Solubility measurements for polymorphic compounds are often accompanied by solvent-mediated phase transformations. In this study, solubility measurements from undersaturated solutions were employed to investigate the solubility of the two most stable polymorphs of flufenamic acid (FFA forms I and III), tolfenamic acid (TA forms I and II), and the only known form of niflumic acid (NA). The solubility was measured from 278.15 to 333.15 K in four alcohols of a homologous series (methanol, ethanol, 1-propanol, n-butanol) using the polythermal method. It was demonstrated that the solubility of these compounds increases with increasing temperature. The solubility curves of FFA forms I and III intersect at ~315.15 K (42 °C) in all four solvents, which represents the transition temperature of the enantiotropic pair. In the case of TA, the solubility of form II could not be reliably obtained in any of the solvents due to fast solvent-mediated phase transformation. The solubility of the only known form of NA was also determined, and no other polymorphs of NA were observed. The experimental solubility data of FFA (forms I and III), TA (form I), and NA in these four solvents was correlated using the modified Apelblat and λh model equations. The correlated and experimentally determined solubility data obtained serves to (i) guide the accurate determination of the solubility for polymorphic compounds, (ii) assess the role of the solvent in mediating transformations, and (iii) provide a pathway to engineer advanced pharmaceutical crystallization processes for these compounds.

In the context of polymorphism: Accurate measurement, and validation of solubility data

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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