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Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was used to prepare micrometric particles of a labile protein, i.e. , trypsin from aqueous solution without use of any organic solvents. The trypsin particles precipitated had various morphologies under different process conditions, with particle diameters ranging from 0.2 to 4 μm. FTIR, SDS-PAGE, CD and fluorescence spectra were performed to analyze the structural stability of the protein, and trypsin retained above 70% of the biological activity. Besides, chitosan was selected as the polymer carrier in an effort to prepare trypsin composite microparticles via SAA-HCM process. The influences of chitosan molecular weight, polymer/protein ratio and solution concentration on the particle morphology and size distribution were investigated in detail. Non-coalescing spherical composite microparticles with a narrow particle distribution (0.2–3 μm) could be obtained. The SAA-HCM prepared particles were amorphous as demonstrated by XRD and had a loading efficiency about 90%. The protein release profiles of the composite microparticles were evaluated using both the immersion condition and a Franz diffusion cell. Finally, the distribution of the protein within the particles was characterized through CLSM analysis of FITC-labeled trypsin-loaded chitosan microparticles. The SAA-HCM process is demonstrated to be a protein-friendly and promising technique for production of protein and polymer/protein composite particles formulations from aqueous solutions for drug delivery systems. [ABSTRACT FROM AUTHOR]

Abstract: The data of the liquid volume expansion could normally be used as one of the thermodynamic criteria to decide an appropriate process of supercritical fluid based micronization techniques. The liquid volume expansion data were predicted by the vapor–liquid phase equilibrium calculation of two binary systems (CO2/acetone and CO2/ethanol) using Peng–Robinson equation of state. The results indicated that the liquid volume expansion of CO2/acetone mixtures was much larger than that of CO2/ethanol mixtures at the specified temperature and pressure. According to the thermodynamic criterion, acetone was affirmed to be a good solvent for supercritical antisolvent process (SAS) due to the higher liquid volume expansion, while ethanol was suitable for supercritical assisted atomization (SAA). This thermodynamic criterion was applied to the micronization of cholesterol and spherical particles were prepared in various organic solvents by SAA with an enhanced mixer. When the liquid volume expansion was lower than 80%, SAA could be successfully conducted and the good morphology and size distribution of the cholesterol particles were obtained. If the liquid volume expansion was higher than 140%, the solute would precipitate in the mixer before the atomization leading to the blockage of nozzle due to the antisolvent effect. In that case, the cholesterol particles in the mixer maintained the same morphology and crystalline structure as the SAS processed. This criterion is a practical and accessible tool to successfully implement the SAA process avoiding undesirable precipitation in the mixer. [Copyright &y& Elsevier]

Abstract: Supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM) was used to produce lysozyme microparticles with controlled particle size distribution in the range for aerosol drug delivery. The process is based on the atomization effect of carbon dioxide. The solubilization of certain amount of carbon dioxide in the solution plays the key role and the HCM can intensify mass transfer between carbon dioxide and liquid feedstock greatly. Water was used as the solvent to solubilize lysozyme and thus no organic residual was detected. The influences of process parameters on particle formation were investigated including temperature in the precipitator, pressure and temperature in the mixer, concentration of the solution and feed ratio CO2/solution. The particles were characterized with respect to their morphologies and particle size: well defined, spherical and separated particles with diameters ranging between 0.2 and 5μm could be always produced at optimum operating conditions. Bio-activity assay showed that good activity maintenance of higher than 85% for lysozyme was usually achieved. Solid state characterizations were further performed to investigate the changes of lysozyme in the process. Fourier transform infrared spectroscopy indicated that no change in secondary structure had occurred for processed lysozyme. X-ray diffraction analysis showed that the lysozyme particles produced remained similarly amorphous as the raw material. Differential scanning calorimetry and thermogravimetry analysis revealed that there was no significant difference in water association but with the increase of water content after processing. [Copyright &y& Elsevier]

