Insights into Pharmaceutical Nanocrystal Dissolution: A Molecular Dynamics Simulation Study on Aspirin

Abstract

The presented molecular dynamics simulations are the first simulations to reveal dynamic dissolution of a pharmaceutical crystal in its experimentally determined shape. Continuous dissolution at constant undersaturation of the surrounding medium is ensured by introducing a plane of sticky dummy atoms into the water slab. These atoms have a strong interaction potential with dissolved aspirin molecules, but interactions with water are excluded from the calculations. Thus, the number of aspirin molecules diffusing freely in solution is kept at a low value and continuous dissolution of the aspirin crystal is monitored. Further insight into face-specific dissolution is drawn. The dissolution mechanism of receding edges is found for the (001) plane. These findings are in good agreement with experimental results. While the proposed dissolution mechanism for the (100) plane is terrace sinking on a rough surface, no pronounced dissolution of the perfectly flat face is seen in the present work. Molecular simulations of pharmaceuticals in their experimentally obtained structure therefore have shown to be especially suited for the investigation of dissolving faces, where the edges have a pronounced effect. In contrast to previous studies a propagation of the dissolution front into the crystal face is reported, and the crystal bulk is stable over the whole simulation time of 150 ns.

In Silico Prediction of Growth and Dissolution Rates for Organic Molecular Crystals: A Multiscale Approach

“…Pronounced differences were observed in the face-specific dissolution behavior. A dissolution mechanism via receding edges was found for the (001) plane, which is in good agreement with experimental results [40,50]. However, while the proposed dissolution mechanism for the (100) plane is terrace sinking on a rough surface, no pronounced dissolution of the perfectly flat face was seen.…”

“…The distance threshold and the orientation tolerance parameters, characterizing maximal deviations from the reference crystal molecular positions and orientations, have also proven to be appropriate indicators of a correct representation of the crystal-water interfaces by the force fields [49]. The consideration of all of these aspects led us to the choice of the Merck molecular force field for the simulation of aspirin crystal dissolution in our further works [40,50].…”

“…We overcame these limitations with MD simulations of an entire aspirin nanocrystal in its experimentally determined shape revealing the (100), (001), (011) and (110) faces, cf. Figure 2a [40,50]. It was cut from a pre-equilibrated supercell (310 K and ambient pressure of 1 bar) using the VMD [100] program.…”

“…A simple approach to simulate crystal dissolution at constant undersaturation of the surrounding medium at comparably low computational cost was devised and demonstrated by our group [50]. In our MD simulations of aspirin nanocrystal dissolution [40,50], we proposed to use virtual atoms (sticky dummy atoms), which have a strong interaction potential with dissolved aspirin molecules, whereas interactions with water are excluded.…”

“…Figure 1 presents a multiscale protocol, elaborated based on our previously published studies and findings [40,[49][50][51][52].…”