Accurate Measurement and Validation of Solubility Data for Polymorphic Compounds

Polymorphism, a phenomenon that enables molecules to exhibit multiple crystalline phases, is estimated to occur in up to 80% of molecules that display a pharmaceutical application, affecting primarily their solubility, which correlates with bioavailability in compounds that present poor aqueous solubility.(1) Therefore, the inadvertent occurrence of polymorphism during a pharmaceutical manufacturing process might have adverse effects on drug product properties. One parameter of utmost importance needed to understand and control polymorphism is the solubility of a compound in a particular solvent or solvent mixture. However, solubility measurements for polymorphic compounds are often accompanied by solvent-mediated phase transformations.

Generally, solubility measuring techniques are grouped into isothermal and polythermal methods. The former measures the solubility at preset temperatures for unspecified concentrations by adding an excess of solid, forming a slurry or suspension. However, the equilibration times often employed in isothermal methods (typically ≥24 h) might hamper the accurate determination of the solubility for metastable forms because of possible solvent-mediated phase transformations. This represents a major issue when reviewing existing solubility data as emphasized in a recent editorial published by the Journal of Chemical & Engineering Data.(2)

Here, the polythermal method that determines the temperatures at which solubility is attained for suspensions with known composition at specific heating rates might be better suited to determine the solubility of polymorphic compounds while circumventing solvent-mediated phase transformations. In particular, when commercially available equipment such as the Crystal 16 and Crystalline are coupled with in situ solid-state characterization.(3)

This webinar presented by Dr Torsten Stelzer and Dr Vilmali Lopez-Mejias from the University of Puerto Rico provided guidance to accurately measure and validate the solubility of polymorphic compounds from an undersaturated solution employing the polythermal method.

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  1. Hilfiker R. Polymorphism. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA; 2006.

  2. Königsberger E. Editorial: Guidelines for the Measurement of Solid–Liquid Solubility Data at Atmospheric Pressure. J Chem Eng Data [Internet]. 2019 Feb 14;64(2):381–5. Available from:

  3. Vázquez Marrero VR, Piñero Berríos C, De Dios Rodríguez L, Stelzer T, López-Mejías V. In the Context of Polymorphism: Accurate Measurement, and Validation of Solubility Data. Cryst Growth Des [Internet]. 2019 Jul 3;19(7):4101–8. Available from: