Exploring the solvent effect on risperidone (form I) crystal morphology: A combination of molecular dynamics simulation and experimental study

The solvent effect significantly influences the morphology of a substance crystallized from the solution. It is crucial to select appropriate solvent systems to produce active pharmaceutical ingredients (API) with ideal crystal habits. In this work, the effect of different solvent systems on the crystal morphology of risperidone (form I) was investigated by combining molecular dynamics (MD) simulation with experi-mental studies. The crystals of risperidone (form I) were obtained from solvents via a method of slow -cooling crystallization. The modified attachment energy (MAE) model was used to predict the crystal habits of risperidone (form I) in six pure solvent systems (methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate and acetone) and three binary solvent systems (ethanol + water, 2-propanol + water and acetone + water). It turns out that the MAE model has good applicability in predicting the crystal habits of risperidone (form I) in the solvents. In addition, the structure of the dominant crystal faces was ana-lyzed to explain the solvent effect on the crystal morphology. It is found that the vast u-shape structures on the (11-1) and (011) faces can prevent the adsorption of the solute molecules, resulting in the large morphological importance of these two crystal faces. Besides, the analysis of the radial distribution func-tion (RDF) and mean square displacement (MSD) were conducted to help understand the interactions between solvents and crystal faces. The results show that the interactions between crystal faces and sol-vents are composed of three types of forces, and the rapid diffusion of the solvent molecules on the (11- 1) and (011) face can lead to strong interactions. (c) 2023 Elsevier B.V. All rights reserved.