SEDS工艺制备丝素纳米颗粒及其表征

以丝素蛋白为原料,以六氟异丙醇为溶剂,采用超临界流体强制分散溶液（SEDS）工艺制备了丝素纳米颗粒。单因素实验考察了压力、溶液浓度、溶液流速和CO2流速等因素对丝素纳米颗粒平均粒径分布的影响,并通过Zeta电位、HS-GC、FTIR、XRD和DSC等技术手段对制备的丝素纳米颗粒进行了表征。动态激光光散射仪检测结果表明：随压力、溶液浓度和流速的增大,丝素纳米颗粒平均粒径增大;随CO2流速的增大,丝素纳米颗粒平均粒径减小,最小达到298nm。丝素纳米颗粒Zeta电位为?39mV。HS-GC表明丝素纳米颗粒有机溶剂残留量为20μg/L。FTIR表明经SEDS工艺处理后丝素化学结构和官能团不会发生变化。XRD和DSC显示经SEDS工艺处理后丝素内部分子结构发生重排,由无规则卷曲向β折叠转换。     

超临界流体强制分散溶液技术及其在药物领域的应用

超临界流体强制分散溶液技术以其独特的优点,在药物超细化和微胶囊化等方面得到了广泛的应用。介绍了该技术的基本原理及工艺改进的研究情况,综述了该技术在药物及药物载体超细微粒和药物微囊制备方面的应用进展。利用SEDS过程能制备粒度分布窄的微米级甚至纳米级的微粒,能够将残留溶剂减小到非常低的质量浓度并且容易控制微粒粒径及粒度分布。     

超临界流体技术制各类胡萝卜素纳米颗粒

Based on the solubility in supercritical CO2, two strategies in which CO2 plays different roles are used to make quercetine and astaxanthin particles by supercritical fluid technologies. The experimental results showed that micronized quercetine particles with mean particle size of 1.0-1.5 µm can be made via solution enhanced dis-persion by supercritical fluids (SEDS) process, in which CO2 worked as turbulent anti-solvent; while for astaxan-thin, micronized particles with mean particle size of 0.3-0.8 µm were also made successfully by rapid expansion supercritical solution (RESS) process.     

Application of organic nonsolvent in the process of solution-enhanced dispersion by supercritical CO2 to prepare puerarin fine particles

An organic nonsolvent, dichloromethane was employed in the process of solution-enhanced dispersion by supercritical CO₂ (SEDS) to prepare fine particles of puerarin. A 2³ factorial experiment was designed to investigate and identify the relative significance of the processing parameters on the surface morphology, particle size and particle size distribution of the products. The effect of the nonsolvent/solvent ratio was found to be dominant in the results regarding particle size. Increasing the nonsolvent content of the puerarin solution decreased the particle size significantly. After optimization, the resulting puerarin nanoparticles exhibited a good spherical shape, a smooth surface and a narrow particle size distribution, with a mean particle size of 0.19 μm. After SEDS processing, the measurements of high performance liquid chromatography (HPLC), ultraviolet (UV) and mass spectrometry (MS) indicated there was no change in the chemical composition of puerarin particles; Fourier transform infrared (FTIR) spectroscopy measurement found the minor structural changes occurred on a molecular level; X-ray powder diffraction (XRPD) analysis revealed that the physical state of puerarin shifted into an amorphous form; and a significant increase in the dissolution rate of puerarin nanoparticles was observed. The SEDS process combined with the addition of dichloromethane could produce puerarin nanoparticles without contamination.     

