Interrogating the\nSolid–Solid Phase Transition\nBehavior of a Molecular Crystal with a Diverse Range of Solid-State\nAnalytical Techniques and Computational Predictions

The solid–solid phase transition behavior of 2-(4-(hydroxymethyl)phenyl)ethan-1-aminium\nchloride or HPEA-Cl was thoroughly investigated using thermal analytical\ntechniques (differential scanning calorimetry (DSC) and hot-stage\nmicroscopy), single crystal X-ray diffraction, Raman microscopy, variable\ntemperature synchrotron X-ray powder diffraction (VT-SXRPD), and crystal\nstructure prediction (CSP). HPEA-Cl exists in at least three crystalline\nmodifications: Forms 1, 2, and 3. Upon heating, Form 1 undergoes a\nsolid–solid transition to Form 2 at ca. 151–153 °C.\nThe first-order transition is consistent with a non-topotactic or\nnucleation and growth mechanism. Form 3 is highly metastable and rapidly\ntransforms to either Forms 1 or 2. To complicate matters, the nucleation\nof Form 3 is stochastic. These two observations made it extremely\ndifficult to characterize this physical form. Utilizing ultrafast\ncontinuous <i>in situ</i> VT-SXRPD to monitor phase transition\nbehavior, we also performed CSP and free energy calculations to comprehend\nsignificant enthalpy changes during the phase transition. This study\nhighlights the necessity of combining various solid-state characterization\ntechniques and computational predictions to interrogate the solid–solid\ntransition behaviors of molecular crystals.