Abstract: Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was used to prepare bovine serum albumin (BSA) microparticles. Water was used as the sole solvent. A hydrodynamic cavitation mixer was applied to improve mass transfer and achieve a continuous near-thermodynamic-equilibrium solubilization of SC-CO2 in the liquid solution. Under the different conditions, the prepared BSA microparticles had various morphologies, such as corrugated particles, smooth hollow spherical particles and cup particles, with particle diameters ranging from 0.3 to 5μm. The microparticle formation process was elucidated with the shell formation and central bubble mechanism. Compared to native BSA, BSA microparticles did not show significant change in primary structure, according to the results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The secondary structure of BSA was characterized by Fourier transform infrared spectroscopy (FT-IR). No new peaks were observed after SAA-HCM processing. In addition, the crystalline structure of the BSA microparticles was demonstrated to be amorphous because of the sudden supersaturation in the precipitation process. The SAA-HCM process is expected to be a promising technique for producing microparticles suitable for pulmonary delivery of therapeutic macromolecules. [ABSTRACT FROM AUTHOR]

Abstract: A novel micronization technique so-called supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM) was used to produce the sodium cellulose sulfate (NaCS) microparticles with well-defined spherical morphologies and controlled particle size distributions in aqueous solution. The process parameters such as mixer temperature and pressure, the mass flow ratio, precipitator temperature, solution concentration and the molecular weight of NaCS were investigated in detail to evaluate their influences on the morphologies and size distributions of precipitates. Spherical NaCS particles with mean diameters ranging from 0.3 to 3.0μm were produced at the optimum operating conditions and narrow particle size distributions were obtained. It is natural to put forward the particle formation mechanism of deflated balloons. Compared with the unprocessed NaCS, there was no significant change on the primary structure and stability of the NaCS processed by SAA-HCM verified by Fourier transform infrared spectroscopy. The X-ray diffraction and thermo-gravimetric analysis were also used to investigate NaCS modifications and a slight change in crystalline state with higher thermal stability was observed when treated by SAA-HCM process. The results indicated that NaCS micronization by SAA-HCM process was expected to be a promising technique for drug delivery system. [Copyright &y& Elsevier]

Abstract: A hydrodynamic cavitation mixer (HCM) was introduced in the supercritical fluid assisted atomization (SAA) process to improve mass transfer. SAA-HCM resulted in a more homogenous primary droplet and, as a consequence, narrower particle size distributions. Levofloxacin hydrochloride (LH) being selected as a model drug, the effects of cavitation generator on morphology, size, and distribution of precipitated particles were evaluated. In addition, the influences of several process parameters, such as the feed ratio between CO2 and liquid solution, solute concentration, etc., were investigated in detail. Spherical amorphous micron-sized particles were obtained at different CO2-solution feed ratio and solute concentrations. In all cases, particles with diameters smaller than 2.1μm were produced. The SAA-HCM is expected to be a promising technique for producing microparticles suitable for pulmonary delivery in drug delivery applications. [Copyright &y& Elsevier]

Graphical abstract Abstract Chemotherapeutics are used extensively in cancer and encapsulating the drug in nanoparticles is an effective method to enhance therapeutic efficacy and reduce side effect. In this work, DOX-loaded chitosan nanoparticles were prepared using supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) from aqueous solution. The influences of solution concentration, CO 2 /solution ratio, mixer pressure, chitosan/DOX ratio and chitosan molecular weight on particle morphologies and sizes were investigated in detail. Well defined spherical nanoparticles with average diameter ranging from 120 nm to 250 nm were obtained, and the loading efficiency was up to 90%. FT-IR result showed that the structure of DOX was not changed after the SAA-HCM process. Zeta potential of the nanoparticles was about +50 mV. The in vitro drug release behavior conducted in the media with pH of 4.5, 6.5 and 7.4 respectively showed strongly pH responsive. In vitro cytotoxicity profiles revealed that the activity of DOX was well maintained after loaded into chitosan nanoparticles. The SAA-HCM process was demonstrated to be a promising technique for one-step production of polymer/drug composite nanoparticles suitable for cancer drug delivery from aqueous solution. [ABSTRACT FROM AUTHOR]

Parathyroid hormone (PTH1–34)-loaded dry powders were fabricated from aqueous solution for pulmonary administration using supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM). Herein, chitosan oligosaccharide (CSO) was selected as a carrier in an effort to enhance transmucosal absorption of the drug. Well-defined, separated and spherical PTH(1–34)/CSO composite microparticles were obtained, and the particles size could be well controlled with narrow distribution. Aerodynamic performance was determined using next generation impactor (NGI), and the mass median aerodynamic diameter (MMAD) ranged strictly 1–5 μm range with fine particle fraction (FPF) up to 63.51%. The structural integrity of coprecipitated PTH(1–34) was validated by HPLC, FT-IR and circular dichroism, and a high loading efficiency up to 92.8% was obtained. TGA analyses revealed its thermal stability was preserved and XRD patterns showed amorphous structure of particles. The SAA-HCM process is proposed as a green technique for preparation of inhalable protein/polymer composite dry powders without use of any organic solvents. [ABSTRACT FROM AUTHOR]

