Polymorphic Stability Shifts, Co-Crystals, and Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid–Salicylamide

The thermodynamic phases of salicylic acid (SA) and salicylamide (SM) and their respective domains in a T-X diagram were determined experimentally from 25 °C to melting. Besides a new SA-SM co-crystal, three crystalline solid solutions (CSSs) were found, of which two belonged to polymorphic forms of SM. Form I of SM is thermodynamically stable across all temperatures when chemically pure. However, when SA is added to SM, a complete thermodynamic stability transition takes place to the CSS of SM Form III between ca. 59 and 72 mol % SM in SA at temperatures between 115 and 127 °C. In addition, a relatively large coexistence domain exists wherein the CSS phases of SM Forms I and III are equally stable thermodynamically and persist indefinitely. The polymorphic coexistence domain and stability shift provide a striking example of how CSSs can seemingly alter thermodynamic stabilities in polymorphic systems in the presence of a second component such as impurities. Implications for polymorph screening are discussed, together with a thermodynamic explanation for the phenomenon of disappearing polymorphs. The reasons for the complex T-X phase diagram are explained in concert with a detailed analysis of thermal events observed in differential scanning calorimetry (DSC) analyses. Finally, a solvent-free solid–liquid equilibrium (SLE) diagram (Roozeboom plot) is presented using 40 wt % MeOH in H2O. The solvent solubility enhancing effects from the CSS phases of SA and SM Form I were measured experimentally up to the respective solvi at 25 °C. These solvi correspond to the limits of miscibility of 5.8 mol % SM incorporated in the SA lattice and 2.0 mol % SA incorporated in the SM lattice.