Thermodynamic Stability Transitions and Coexistence of Two Polymorphs via Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid and 2,3-Dihydroxybenzoic Acid

The thermodynamically stable phases of salicylic acid (SA) and 2,3-dihydroxybenzoic acid (23DHBA) have been determined experimentally in a T-X phase diagram from 25 °C to melting and in a ternary phase diagram with a solvent at 25 °C. Three crystalline solid solution (CSS) phases were obtained of which two belonged to two polymorphs of 23DHBA. The solid-state miscibility of SA was determined to be 0.9 mol % 23DHBA, whereas the solvus of Form II of 23DHBA was estimated to be around 22 mol % SA, at 25 °C. The CSS formation resulted in a thermodynamic coexistence domain where the two polymorphs of 23DHBA coexist indefinitely at all investigated temperatures up to the peritectic isotherm. A polymorphic stability shift is also in effect across a larger portion of the phase diagram at a higher content of SA. In this region, Form II of 23DHBA, which is metastable and largely inaccessible when chemically pure, is thermodynamically more stable than Form I. The underlying reason for the thermodynamic stability transitions is explained and conceptualized through the solvent solubilities of the corresponding CSS phases of 23DHBA and SA measured in 40 w% MeOH in H2O at 25 °C. This example negates surface adsorption as the underlying mechanism for stabilizing "metastable" polymorphs in the presence of structurally similar additives or impurities. In addition, two novel crystal forms were found and their crystal structures were resolved, showing an anhydrous polymorph and a hydrate of 23DHBA. Implications for chemical and pharmaceutical development are discussed.