Can Multiple Solubilities Co-Exist in a Single Crystal? Hazards and Opportunities

Crystallization is a separation process commonly found in the production of bulk chemicals, food additives, and pharmaceuticals. In the pharmaceutical industry, crystal solubility dictates a drug’s bioavailability, and thus its ability to have an effect on the patient. In a recent publication, we found that 79% of challenging scenarios on impurity rejection in pharmaceutical crystallizations involved impurities incorporated inside the drug’s crystal lattice [1]. Challenging impurities pose an issue due to effects on drug stability and toxicity to the body, which has been the subject of recent drug recalls [2].

This study investigates how impurities are distributed through crystal lattices, and their effect on drug solubility and dissolution using systems of dyes incorporated to a common pharmaceutical (acetaminophen, the active ingredient in Tylenol). Our results illustrate that anisotropic impurity incorporation into specific crystal facets can lead to anisotropic dissolution behaviors, where regions containing the impurity quickly dissolve upon exposure to a solvent. This may be due to localized solubility gradients within a single crystal, owing to an uneven distribution of impurity and thus an uneven disturbance of the lattice stability by the incorporated impurities.

These results have various implications, some concerning and others which present opportunities for drug purification and materials design. A potentially concerning implication in the case of pharmaceuticals is the faster crystal dissolution rate of the crystal regions containing the impurity, leading to a fast release and absorption of a potentially toxic impurity by the patient. On the other hand, the ability to tune dissolution kinetics in a crystal by controlling its purity can provide new avenues using safe additives as lattice modifiers, furthering the field of crystal engineering. The possibility of controlled-release medications utilizing a rapid onset could be made possible by enhanced dissolution from a purposeful additive, followed by the extended dissolution of the remaining API for longer lasting residual effect.

[1] Nordstrom, F. L.; Sirota, E.; Hartmanshenn, C.; Kwok, T. T.; Paolello, M.; Li, H.; Abeyta, V.; Bramante, T.; Madrigal, E.; Behre, T.; Capellades, G. Prevalence of Impurity Retention Mechanisms in Pharmaceutical Crystallizations. Organic Process Research & Development 2023, 27 (4), 723-741. DOI: 10.1021/acs.oprd.3c00009.

[2] US Food and Drug Administration. Guidance for Industry: M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, 2018. URL: https://www.fda.gov/media/85885/download.