Impurity retention and pharmaceutical solid solutions: visualizing the effect of impurities on dissolution and growth using dyed crystals

Pharmaceutical solid solutions are gaining increased interest as alternatives to salts and co-crystals for the enhancement of drug solubility and dissolution kinetics. Industrially, they are also responsible for the entrapment of potentially toxic impurities in drug substances. The accidental incorporation of process impurities into the lattice of a growing crystal, or the intentional incorporation of an additive, can vastly alter the product's properties. Reported effects include solubility enhancements, changes in melting point, shifting polymorph stabilities, growth inhibition, and change in crystal habit, among others. This work combines the fields of impurity rejection, solid solutions, and dyeing crystals, to provide visual evidence of those effects, and to further demonstrate how impure regions in a single crystal can present vastly different behaviors to the purified regions of the same crystal. The work revolves around four model host-guest pairs, two of them previously unreported. These include mixed crystals of acetaminophen with curcumin, sulforhodamine B, and acid fuchsin, as well as potassium sulfate dyed with acid fuchsin. Results challenge common assumptions in the study of multicomponent crystals, demonstrating how neglecting composition anisotropy may lead to misdiagnosing solid solutions as surface adsorbed impurities in impurity retention diagnostics, and how neglecting the habit-modifying effects of dissolved impurities may lead to the use of erroneous models for growth inhibition. At the same time, we present opportunities for the development of novel impurity rejection and crystal engineering strategies, aiding the growth of anisotropic crystals with properties that can be fine-tuned in continuum.