Interrogating the Solid–Solid Phase Transition Behavior of a Molecular Crystal with a Diverse Range of Solid-State Analytical Techniques and Computational Predictions

The solid–solid phase transition behavior of 2-(4-(hydroxymethyl)phenyl)ethan-1-aminium chloride or HPEA-Cl was thoroughly investigated using thermal analytical techniques (differential scanning calorimetry (DSC) and hot-stage microscopy), single crystal X-ray diffraction, Raman microscopy, variable temperature synchrotron X-ray powder diffraction (VT-SXRPD), and crystal structure prediction (CSP). HPEA-Cl exists in at least three crystalline modifications: Forms 1, 2, and 3. Upon heating, Form 1 undergoes a solid–solid transition to Form 2 at ca. 151–153 °C. The first-order transition is consistent with a non-topotactic or nucleation and growth mechanism. Form 3 is highly metastable and rapidly transforms to either Forms 1 or 2. To complicate matters, the nucleation of Form 3 is stochastic. These two observations made it extremely difficult to characterize this physical form. Utilizing ultrafast continuous in situ VT-SXRPD to monitor phase transition behavior, we also performed CSP and free energy calculations to comprehend significant enthalpy changes during the phase transition. This study highlights the necessity of combining various solid-state characterization techniques and computational predictions to interrogate the solid–solid transition behaviors of molecular crystals.