Preparation Of Drug Particles Via The Process Of Rapid Expansion Of Supercritical Fluid And Its CFD Simulation

Over the past few decades,supercritical fluid?SCF?technology has been widely used in the preparation of drug particles.The SCF technology can effectively overcome the disadvantages of using organic solvents,product degradation and wide particle size distribution in traditional particle formation methods.The rapid expansion process of supercritical solution?RESS?is one of the simplest and effective methods among the variety of SCF technologies for drug micronization.The technology of RESS has the following advantages:simple equipment,mild operation condition,controllable product size and narrow particle size distribution and avoiding degradation and so on.The main parameter indispensable for the successful design of supercritical fluid-based techniques is the solubility data of substances in different operating conditions.The measurement of the solubility is an important research part in particle preparation by RESS.Ethosuximide,as a kind of succinimide anticonvulsant was chosen as the model drug in this study.A simple static method by determining the cloud point pressure was employed to measure the solubility of ethosuximide in supercritical carbon dioxide?SC-CO₂?at various temperatures T/K=?313.15,318.15,323.15 and 328.15?and in pressures P/MPa=?9-15?.The experimental results generally revealed that the solubility of ethosuximide in SC-CO₂increases with the enhancing pressure when the temperature was kept constant.On the contrary,the solubility decreases with the increasing temperature at constant pressure.Moreover,the measured solubility data were successfully correlated by four semi-empirical models including Chrastil,Bartle et al.,Kumar and Johnston?K-J?and Mendez-Santiago-Teja?MST?.The results of this study provide the effective fundamental for the probable processes based on SC-CO₂.Experimental study on the RESS process of has been conducted for more than 20 years,however,numerical simulation,as a good complementary tool can enhance the analysis and understanding of the fluid flow,thus to optimize the experimental process.Therefore,a two-dimensional model was established and the software FLUENT was used to simulate the flow field of the RESS process.The characteristics of the flow field were analyzed and the influence of inlet temperature and inlet pressure were investigated.The results show that the pressure drops below the supercritical state before the nozzle exit,so the nucleation of the solute completed before reaching the nozzle exit.In addition,the lower inlet temperature and higher inlet pressure correspond to a higher density drop,so the solute will reach a higher degree of supersaturation during the SC-CO₂ expansion process,which is conducive to the formation of smaller particles.In addition,RESS experiments were conducted to study the micronization of ethosuximide.Effects of three operating parameters including the extraction pressure,extraction temperature and post-expansion temperature on the particle size and morphology of ethosuximide were explored and discussed.The experimental results showed that the size and morphology of ethosuximide particles processed by the RESS process were much better than that of raw materials.The decreasing extraction temperature,increasing extraction pressure will reduce the particle size.However,the increase of post-expansion temperature not only causes particle size increase,but also aggravates the agglomeration of particles.An optimal RESS process condition was determined as the extraction temperature of 313.15 K,extraction pressure of 25 MPa,and post-expansion temperature of 273.15 K.The minimum particle size of 1.89?m was obtained under the optimal condition.The experimental results successfully verified the simulated flow field of the RESS process and the study of single-phase nucleation thermodynamics in the supercritical fluid.