Theoretical Study On Crystal Structure Prediction Of Polymorph Drug

Since the structure of crystal determines its main physical and chemical properties, information of crystal structure is essential for the crystallization process. On the one hand, the growth morphology of crystal can reflect its internal structure, thus correct crystal structure is the premise of crystal morphology prediction. On the other hand, the prediction all polymorphs that may arise made it possible for us to generate the specified crystal form. These two aspects are very helpful for crystallization process, and so for QSAR identify, molecular design and process control.Ribavirin is a first-line antiretroviral therapy chemical drug, clinically used it for treatment of disease caused by virus infection, such as viral pneumonia, bronchitis, skin herpes and so on. Ribavirin crystals have four different polymorph, which are A-form, B-form, C-form and D-form. In industry, the A-form crystal of ribavirin is the advantage polymorph form. This article studied the thermodynamic properties of A-ribavirin and the conversion between A-ribavirin and B-ribavirin based on the previous work.1. Determined the solubility of ribavirin (mixed crystal) in six pure solvents (formic acid, DMSO, water, ethanol, n-propanol, acetone) and two binary mixture solvents (acetone+water and n-propanol+water). Then predicted their thermodynamic properties by model fitting. The results show that:(1) The solubility order in pure solvents is formic acid> DMSO> water> ethanol> n-propanol> acetone. For binary mixture solvents, the solubility data approached to the maximum value when water proportion increased approximately to xwater= 0.93. (2) The best model for pure solvents and mixture solvents are modified Apelblat equation and Wilson model, respectively. (3) The mixing properties in pure solvents were predicted on basis of Wilson model parameters. Thermodynamic functions of all solution were obtained from the van’t Hoff equation.2. Prepared A-ribavirin, B-ribavirin and explored the conversion between the two crystal forms. The results show:(1) A-ribavirin was obtained by recrystallization in methanol, while B-ribavirin was made by dilution crystallization with DMF as solvent and acetone as eluted agent. (2) Studied the conversion between the two crystal forms by DSC and XRD.3. Studied the solubility of A-ribavirin in the same solvents with chapter 1. Then predicted their thermodynamic properties by model fitting. The results show that:(1) The solubility characteristic of A-ribavirin in all solvents are the same as that of ribavirin, so as well the model fitting results and thermodynamic properties. (2) The solubility of A-ribavirin was less than that of ribavirin in various solvents.