Ultrasound Intensified Solution Crystallization Process Of Small Organic Molecule And Mechanism Investigation

The study of ultrasound intensified solution crystallization process of small organic molecule has always been the focus of attention in the crystallization field around the world.Usually,most studies about sonocrystallization focused on improving the crystal product properties and enhancing the process-intensification effect.While,these studies lack exact mechanisms for the influence of ultrasound on the local solution chemistry,conformer transformation and molecular self-assembly,at the molecular level.This paper selected four kinds of organic small molecular crystallization systems to study the effect of ultrasound on the crystal nucleation,polymorph control,solventmediated polymorph transformation and crystal growth,to reveal the kinetics mechanism or molecular mechanism of ultrasonic effects on each crystallization process.Firstly,based on the classical nucleation theory,the nucleation kinetics of Lglutamic acid(LGA)influenced by ultrasound was investigated.The study measured the induction time and metastable zone data,and calculated the nucleation parameters using the Sangwal and Nyvlt metastable zone models.According to the analysis of nucleation parameters,the study revealed that the promoting effect of ultrasound on the LGA nucleation could be ascribed to the reduction of the minimum crystal nuclei size,and the decrease of the energy barrier for nucleation.The ultrasound-assisted quench crystallization realized the polymorph control of LGA.Secondly,based on the pre-nucleation cluster theory,this paper investigated the conformational polymorph nucleation of tolbutamide affected by ultrasound in the polar solvents,and the molecular mechanism.In ethanol,the ultrasound promoted the nucleation of the most stable form II at lower supersaturation,while,the nucleation of unstable form III was promoted at higher supersaturation.The tolbutamide polymorph was not changed in other solvents in the presence of ultrasound.The quantum chemistry computation predicted the possible types of aggregates in the solution by the energies calculated.Combining the spectroscopy analysis with molecular dynamics simulation,the conformational distribution and aggregates change in the solution were traced.Consequently,the paper inferred the way of ultrasound-affected the pre-nucleation clusters for tolbutamide,and further proposed a nucleation pathway for the conformational polymorphs affected by ultrasound.Subsequently,the enhancement of ultrasound on the solvent-mediated theophylline polymorph transformation was investigated.The ultrasound shortened the whole transformation time,including the nucleation period and reconstruction period of the stable crystals.Based on the difference of ultrasound-promoted nucleation efficiencies for various solvents,combined with the solute-solvent interaction energy calculated by the quantum chemistry computation,the molecular self-assembly nucleation pathway in the presence of ultrasound was proposed to explain the effect of ultrasound on the solute-solvent interaction during the nucleation process.The kinetics parameters of polymorph transformation were fitted by the Avrami-Erofeev model,and a method to change the polymorph transformation kinetics by ultrasonic was proposed.In addition,the theophylline form V,which was difficult to nucleate under conventional crystallization conditions,was steadily prepared by the ultrasound-assisted polymorph transformation process.Finally,the crystal habit of salicylamide modified by ultrasound and additives was investigated.According to the molecular dynamics simulation,the change of crystal habit was attributed to the different adsorption intensity and the movement behavior of additive molecules on the various crystal faces.Salicylamide crystals with smaller size were obtained with both ultrasound and additives(theophylline and PVP).The possible explaination was that more crystal nuclei were generated with the collapse of cavitation bubbles,and consuming the supersaturation used for crystal growth.Based on the above studies for the nucleation mechanism affected by ultrasound,the ultrasound could influence the molecular interactions.Thus,the ultrasound changed the movement behavior of PVP K15 molecules on the salicylamide crystal faces,affecting the growth of each crystal face,and resulting in a rectangular plate-like crystal.