不同溶剂条件下利用SEDS法制备乙基纤维素微粒的实验研究

分别利用二氯甲烷、丙酮和乙醇作为溶剂采用超临界流体增强溶液分散法(SEDS)制备了乙基纤维素微粒,考察了不同压力、温度和溶剂条件下所制备微粒的粒径大小及形态。实验表明:在体系亚临界和超临界状态下制备的微粒粒径及形态完全不同;聚合物的玻璃化温度的降低对微粒的形态影响比较大;溶剂对微粒粒径及形态也有较大影响,特别是对可制备微粒的压力及温度的范围的影响。     

超临界微粒化技术及其催化剂制备方面的应用

超临界流体用于制备超细粒子是一项新的技术,笔者综述了两种形成微粒的方法:超临界快速膨胀法(RESS)和超临界抗溶剂法(SAS),并对以SAS为基础的新技术气溶胶溶剂萃取(ASES)、超临界流体溶液分散法(SEDS)、强化传质超临界抗溶剂过程(SAS-EM)原理进行了简洁的介绍.且简洁介绍了影响粒子尺寸和分布的相关因素.着重说明了超临界流体技术在催化剂方面的应用,最后指出了该技术存在的主要问题和发展前景.     

Precipitation and Characterization of Chelerythrine Microparticles by the Supercritical Antisolvent Process

Chelerythrine was successfully micronized from methanol solution using Supercritical Carbon Dioxide (SC‐CO₂) as an antisolvent via the Solution Enhanced Dispersion by Supercritical Fluids through the Prefilming Atomization (SEDS‐PA) process. The morphology and particle size of the chelerythrine microparticles were visually analyzed by scanning electron microscopy (SEM). For the purpose of the optimizing operating conditions of the SEDS‐PA process, the influences of the experimental variables, i.e., temperature, pressure, solution flow rate and initial solution concentration, on the particle size and morphology of chelerythrine microparticles are discussed in detail. The results show that the best process conditions for the micronization of chelerythrine are: T = 313 K, P = 20 MPa, C = 2.0 g/L and F = 2.0 mL/min. The precipitates obtained under the optimized experimental conditions are short rod‐like chelerythrine microparticles with a mean particle size of 0.1–1 μm in width.     

Characterization of molecular interaionic and intraionic crosslinkable sulfonated poly(ether ether ketone‐alt‐benzimidazole) membrane

Lysozyme-loaded polymeric composite microparticles were successfully coprecipitated by solution-enhanced dispersion by supercritical CO₂ (SEDS), starting with a homogeneous organic solvent solution of lysozyme/poly(L -lactide)/poly(ethylene glycol) (lysozyme/PLLA/PEG). The effects of different drug loads (5, 8, and 12% w/w), PLLA Mw (10, 50, 100, and 200 kDa), PEG contents (0, 10, 30, and 50% PEG/(PLLA+PEG) w/w), and PEG Mw (400, 1000, and 4000 kDa) on the surface morphology, particle size, and drug release profile of the resulting composite microparticles were investigated. The results indicate that the size of the microparticles decreased and the rate of drug release increased with an increase in drug load, PEG content, or PEG Mw; the particle size first increased and then decreased with an increase in PLLA Mw, and the drug release was controlled by both particle size and PLLA Mw. The Fourier transform infrared spectrometer analysis and circular dichroism spectra measurement reveal that no significant changes occurred in the molecular structures during the SEDS processing, which is favorable to the production of protein–polymer composite microparticles for a protein drug delivery system. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

预成膜雾化超临界流体强制分散溶液过程及应用

设计了预成膜二流式喷嘴用于超临界流体强制分散溶液(SEDS)过程以获得良好的雾化与传质效果。采用预成膜雾化的SEDS(SEDS-PA)过程对胡萝卜素、麻黄素及黄芩甙进行了超细和聚合物包覆实验以考察该法制备药物微粒和载药聚合物微粒的有效性。通过SEM及光学显微镜照片分析微粒形态,用分光光度法检测药物在聚合物微粒中的含量。实验表明,通过SEDS-PA过程可成功地对天然药物超细化,并用聚合物对其包覆,从而制备药物微粒及载药聚合物微粒。     

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.     

