Understanding Crystal Cleavability and Physical Properties of Crystal Surfaces Using in Silico Simulation.

In the drug formulation process, compound dissolution rate and wettability may be improved by grinding. However, there is no method to understand the effects of the wettability of the crystal facets of the ground product. Here, acetylsalicylic acid (ASA) was used to evaluate the changes in crystal morphology and dissolution rate by jet milling using powder X-ray diffraction and in silico simulation. Several cleavage facets were observed in cube crystals, and the (0 0 2) facet was observed in plate crystals. Furthermore, the dissolution rate of the ground samples per unit area decreased with the cleavage of the (1 0 0) and (0 0 2) facets. The polar surface energy of the ground sample decreased with increasing grinding pressure. The simulation results showed that the absolute attachment energy of the (1 0 0) and (0 0 2) facets was lower than that of the other crystal facets. Moreover, atoms with low polarity were present on the crystal surface of (0 0 2). The wettability and dissolution rate of the (0 0 2) facet were worse than those of the (1 0 0) facet. It was suggested that the dissolution rate of the ground sample was affected by the wettability of the crystal facet caused by the cleavage. The cleavability and wettability may be understood by simulation.

[Prediction of the Crystal Growth Mechanism of Aspirin Using Molecular Simulations].

Controlling the physicochemical properties of a drug formulation is important for proper drug efficacy, since in the gastrointestinal tract many drugs undergo dissolution, limiting their efficacy. Factors affecting a drug's physicochemical properties include its crystal habit. Therefore, we predicted the crystal habit by molecular simulation for the purpose of controlling crystal morphology. In this study, we used aspirin as a model compound. By performing simulations based on known crystal structure data, we trained the simulation algorithm to produce the cubic and plate-like morphologies of crystals actually obtained. By these methods, we showed that the crystal plane of the crystal form actually obtained coincides with the characteristic crystal plane obtained by simulation. Furthermore, to consider the influence of the crystallization solvent on crystal growth, we simulated adsorption of solvent molecules on characteristic crystal planes. The difference in adsorption energy of the solvent molecules prevents the aspirin molecules from attaching to the crystal plane. As a result, we concluded that the crystal habit was caused by the difference in growth rate of the crystal plane. By applying the methods developed in this research, the growth of crystal planes can be predicted by molecular simulation, making it possible to efficiently obtain crystal forms with optimal physical properties for drug development. We believe that further development of this approach will lead to dramatic decreases in the cost and duration of drug development.