| The development of new drugs is suffering from the poor water solubility of insoluble drugs.How to improve the solubility of poorly soluble drugs and thus their bioavailability has become a huge challenge.It is well known that solvents play a decisive role in the pharmaceutical industry.Besides,solvents are frequently used in most strategies(such as salt formation,solid dispersions,etc.)to enhance the solubility of poorly soluble drugs.As been reported that it is the key to understand the exact interactions between drugs and solvents for identifying optimal solvents.However,there is no clear explanation for the huge difference in the solubility of drugs in water and organic solvents as well for the exact influence of temperature and solvent composition on the interaction between drugs and solvents,which has been a lack of systematic research so far.Therefore,molecular dynamics(MD)simulations are employed to systematically investigate the interactions of poorly soluble ibuprofen with water,organic solvents and ethanol-water mixtures as well as the solubility differences in these solvents.This thesis is organized as follows:(1)MD simulations are employed to address the temperature effects on the solvation of ibuprofen in water with temperature ranging from 298.15 K to 333.15 K.The results demonstrate that the formation of aggregates of ibuprofen in water is mainly related to the strong self-associated hydrogen bonds(HBs)between ibuprofen molecules.The increase in temperature has little influence on the structures of ibuprofen-ibuprofen HBs while weakens the strength of these HBs leading to a higher diffusion rate,which is favorable for the ibuprofen solubility in water.It is consistent with the changing trend of experimental solubility of ibuprofen.(2)MD simulations are used to study the solvation structure and interaction mechanism of ibuprofen in different organic solvents(methanol,ethanol,1-propanol,acetone)in order to reveal the impact of the solvent structure on ibuprofen-solvent interaction.The results show that the van der Waals interactions and hydrogen bond interactions between ibuprofen and solvents have an important effect on the solubility of ibuprofen,and their synergistic effect is beneficial to the dissolution of ibuprofen.The number of hydrogen bonds between ibuprofen and acetone is the smallest,but their strength is the strongest;the structures of the hydrogen bonds between ibuprofen and the other three alcohol solvents are little affected by the length of the alkyl chain,and the hydrogen bond strength increases with as the alkyl chain grows.(3)MD simulations are used to explore the solvation structure and interactions of ibuprofen in ethanol-water mixtures.The effect of the amount of water on the ibuprofen-solvent interactions is investigated.It is found that as the amount of water increases,ibuprofen tends to self-associate and the interactions between ibuprofen and the solvent is weakened,resulting in the lower solubility of ibuprofen in ethanol-water mixtures.Ibuprofen is preferentially solvated by ethanol through hydrogen bonding interactions.Increase in the amount of water will weaken the strength of hydrogen bonds and also change the hydrogen bond structure.The diffusion coefficient of solvent molecules shows a strong dependence on the amount of water.Therefore,the interactions of poorly soluble ibuprofen with water,organic solvents and ethanol-water mixtures as well as the solubility differences in these solvents has been systematically investigated at the molecular level by considering the influence of temperature,solvent structures,and the solvent composition,respectively.This work is expected to provide theoretical support for the solvent screening in the formulation preparation of poorly soluble drugs. |