Micronization of Gefitinib Using Solution‐Enhanced Dispersion by Supercritical CO2

The antineoplastic gefitinib has a low aqueous solubility, leading to poor absorption rates. To overcome this problem, microparticles (MP) were prepared using solution‐enhanced dispersion by supercritical fluids (SEDS) with supercritical CO₂ and the cosolvents dichloromethane and ethanol. The results showed that the use of SEDS resulted in the formation of smaller particles and rendered the usually heterogeneous crystals of the crude drug pure and uniform. Furthermore, the reduction in the MP size increased the dissolution rate of gefitinib, and in vitro cytotoxicity assays indicated that the MP inhibited the proliferation of A549 cells to a larger extent than did the crude drug. Given the beneficial properties of the MP, SEDS could potentially be used to micronize drugs for therapeutic applications.     

Continuous synthesis of monodispersed silver nanoparticles using a homogeneous heating microwave reactor system

Continuous synthesis of silver nanoparticles based on a polyol process was conducted using a microwave-assisted flow reactor installed in a cylindrical resonance cavity. Silver nitrate (AgNO(3)) and poly(N-vinylpyrrolidone) (PVP) dissolved in ethylene glycol were used respectively as a silver metal precursor and as a capping agent of nanoparticles. Ethylene glycol worked as the solvent and simultaneously as the reductant. Silver nanoparticles of narrow size distributions were synthesized steadily for 5 h, maintaining almost constant yield (>93%) and quality. The reaction was achieved within 2.8 s of residence time, although nanoparticles were not formed under this flow rate by conventional heating. A narrower particle size distribution was realized by the increased flow rate of the reaction solution. Nanoparticles of 9.8 nm average size with a standard deviation of 0.9 nm were synthesized at the rate of 100 ml h(-l).     

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.     

A Novel Preparation Method for Camptothecin (CPT) Loaded Folic Acid Conjugated Dextran Tumor-Targeted Nanoparticles

In this study, folic-dextran-camptothecin (Fa-DEX-CPT) tumor-targeted nanoparticles were produced with a supercritical antisolvent (SAS) technique by using dimethyl sulfoxide (DMSO) as a solvent and carbon dioxide as an antisolvent. A factorial design was used to reveal the effect of various process parameters on the mean particle size (MPS) and morphology of the particles formed. Under the optimum operation conditions, Fa-DEX-CPT nanoparticles with a MPS of 182.21 nm were obtained. Drug encapsulation efficiency and loading efficiency were 62.13% and 36.12%, respectively. It was found that the concentrations of the camptothecin (CPT) and dextran solution had a major influence upon morphology and shape of the final product. In addition, the samples were characterized by Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) with the purpose of developing a suitable targeted drug delivery system for cancer chemotherapy.     

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.     

基于超临界流体抗溶剂原理的造粒技术及其装置研究进展

超临界抗溶剂造粒技术由于具有操作条件温和、制得的微粒有机溶剂残留少、微粒粒径和形态可控等优点,已广泛地应用于药物运输体系的研究当中。本文简要介绍了超临界抗溶剂造粒技术的基本原理、装置组成和基本分类;从技术发展、喷嘴改进、技术结合、产品收集等方面,详细阐述了GAS、ASES、SEDS、SEDS-PA、SpEDS、SAS-EM、SAS-IJ、连续式RESS以及RESAS等基于超临界流体抗溶剂原理的造粒技术及其装置的改进过程;然后对目前其中存在的颗粒团聚、产品收集难和装置资源没有充分利用等问题提出了可能的解决方案;最后从数学模型的建立和规模化两方面,对超临界抗溶剂造粒技术基础理论的完善及其装置的改进进行了展望。     

