Navigating phase behaviour in pharmaceuticals to enable phases with desired properties

Abstract

Many active pharmaceutical ingredients (APIs) exhibit crystalline polymorphism and only one of those polymorphs is the most stable one. Moreover, the solubility of recently developed APIs is often limited, leading to formulations containing metastable polymorphs, amorphous material or stabilised supersaturated solutions. Before marketing such formulations, it must be ensured that they persist up to their expiration date, on average about three years. Despite considerable progress in crystal structure prediction (CSP), it remains difficult to foresee which of the predicted crystalline forms will be found experimentally. In part, this is due to difficulties in predicting the crystallisation kinetics of the different polymorphs and therefore the ability to assess crystallisation kinetics needs to be improved. Each molecule remains to be tested experimentally and if necessary unary and binary phase diagrams need to be constructed for a complete picture of their phase behaviour, which will provide a basis for formulation design and risk assessment in case a metastable state is chosen for the formulation. The COST action BEST-CSP is contributing to calibrate stability calculations in CSP by preparing a benchmark of experimental physical data on the organic solid state. Hopefully, this will improve the calculation of the Gibbs free energy of the different polymorphs and therefore predictions on the phase behaviour of an API. Still, for now, each molecule remains a separate case with its particularities, which requires experimental study of its thermodynamic and kinetic behaviour before the stability assessment of its solid state can be completed.