Solid-form Transition Temperature Prediction from a Virtual Polymorph Screening – A Reality Check

The focus of this study is estimation of uncertainty of solid form transition temperature (T_tr) prediction based on the 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 is. 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.