Particle design using supercritical fluids: Literature and patent survey

As particle design is presently a major development of supercritical fluids applications, mainly in the pharmaceutical, nutraceutical, cosmetic and specialty chemistry industries, number of publications are issued and numerous patents filed every year. This document presents a survey (that cannot pretend to be exhaustive!) of published knowledge classified according to the different concepts currently used to manufacture particles, microspheres or microcapsules, liposomes or other dispersed materials (like microfibers):RESS: This acronym refers to ‘Rapid Expansion of Supercritical Solutions’; this process consists in solvating the product in the fluid and rapidly depressurizing this solution through an adequate nozzle, causing an extremely rapid nucleation of the product into a highly dispersed material. Known for long, this process is attractive due to the absence of organic solvent use; unfortunately, its application is restricted to products that present a reasonable solubility in supercritical carbon dioxide (low polarity compounds).GAS or SAS: These acronyms refer to ‘Gas (or Supercritical fluid) Anti-Solvent’, one specific implementation being SEDS (‘Solution Enhanced Dispersion by Supercritical Fluids’); this general concept consists in decreasing the solvent power of a polar liquid solvent in which the substrate is dissolved, by saturating it with carbon dioxide in supercritical conditions, causing the substrate precipitation or recrystallization. According to the solid morphology that is wished, various ways of implementation are available:GAS or SAS recrystallization: This process is mostly used for recrystallization of solid dissolved in a solvent with the aim of obtaining either small size particles or large crystals, depending on the growth rate controlled by the anti-solvent pressure variation rate;ASES: This name is rather used when micro- or nano-particles are expected; the process consists in pulverizing a solution of the substrate(s) in an organic solvent into a vessel swept by a supercritical fluid;SEDS: A specific implementation of ASES consists in co-pulverizing the substrate(s) solution and a stream of supercritical carbon dioxide through appropriate nozzles.PGSS: This acronym refers to ‘Particles from Gas-Saturated Solutions (or Suspensions)’: This process consists in dissolving a supercritical fluid into a liquid substrate, or a solution of the substrate(s) in a solvent, or a suspension of the substrate(s) in a solvent followed by a rapid depressurization of this mixture through a nozzle causing the formation of solid particles or liquid droplets according to the system.The use of supercritical fluids as chemical reaction media for material synthesis. Two processes are described: thermal decomposition in supercritical fluids and hydrothermal synthesis.We will successively detail the literature and patents for these four main process concepts, and related applications that have been claimed. Moreover, as we believe it is important to take into account the user's point-of-view, we will also present this survey in classifying the documents according three product objectives: particles (micro- or nano-) of a single component, microspheres and microcapsules of mixtures of active and carrier (or excipient) components, and particle coating.     

Effect of Solvent on Nanoparticle Production of β‐Carotene by a Supercritical Antisolvent Process

Production of micro‐ to nano‐sized particles of β‐carotene was investigated by means of solution‐enhanced dispersion by supercritical fluids (SEDS). β‐Carotene was dissolved in dichloromethane (DCM), N,N‐dimethylformamide (DMF), n‐hexane, or ethyl acetate, and supercritical CO₂ served as an antisolvent. The effects of the organic solvents, operating pressure, and temperature were examined. The morphologies of the particles produced by the SEDS were observed by field emission‐scanning electron microscopy and particle sizes were determined by image analysis. Irregularly shaped microparticles were produced in the system with DCM and DMF solution. Plate‐like microparticles were generated by using n‐hexane solution and irregular nanoparticles by ethyl acetate solution. The optimum operating conditions were found to be ethyl acetate as solvent in a defined pressure and temperature range.     

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.     

Preparation of Emodin‐Polyethylene Glycol Composite Microparticles Using a Supercritical Antisolvent Process

Emodin‐polyethylene glycol (PEG) composite microparticles were obtained from a dichloromethane‐methanol mixture via the solution‐enhanced dispersion by supercritical fluids through prefilming atomization (SEDS‐PA) process. Morphologies, particle sizes (PSs), and emodin contents of the composite microparticles were analyzed by scanning electron microscopy and UV‐visible spectrophotometry. The crystallinity change of emodin before and after the SEDS‐PA process was demonstrated by X‐ray powder diffraction (XRD). The composite microparticles present nubbly, rod‐like emodin dispersed in PEG or a nubbly, sheet emodin inlay on PEG, with PSs ranging between 3 and 12 μm. The PSs of the composite microparticles increase with the increase of temperature, decrease with the increase of pressure, and do not seem to depend on the emodin content of the initial solute and on the solution flow rate. The emodin contents of the composite microparticles increase with the increasing emodin content in the initial solute and temperature and decrease with increasing solution flow rate.