Estimation of the Solubility of Metastable Polymorphs: A Critical Review

Abstract

Solubility measurements of metastable polymorphs are often complicated by solvent-mediated transformation toward more stable forms. In this review, we first summarize potential experimental methods to estimate the solubility of metastable polymorphs. Then, we discuss a methodology based on a thermodynamic model, which allows solubility predictions from (i) solubility data of the stable form, and (ii) solid-state properties of the stable and metastable forms.

Polymorph control in batch seeded crystallizers. A case study with paracetamol

“…These data were described by a thermodynamic model in our previous article. 32 Here, we simply fit the experimental data with the following exponential expressions: , while T is the temperature in Kelvin. The results of the fitting are represented by solid lines in Fig.…”

A novel crystal form of metacetamol: the first example of a hydrated form

“…This is especially important in the field of pharmaceuticals (Stahl & Wermuth, 2002;Karki et al, 2007;Brittain, 2009). Two different solid forms of an active pharmaceutical ingredient (API) may drastically differ in their properties (stability, solubility, dissolution rate and many others), which strongly affects their possible applications (Bernstein, 2002;Healy et al, 2017;Nicoud et al, 2018). More than a quarter of the substances in the European Pharmacopoeia are formulated as hydrates (Griesser, 2006).…”

The Polymorphism of Drugs: New Approaches to the Synthesis of Nanostructured Polymorphs

“…If thermodynamics assume the dominant role in the synthesis of polymorphs, stable structures with the lowest free energy are formed. If the kinetics dominate, metastable polymorphous structures with larger free energy are formed [19,20]. Therefore, control over thermodynamic and kinetic parameters during the synthesis of a polymorphous compound is necessary in both fundamental and applied studies.…”