Polymorphic Stability Shifts, Co-Crystals, and Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid–Salicylamide
Mitchell Paolello, Seyed Sepehr Mohajerani, Brian Linehan, Francesco Ricci, Gerard Capellades, Fredrik L. Nordström
Abstract
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 H 2 O. 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.