| Crystallization technology, as an efficient separation and purification technology, owns the merits of low energy cost, high fineness and seclectivity and is widely used, especially in the manufacturing process of the pharmaceuticals. Recently, it has made remarkable progress and received much recognition and attention. Solution crystallization is one of the most wildly used crystallization technology and also the main way for producing pharmaceuticals. The degree of supersaturation and the kind of solvent are the key factors in the solution crystallization process that seriously affect the crystal morphological indices, such as the morphology and particle size distribution, and then influence the physical and chemical properties and function of the crystal proucts. Unfortunately, most of us are lacking to recognize the importance of crystal morphology and the research does not establish the relation between crystal morphology, solute system and solvent environment. Computer molecular modeling owns the merits of fast calculation and low cost, which is an active field of research and developes fast. Now, molecular modeling and chemical experiment are equally important and keep pace with each other. Therefore, combining molecular dynamic simulation with force field and experimental preparation and characterization of crystals in different solvents to quantify the interaction between the solvent environment and the crystal growth interface, to construct the prediction model of real crystal habit based on the solvent effects, to build the qualitive and quantitative relation between solute system, solvent environment and crystal morohology, to direct the seclection of solvents for industrial crystallization and then understanding the crystallization behavior systermatically and key regulation mechanism during the crystal growth process, are of great significance both theoretically and economically.In this paper, based on the solution crystallization process, molecular modeling technology for the assistance, the study of the crystallization nucleation, crystal growth, morphology prediction and the growth mechanism of layered crystals for solute-solvent system was developed. The main contents of the full text are as follows:1. The supersaturation effect on the crystal growth was systermatically developed. Benzoic acid crystals were prepared in different supersaturations (0.67 kg/m3-3.2 kg/m3) by using natural cooling method. Crystal morphology was observed. The aspect ratio change of prepared crystals was measured according to the variation of supersaturation. Combinding PCFF force field and molecular dynamics simulation, the crystal habits of benzoic acid at different supersaturated aqueous solutions were predicted. The simulated results agreed well with the experimental results and we explained the evolution of crystal morphology and aspect ratio changes.2. The real crystal habit prediction model based on the solvent environment has been innovatively constructed and can be attached to the qualitative analysis of the effect of the solvent on the crystal structure, morphology and aspect ratio. Here, the dirithromycin (DIR) was seclected as the pharmaceutical model. According to the structures of different DIR solvates, the ideal crystal habit and modified crystal habit of DIR in different solvents were predicted by attachment energy (AE) model and modified attachment energy (MAE) model, respectively. The relation between solvates structure, ideal crystal habit and modified crystal habit was compared and analysised. In order to verify the correctness of the crystal habit prediction model, the slow solvent evaporation method was used to give the real crystal morphology in different solvents.3. The crystal habit prediction model and research methods were comprehensively promoted to achieve the quantitative regulation of crystal morphology. A small organic molecule drugs benzoic acid was selected as an object to study the solvent effect on the acid crystal morphology, crystal form and aspect ratio. Firstly, the solvent/solute interface interactions were calculated to give crystal morphology and aspect ratio of benzoic acid in different solvents by molecular dynamics simulation. The relationship between the aspect ratio and the property of different solvents, such as polar, dielectric constant, solubility, molecular weight, vapor pressure and evaporation rate, etc. was established. We further calculated the crystal habit of benzoic acid in nearly 20 kinds of solvents. The quantitative relationship between aspect ratio and solvent polarity, solvent relative molecular size was constructed. The computer simulation not only realized the secondary screening of crystallization solvent, thus saving the cost of the experiment, but also developed the nature of the law between the aspect ratios of solvent properties to quantitatively regulate the morphology of the crystals.4. The growth mechanism of layered crystals of organic compounds was studied. Multilayer structures of DIR drug particles, which have an extended hexagonal columnar morphology, size in the micron level, the number of layers in 3-15, were prepared by solvothermal method. The effects of solvothermal time on the layers of crystal morphology were developed. By growing a single crystal experiment, the crystal structure of DIR in DMF solvent was obtained. We calculated the different attachment configuration change in energy ΔE by COMPASS force field and molecular dynamics simulation. The result confirms that the oriented attachment tends to occur on the crystal plane (001). Binding experiments and simulations, the layered crystalline particles of organic compounds were first demonstrated and reported by oriented attachment growth mechanism. |
PDF Full Text Request