Study On Controlling Crystal And Particle Morphology Of Product In Solution Crystallization

Needle-like and flaky-like crystals usually cause problems in downstream processes due to low bulk density and poor dispersity.Solution crystallization process is very complex so that it is hard to optimize the morphology with empirical operation experiences.Aiming to control morphology and particle size,the thesis studies the effects of crystal structure,operating parameters and crystallization environment(solvents,additives)on nucleation,crystal growth and agglomeration.Gabapentin(GBP)is widely used as an antiepileptic drug.In general crystallization process,plate-like crystals are obtained resulting in poor quality of products.In this work,the solubility of GBP and ternary phase diagram were determined in alcohol-water mixtures.The solubility had extreme value and molecular dynamic simulations revealed that molecular association played a key role.The transition temperature and critical water activity were calculated and a relationship between them was established to estimate the relative stability of GBP anhydrate and hydrate.Rod-like crystals of GBP anhydrate can be obtained by controlling temperature and solvent composition.DL-methionine is an important feed additive.Most home-grown crystals are needles or elongated plates which the micrometric properties differ greatly from foreign products.In this study,high-throughput additive screening experiments had been carried out and four types of additives were selected.Five additives were found effective to modify crystal shape and increase bulk density.The study on cellulose derivatives showed that they could retard induction time and inhibit polymorphic transformation.Molecular simulations revealed that the additive can be selectively adsorbed onto crystals faces.The crystal growth rates of dl-methioine were determined.Cellulose derivatives could significantly inhibit the length growth rate so that the aspect ratio of crystals was decreased.In solution crystallization,spherical agglomeration method can be employed to enhace the production performance of needle-like crystals.Benzoic acid was selected as the model material.For in situ monitoring the antisolvent crystallization process,ATR-FTIR was used and calibration experiments of benzoic acid-ethanol-water mixtures were performed.A calibration model between solute concentration and infrared spectrum was built using multivariate calibration approaches.Then the effects of operating parameters on crystal habit and size of benzoic acid were investigated.It turns out that water content and size of seeds are crucial factors which enable to control the sphericity and compressiblity of agglomerated partilces.Lithium carbonate is available for therapeutic uses in treating mania and bipolar disorders.But the needles or plates prepared in solution crystallization are not in favor of tableting.Studies were performed on the influences of temperature,supersaturation and additives on nucleation,crystal growth and agglomeration.It was found that phosphates could strongly inhibit the nucleation of lithium carbonate and induce noncrystallographic branching leading to the formation of spherulites with core-shell structure.Two formation mechanisms were proposed to illustrate the stepwise evolution of core-shell spheres under different conditions.Based on the study,spherulites with different structure and particles size can be modified and preparation performance of products has been promoted.The thesis has carried out both theoretical and experimental researches,and the crystal morphology of four model materials has been significantly improved.It provides theoretical basis and technical support for optimizing particle morphology of related substances.