Automated In Silico Energy Mapping of Facet-Specific Interparticle Interactions

Abstract

Particle–particle interactions impact the processability and performance of drug products. Faceted particulates exhibit distinct surface chemistries that affect their adhesion, causing downstream processing challenges such as poor flow, punch sticking, and compaction. Currently, there is a lack of tools to assist formulators in predicting these challenges based on particle properties. Here, we present a methodology for navigating the energy landscape of interparticle interactions. We used molecular mechanics to calculate the interactions between slabs of molecules representing distinct facets. The workflow enables a rapid assessment of the total energy landscape between interacting particles, providing insight into the effects of different surface chemistries and molecular topologies. Previously, the strongest interaction (lowest energy) was used to calculate the propensity to adhere, but we demonstrate that this does not always predict an accurate description of the likely surface interactions. We chose paracetamol to demonstrate the application of this methodology. The most cohesive facets were (101) and (10-1). Comparing surface interactions between particles allows a ranking of the most energetically compatible surfaces. The significance of this ranking and understanding how surface chemistry can impact interparticle interactions is a step toward assisting formulation decisions and improvements in product performance.

Relating Crystal Structure to Surface Properties: A Study on Quercetin Solid Forms

“…Although the use of molecular modeling and crystal engineering approaches to attempt to rationalize macroscopic particle properties (e.g., thermal, mechanical, solubility) is becoming more common, these are still not widely used to investigate surface properties. This is likely due to the difficulty in experimentally measuring particle surface properties, as well as in computationally describing crystalline surfaces, particularly for complex structures such as solvates or cocrystals. , …”

“…This is likely due to the difficulty in experimentally measuring particle surface properties, as well as in computationally describing crystalline surfaces, particularly for complex structures such as solvates or cocrystals. 22,23 The experimental determination of bulk surface properties of powders includes contact angle measurements and inverse gas chromatography (IGC). 4 Finite dilution inverse gas chromatography (FD-IGC) has been demonstrated as a practical technique for measuring surface energy in a range of probe molecule surface coverages.…”

What has scripting ever done for us? The CSD Python application programming interface (API)

“…Analysis and generation of conformations (Bruno et al, 2004;Cole et al, 2016Cole et al, , 2018 Ligand-based and field-based virtual screening (Giangreco et al, 2021) Crystal form analysis modules ccdc.particle Crystal particle analysis (Bryant et al, 2018;Moldovan & Maloney, 2024) ccdc.morphology Crystal morphology analysis (Clydesdale et al, 1991)…”

Surface Analysis─From Crystal Structures to Particle Properties

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