Design Of Drug Particles Based On Oiling-out Crystallization

Oiling-out crystallization refers to a crystallization process where the solution splits into two liquid phases with different compositions,viscosities,densities,and other physical properties before crystal nucleation.The two liquid phases exist as a dispersed phase（oil droplets）and a continuous phase.Currently,several challenges,including unclear mechanism of oiling-out,the lack of prediction model of oiling-out and controlling mechanism of morphology characteristics and chemical components for drug particles,need to be solved for optimization of the pharmaceutical oiling-out crystallization process.In response to these problems,this thesis revealed the mechanism of oiling-out from the perspective of intermolecular interaction,and established the oiling-out prediction models based on machine learning.In addition,to guide the design of drug particle morphology and components,this work determined different oiling-out phase diagrams and summarized their determination methods.Firstly,this work analyzed the thermodynamic phase diagrams（binary phase diagram,ternary phase diagram,single-drug component system phase diagram,and dual-drug component system phase diagram）involved in oiling-out crystallization.The methods for determining the oiling-out thermodynamic phase diagrams were also summarized.An oiling-out mechanism based on isosteric adsorption heat was proposed from the aspect of molecular interaction,and a corresponding oiling-out prediction model was established.Machine Learning-based prediction models were developed using Big Data Analysis to build an oiling-out behavior prediction and screening model.To sum up,the prediction mechanisms of oiling-out were built both from the aspects of Isosteric Adsorption Heat Theory（Molecular Interaction）and Machine Learning（Big Data Analysis）.Secondly,based on the phase diagrams of（drug-solvent）or（drug-solvent₁-solvent₂）,morphology and the particle size distribution of crystalline product were successfully controlled in the oiling-out crystallization process.Furthermore,by introducing crystallization in the oil droplets formed in water solution,a highly efficient and green oiling-out spherical crystallization（OOSC）technique was developed.Particles with a high degree of sphericity,density,flowability,and tunable particle size distribution were obtained.By coupling crystallization and granulation,OOSC could significantly reduce the operation cost.Finally,according to the phase diagrams of（drug₁-drug₂-water）,an oiling-out spherical co-agglomeration（OOCA）technology was developed,eco-friendly and able to prepare spherical particles with tunable pharmaceuticals ingredients.OOCA technique can incorporate drugs with synergistic effects into the spherical particle,showing application prospect in combination drugs.Both co-oiling-out and single-oiling-out are capable of realizing OOCA,highly expanding the potential application of the OOCA technique in the pharmaceutical industry.In addition,based on isosteric adsorption heat and polarity theories,an effective screening strategy of（drug₁-drug₂-water）system applicable for OOCA technique was established via simulation and computation,which could significantly reduce the use of energy and resources in the screening process and improve the promotion efficiency of this technology substantially.