Abstract: Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA–HCM) was used to micronize insulin from aqueous solution without use of any organic solvents. Insulin microparticles produced under different operating conditions including solution type, solution concentration and precipitator temperature presented distinct morphologies such as highly folded, partly deflated, corrugated or smooth hollow spherical shape. Solution concentration had a striking influence on particle size, and insulin microparticles produced from acidic solution had mean diameters increasing from 1.4μm to 2.7μm when protein concentration increased from 3g/L to 50g/L. HPLC chromatograms showed no degradation of insulin after SAA–HCM processing and FTIR, CD and fluorescence data further confirmed the structural stability. TGA analysis revealed that insulin microparticles remained moderate moisture content compared with raw material. In vivo study showed that insulin processed by SAA–HCM from acidic solution retained identical bioactivity. SAA–HCM is demonstrated to be a very promising process for insulin inhaled formulation development. [Copyright &y& Elsevier]

Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was proposed as a green technique to fabricate insulin-loaded dry powders for inhalation administration. N -trimethyl chitosan (TMC), a polymeric mucoadhesive absorption enhancer, was synthesized and successfully micronized from aqueous solution using SAA-HCM. The prepared well-defined spherical TMC microparticles with preserved structure and thermal stability were potential carriers for delivery of proteins. Then, insulin-loaded TMC microparticles with high loading efficiency were coprecipitated from aqueous solutions using SAA-HCM without use of any organic solvents. The polymer/protein ratio revealed to be a factor influencing the particle morphology, and non-coalescing composite microparticles in amorphous state mainly ranging from 1 μm to 5 μm could be obtained in this work. Aerodynamic properties were assessed by next generation impactor (NGI) and the mass median aerodynamic diameter (MMAD) lied inside the inhalable range of 1–5 μm, while fine particle fraction (FPF) reached above 60%. The structural integrity of encapsulated insulin was confirmed by HPLC, circular dichroism and fluorescence spectroscopy. In vivo study demonstrated that TMC could enhance the absorption and bioavailability of the pulmonarily administered insulin formulation for SD rats. These results suggest that TMC microparticles could be efficiently prepared as a promising vehicle for drug delivery, and SAA-HCM is a promising technique to prepare inhalable polymer/protein composite dry powders. [ABSTRACT FROM AUTHOR]

Abstract: Supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM) was used to prepare chitosan microparticles with the well-defined spherical morphology and the controlled particle size distribution as a promising carrier for drug delivery system. Chitosan with different molecular weights (3kDa, 50kDa, 300kDa) was successfully micronized, in which water was used as the solvent for 3kDa chitosan, while 1.0% (v/v) acetic acid aqueous solution was used for 50kDa and 300kDa chitosan, respectively. The process parameters including operating pressure and temperature in the mixer, mass flow ratio of CO2/solution, precipitator temperature and solution concentration were explored to evaluate their influences on the morphologies and size distributions of precipitated particles. Results showed that particle size tailoring (ranging between 0.2 and 5μm) could be achieved through modulation of the process parameters. After processing by SAA-HCM, Fourier transform infrared spectroscopy did not indicate significant change in the main structure of chitosan microparticles. Compared with raw materials, a decrease in crystallinity and thermal stability was observed for the SAA-HCM processed chitosan microparticles, as demonstrated by X-ray diffraction, thermogravimetric analysis and differential scanning calorimetry. [Copyright &y& Elsevier]

Highlights: [•] Separated and spherical chitosan oligomers microparticles were produced from water. [•] Particle size could be tailored and distribution was narrow in the range of 0.5–3μm. [•] FTIR, TGA and DSC results confirmed chitosan oligomers molecular structure stability. [•] Mass median aerodynamic particle size ranged inside 1–2μm suitable for inhalation. [ABSTRACT FROM AUTHOR]