The focus of this study is an estimation of uncertainty of solid-form transition temperature (T tr) prediction based on modern virtual polymorph screening calculations. That was done through error propagation, utilizing estimated uncertainties of the relative free energy predictions at 0 K as well as of finite-temperature contribution to the polymorphic relative free energy. It was found that the uncertainty of the T tr prediction displays an inverse dependence on the difference of slopes of the intersecting relative free energy curvesthe lower the difference, the higher the uncertainty of T tr prediction. The results demonstrated that the error of T tr prediction is expected to be high (up to ∼260–270 K), especially at the temperature range close to ambient and above. The lowest uncertainty of T tr prediction at room temperature is expected to be ∼50 K in the case of virtual forms being separated by 10 kJ/mol at 0 K.

Although there are a number of computational approaches available for the aqueous solubility prediction, a majority of those models rely on the existence of a training set of thermodynamic solubility measurements or/and fail to accurately account for the lattice packing contribution to the solubility. The main focus of this study is the validation of the application of a physicsbased aqueous solubility approach, which does not rely on any prior knowledge and explicitly describes the solid-state contribution, in order to guide the improvement of poor solubility during the lead optimization. A superior performance of a quantum mechanical (QM)-based thermodynamic cycle approach relative to a molecular mechanical (MM)-based one in application to the optimization of two pharmaceutical series was demonstrated. The QM-based model also provided insights into the source of poor solubility of the lead compounds, allowing the selection of the optimal strategies for chemical modification and formulation. It is concluded that the application of that approach to guide solubility improvement at the late discovery and/or early development stages of the drug design proves to be highly attractive.

A computational investigation of the potential source of kinetic hindrance for the late appearance of pharmaceutically relevant stable forms of ritonavir, rotigotine, ranitidine hydrochloride, and pharmaceutical compound A was performed along the crystallization coordinates of the relative rates of conformational interconversion, crystal nucleation, and growth. Conformational distribution, classical nucleation, and growth morphology theories were utilized, respectively, to compare the results with those of polymorphic systems, famotidine, nimodipine, paracetamol, indomethacin, tolfenamic acid, and mebendazole for which kinetic hindrance of the stable forms was not reported. The results did not support a potential mechanism of kinetic hindering of the stable polymorphic form due to nucleation and growth limited crystallization. However, a low population of crystallographic conformations of the stable forms in solution allowed us to distinguish the behavior of the late-appearing stable systems from other polymorphic systems. To account for the low crystallographic conformer population as the potential source for kinetic hindrance, we suggest that self-association of the monomeric active pharmaceutical ingredients molecules precedes over nucleation in solution. As an implication to crystal structure prediction studies, it is suggested to complement the analysis of the lattice energy landscape of conformational polymorphs by the prediction of crystallographic conformers distribution in the gas phase and in solvents of potential interest.

Cocrytals as a solid form technology for improving physicochemical properties have grown increasing popular in the pharmaceutical, nutraceutical, and agrochemical industries. However, the list of potential coformers contains hundreds of...

Combining microcrystal electron diffraction (MicroED) and a cloud-based and artificial intelligence implemented crystal structure prediction (CSP) platform to support selection of a stable solid form of remdesivir in quick time.