A Comparison of Methods for Computing Relative Anhydrous–Hydrate Stability with Molecular Simulation

Abstract

The transformation of a pharmaceutical solid from an anhydrous crystal into a hydrated form during drug development represents a risk to a product’s safety and efficacy due to the potential impact on stability, bioavailability, and manufacturability. In this work, we examine 10 classical free energy simulation protocols to evaluate the thermodynamic stability of hydrated crystals relative to their anhydrous forms. Molecular dynamics simulations are used to compute the Gibbs free energies of the crystals of three pharmaceutically relevant systems using two fixed-charge potentials, GAFF and OPLS, as well as the polarizable AMOEBA model. In addition, we explore a variety of water models, including TIP3P, TIP4P, and AMOEBA, for both the interstitial water and the effects of ambient humidity. The AMOEBA model predicts free energy values most consistent with experimental measurements among the models examined. The benefits of a fully polarizable water model relative to fixed-charged models appear to derive predominantly from a better treatment of water’s dipole moment in the crystalline phase. Despite this improved physical treatment, we find that no single model produces reliable predictions of the phase boundary between hydrated and anhydrous crystals from theory alone. However, we show that accurate phase diagrams can be constructed from the simulations by introducing a single experimentally determined coexistence point. With this single experimental data point as input, the phase boundary is correctly predicted within 10% relative humidity on the temperature range of 15 to 75 °C for all three systems examined. Furthermore, we demonstrate that with this known coexistence point as an input, the differences between the various potentials and the water models become insignificant, as all models yield accurate phase boundaries regardless of whether polarization is included due to significant temperature-dependent error cancellation between models.

MDverse: Shedding Light on the Dark Matter of Molecular Dynamics Simulations

“…These peaks corresponded to the same study related to the stability of hydrated crystals (Dybeck et al, 2023). Overall, this analysis revealed that a wide range of temperatures have been explored, starting mostly from 100 K and going up to 800 K.…”

Frontiers of molecular crystal structure prediction for pharmaceuticals and functional organic materials

“…They show nearly quantitative agreement between theory (red lines) and experimentally-derived coexistence points. 186 several contributions to the eventual understanding: It highlighted the stability of form I, which helped explain its insolubility in various solvents and the difficulties in producing other crystal forms experimentally. It showed that the experimental forms discovered included examples of all major packing motifs found on the computational landscape, suggesting that the experimental screen was suitably complete.…”

Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path

“…6−14 This is particularly true for large, flexible APIs and those with complex asymmetric units that contain coformers and/or water molecules. 15 Traditional CSP protocols involve an exhaustive search over various configurations, from space groups and molecule arrangements to internal conformations and unit cell parameters. Efficient force fields and density functional theory (DFT) calculations 16 are often employed to guide this search, but incorporating thermal effects has typically been limited to a small subset of final candidates.…”

“…However, many APIs can exist in multiple stable crystal arrangements, known as polymorphs, with significantly different pharmaceutically relevant properties such as thermodynamic stability, solubility, dissolution rate, and processability. − Polymorphs can be discovered via screening under a variety of experimental conditions (e.g., solvent, pH, salt, temperature, and pressure). Despite significant recent progress in computational crystal structure prediction (CSP) as evidenced by successful blind tests, accurate polymorph prediction for complex molecules remains challenging. − This is particularly true for large, flexible APIs and those with complex asymmetric units that contain coformers and/or water molecules …”

“… 6 − 14 This is particularly true for large, flexible APIs and those with complex asymmetric units that contain coformers and/or water molecules. 15 …”