Dyeing Pharmaceuticals: Visualizing the Effect of Lattice Impurities on Crystal Solubility, Dissolution, and Fragility

Accidental formation of solid solutions between a crystallizing product and a process impurity is the primary mechanism by which unacceptable amounts of potentially toxic impurities incorporate into pharmaceutical crystals. These lattice impurities can drastically change the drug substance’s solubility, dissolution behavior, and fragility. However, these effects are difficult to study when pure and impure crystals are visually indistinguishable from each other. This study uses dyes as model impurities, incorporated in pharmaceutical products to visualize how localized incorporation can lead to distinct localized behaviors within the crystal.

Acetaminophen solid solutions were grown in the presence of three colored impurities: acid fuchsin, curcumin, and sulforhodamine B. Grown products all presented different degrees of composition anisotropy, where specific faces of the crystal incorporated the impurity at higher levels. These crystals were analyzed for isothermal solubility, melting point depression, dissolution kinetics, and fragility upon compression.

Acetaminophen solid solutions presented a higher solubility and lower melting points than the pure material, in some cases reaching a 92% solubility increase with lattice impurity levels at the ppm range. Low levels of impurity (<200 ppm) were also found to play a significant role on crystal fragility, reducing the required force for breakage by an order of magnitude. Dissolution tests showed that impure regions of the anisotropic crystal always dissolve faster than pure regions, regardless of the impurity’s solubility in the solvent and regardless of what faces incorporate the impurity. These observations were cross-validated to be generalizable with well-known dyed crystal system of K₂SO₄ with acid fuchsin.

Effects of process impurities on crystallization goes far beyond their potential role as toxic components in the drug substance. Drug substances retaining small amounts of lattice impurities can present vastly different solubilities, higher fragility, and anisotropic dissolution behaviors. This brings challenges for drug characterization, but also opportunities for solubility and dissolution control.