Polymorphic control in industrial crystallization is vital for the release and bioavailability of active pharmaceutical ingredients (API) and is governed by regulatory authorities. One of the activities routinely carried out in early development is to screen for polymorphs and establish thermodynamic stabilities of the discovered polymorphs. Thermodynamic form control of the target polymorph, normally the development form, is then implemented in the crystallization process to ensure robustness at scale. The API crystallization is always carried out in the presence of process-impurities and is frequently used as a mean for purification. The effect of impurities on the crystallization is well-known in the pharmaceutical industry and has often resulted in isolation issues. Historic literature has posited that impurities adsorb on the surfaces of the crystals and impede crystal growth. However, largely omitted are reports of crystalline solid solutions (CSS) formed between organic molecules wherein two or several components are (partially) miscible in the solid state. Recent work has shown that CSS is a dominant impurity retention mechanism and routinely encountered in industrial crystallization.
[1] The formation of CSS between the product and impurities alters the physiochemical and thermodynamic properties of the host crystals. This often leads to melting property changes and solvent solubility enhancements, also when the impurity is present at relatively low levels. This thermodynamic effect of course also takes place in polymorphic systems. But because the incorporation of impurities is polymorphically selective, changes in their thermodynamic stabilities and interrelationships can occur.
Presented herein are two experimental examples where the relative thermodynamic stabilities of polymorphs change as a result of CSS-formation with a second component. In the first system, a metastable and largely experimentally inaccessible polymorph of 2,3-dihydroxybenzoic acid is made the thermodynamically stable form via CSS-formation with salicylic acid. This leads to both a polymorphic coexistence domain and a polymorphic stability shift that is in effect from 25 °C to melting, starting at only 0.5 w%. In the second example, a metastable polymorph of 3-hydroxybenzoic acid is shown to diverge in thermodynamic stability relative the stable polymorph in the presence of salicylic acid. This leads to an enhancement in metastability between the two polymorphs and a larger driving force for polymorphic conversion. The implications of the results are discussed within pharmaceutical development.
[1] Org. Proc. Res. & Dev., 2023, 27, 4, 723-741
