Navigating Molecular Aggregation in Isonicotinamide Based Cocrystals: Cl···O and C–H···O Tip the Balance towards Metastable Synthon in the Solid State

We report on an investigation aimed at selectively isolating cocrystalline phases through solution crystallization. Isonicotinamide was used as the model compound, and six isomeric dichlorophenols served as coformers. Out of the possible combinations, five novel cocrystals were identified (excluding 2,4-dichlorophenol-isonicotinamide). These solid phases were characterized by using single crystal X-ray diffraction (SC-XRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). This study highlights that dichloro substitution on the phenolic moiety significantly influences the hydroxyl group's behavior in the solid state. For instance, in cocrystals 4 and 5 secondary Cl···O and C–H···O interactions disrupt the typical hierarchy of synthons, allowing the less favored synthons III and IV to form, suggesting that the composition of less favored interactions might sometimes be more effective than favored ones.