Supercritical Fluid Assisted Atomization Introduced By Hydrodynamic Cavitation Mixer (SAA-HCM) For Microparticles Preparation

Micron-particle and sub-micron-particle materials have been widely applied to chemical and its associated industry including catalyst,dope,fuel,dye and superconductive material,especially in pharmaceutical industry.The third form called 'controlled release' and the fourth form called 'target drag' are being the interesting field as a necessary way for drug delivery.The conventional methods for producing fine powders include spray drying,jet and ball milling and recrystallization using solvent evaporation or liquid anti-solvent;however,all of them have in common the disadvantage of poor control of particle size(PS)and particle size distribution(PSD).To solve these problems,an alternative efficient process named supercritical fluid assisted atomization(SAA)that uses supercritical fluids(SCF)as a green medium for the production of micro- and nano-sized particles was proposed.In this work,a novel design mixer,i.e.,hydrodynamic cavitation mixer was introduced into SAA.The supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer(SAA-HCM)process was established and successfully implemented on pharmaceutical compounds,polymers and microcapsules with controlled PSD.Firstly,the SAA-HCM process was successfully developed.In view of the development of supercritical fluid based micronization,it is known that the mixing between CO₂ and liquid solution is the key step in the SAA process.Cavitation may be defined as the rapid expansion and collapse of bubbles or voids within a liquid medium,which disrupts the phase boundary,leading to intensified mixing or reaction of the system.In this paper,a novel design mixer,i.e.,hydrodynamic cavitation mixer was introduce in SAA to improve mass transfer.This SAA-HCM process consists of three feed lines for supercritical CO₂,the solution and hot N₂,respectively,as well as three vessels:mixer,precipitator,and condenser.And this experimental apparatus allowed the dependable controlling of all process variables including the mixer pressure and temperature,CO₂-solution feed ratio,solute concentrations and precipitation chamber temperature etc.The exitences of hydrodynamic cavitation were proved by the concentration change of methylene blue solution which were treat with the hydrodynamic cavitation both in presence of and in absence of cavitation generator,separately.And the effects of hydrodynamic cavitation mixer were further confirmed by the microparticle characteristic produced by SAA-HCM both with and without cavitation generator,separately.Then,roxithromycin(RXM)and levofloxacin hydrochloride(LH)being selected as model drugs,the effects of cavitation generator on morphology,size and distribution of precipitated particles were evaluated in the newly established SAA-HCM procsss.In addition,the influences of several process parameters including the feed ratio between CO₂ and liquid solution,solute concentration etc, were investigated in detail.The results indicated that spherical amorphous micron-sized particles suitable for pulmonary delivery were obtained at experimental conditions when the cavitation generator was fixed in the mixer.The cavitation generator extended the residence time of the mixture as well as improved the mass transfer between the solution and CO₂,which resulted in an intense mixing and formed a homogenous mixture.The PS and PSD of microparticles were greatly influenced by operating parameters No degradation occurred to RXM and LH illustrated by the comparison of the HPLC traces of processed and raw materials.Additional,the effects of several process parameters including the feed ratio between CO₂ and liquid solution,solute concentration,precipitator temperature and mixer pressure were investigated in detail to evaluate the influences on morphology and size of precipitated particles of poly lactic acid(PLA).Furthermore,the PLA/dichloromethane/RXM/CO₂ being selected as a model system,in which RXM was encapsulated in PLA microspheres by using the SAA-HCM process.The effects of several process parameters including the feed ratio between CO₂ and liquid solution,solute concentration,PLA concentration and mixer pressure were investigated in detail to evaluate their influences on morphology, precipitated particles size,RXM loading and release behavior.The results indicated that noncoalescing spherical microparticles have been produced,which was confirmed by scanning electron microscopy(SEM)analysis,setting the precipitator temperature at 50⁰C.A decrease in the mean particle size was observed with the increase of both R and mixer pressure,but the mean particle size remained nearly constant when R ranging from 1.4 to 1.8.The loading,the entrapment efficiency and the release rate were all increased with the increase of both R and mixer pressure.As the PLA composition in solution increased,the mean particle size and the entrapment efficiency increased,but the loading efficiency and the release rate were contrarily decreased.The results also indicated that the loading efficiency,the entrapment efficiency and the release rate decreased,but the mean particle size was increased, when the roxithromycin concentration in solution increased.To understand the SAA-HCM process mechanism,naphthalene and cholesterol being selected as model drugs,the relationship between the binary solvent-CO₂ system or the ternary phase equilibria available and the microparticles characteristics were studied,depending on the principle of SAA or SAA-HCM process.The results indicated that the data of binary solvent-CO₂ system are very important for operation parameters selection,and the CO₂ content achieving equilibrium is the key factor to determine process parameters.On the basis of the ternary solvent-solute-CO₂ phase equilibria calculated using Peng-Robinson equation,the process parameters were determined and spherical amorphous micron-sized naphthalene particles suitable for pulmonary delivery were obtained.Meanwhile the mole fraction of the solid solute in the ternary CO₂/cholesterol/acetone or ethanol liquid mixture was caculated,which is proportional to the partial molar volume fraction(PMVF)of the solvent..Taking into account of the high CO₂ content,the micron-sized cholesterol particles were obtained by the selection of the optimum operation parameters for the SAA-HCM process,and the solute precipitation in the mixer was avoided.Finally,the relationship of the bubble or cloud pressure and the system parameters such as temperature,CO₂ content,solvent content was studied using the statistical association fluid theory,called perturbed chain-SAFT(PC-SAFT)and good results were obtained.The results in the present work would be helpful for scaling up the SAA or SAA-HCM process,and useful for the optimization of operation conditions and process design in microparticles production.