Study On Solvent Environment Manipulating Ibuprofen As A Model Medicine Crystal Growth Mechanism Based On The Molecular Level

Crystallization is widely used in production of the drug active component and their intermediates. Crystal morphology prediction and crystal preparation have become more and more research focus for the scientific research workers.The kind of solvent and additive concentration are the key factors in the solution crystallization process that seriously affect the crystal morphological indices, such as the morphology, particle size distribution and crystal structure,and then influence the properties of the medicine, such as solubility,dissolution rate, flowability, physical and chemical stability and bioavailability.Therefore, in the medicine research and production process, we can obtain the specific crystal form, prevent effective morphology transformation and inhibit the growth of other polymorphism by controlling the solvents, additives and other external conditions.In this paper, the ibuprofen was selected as the pharmaceutical model.Combining experimental preparation with molecular simulation technology,we mainly studied the crystal growth process of ibuprofen, explored the effect of solvents and additives as key factors on the crystal morphological and predicted ibuprofen crystal structure and morphology. The main contents of the full text are as follows:1. We construct a more complete process from molecule to crystal structure to morphology prediction. The optimized structure of ibuprofen molecule was used as the starting points to accurately predict the crystal structure. Based on this crystal structure, we studied the solvent effect on the ibuprofen crystal. Modified crystal habits of ibuprofen in different solvents were predicted by modified attachment energy (MAE) model. Compared with experiment research, we verified the correctness of this prediction model.2. The solvent effect on the ibuprofen crystal morphology, aspect ratio,size distribution and crystal structure was systematically developed. We chose 18 solvent compounds to observe solvent effect on the ibuprofen crystal growth. The relationship between ibuprofen main aspect ratio and solvent relative polarity has been attached to the quantitative analysis. In order to explain the solvent molecule effect on crystal surfaces growth and crystal morphology, we performed the adsorption calculation which could explore the likely binding site and adsorption energy of solvent molecule at the main exposed crystal surfaces.3. The additive effect on the ibuprofen crystal morphology, aspect ratio and crystal structure was analyzed. We chose 14 kinds of benzoic acid additive concentration to observe additive effect on the ibuprofen crystal growth. The relationship between ibuprofen main aspect ratio and benzoic acid additive concentration has been attached to the quantitative analysis. In order to explain the additive molecule effect on crystal surfaces growth and crystal morphology, we performed the adsorption calculation which could explore the likely binding site and adsorption energy of benzoic acid molecule at the main exposed crystal surfaces. The real crystal habit prediction model based on the additive environment has been innovatively constructed. The simulated results agreed well with the experimental results. Therefore, we verified the correctness of this prediction model.This work provides a useful approach to explain the crystal growth mechanism and analyze the effect of solvent environment on the crystal morphology. And the constructed model may guide the solvent selection of pharmaceutical crystallization and computer-aid design of the desirable crystal morphology.