particle size distribution. The cross-interaction effect between the operating temperature and pressure observed in the SAS treatment of fulvestrant was verified by the method of calculated mixture critical point (MCP). The micronized fulvestrant particles showed consistent polymorph as the original API, but with different crystal habits. It is confirmed that the SAS method is applicable for controlling the crystal properties of two APIs, erlotinib HCl and fulvestrant, which require rigorous control of physical characteristics.     

Coprecipitation of Cefuroxime Axetil-PVP composite microparticles by batch supercritical antisolvent process

Batch supercritical antisolvent precipitation (SAS) process was used to coprecipitate Cefuroxime Axetil amorphous (CFA, antibiotic) and Polyvinylpyrrolidone (PVP-K30) for preparing drug-polymer composite particles. Solutions of CFA and PVP-K30 in methanol with overall concentrations of 50-150 mg/ml and polymer/drug ratios of 1/1-4/1 were sprayed into the CO₂ at 70-200 bar and 35-50 °C with drug + polymer solution injection rates of 0.85 and 2.5 ml/min. Spherical particles having mean diameters of 1.88-3.97 μm, distribution ranges of 0.82-9.7 μm (the narrowest distribution) and 0.91-46.64 μm (the broadest distribution) were obtained. Mean particle size was not affected significantly with the change of process parameters. It was only affected by pressure change. On the other hand particle size distribution was affected by pressure, temperature, drug + polymer solution injection rate and concentration. It was observed that temperature and polymer/drug ratio affected the particle morphology most. The drug release rate of SAS-coprecipitated CFA-PVP (1/1) particles was almost 10 times slower than the drug alone. As the ratio of the polymer increased drug release rate also increased due to the wetting effect of PVP.