TY - JOUR
T1 - Polymorphic Stability Shifts, Co-Crystals, and Crystalline Solid Solutions
T2 - The T-X Phase Diagram of Salicylic Acid-Salicylamide
AU - Paolello, Mitchell
AU - Mohajerani, Seyed Sepehr
AU - Linehan, Brian
AU - Ricci, Francesco
AU - Capellades, Gerard
AU - Nordstrom, Fredrik L.
N1 - Publisher Copyright:
© 2024 American Chemical Society
PY - 2024/3/6
Y1 - 2024/3/6
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.cgd.3c01501
DO - 10.1021/acs.cgd.3c01501
M3 - Article
AN - SCOPUS:85186101868
SN - 1528-7483
VL - 24
SP - 2188
EP - 2201
JO - Crystal Growth and Design
JF - Crystal Growth and Design
IS - 5
ER -