Tiny Crystal Defects May Drive Harmful Nitrosamine Formation in Drugs, Purdue Researchers Report at EAS

At a time when nitrosamine contamination continues to rattle pharmaceutical supply chains, new research from Purdue University points to a subtle but significant culprit: tiny, nearly invisible flaws in a drug’s crystalline structure. According to findings presented this week at the Eastern Analytical Symposium (EAS) in Plainsboro, New Jersey, these solid-state reactive species (SSRs)—chemically reactive sites created by crystal defects—may help explain why drugs like ranitidine generate carcinogenic nitrosamines even in the absence of liquid water or traditional solution-phase catalysts.

“We believe that crystal defects are the primary source of degradation for crystalline drugs,” said Jianchao Xu, a researcher in Eric Munson’s lab, at EAS on November 17.

Nitrosamines have forced dozens of U.S. Food and Drug Administration (FDA) recalls over the past five years, spanning blood pressure medications to over-the-counter antacids. Ranitidine HCl, once a widely used drug for decades, became a flashpoint when regulators determined it degrades to form N–nitrosodimethylamine (NDMA), a probable human carcinogen. The FDA’s acceptable daily intake (ADI) for NDMA in ranitidine is just 0.096 micrograms per dose—extremely low. Yet multiple studies, including those under accelerated storage, have shown that NDMA can exceed that threshold under certain conditions.

As the industry scrambled to understand the chemical pathways behind this degradation, multiple research teams explored classic solution-phase and nitrosation mechanisms. But the mechanistic picture has remained incomplete. According to Xu, what caught the Purdue team’s eye was data shared by a pharmaceutical company (GSK), suggesting that ranitidine from one manufacturing site generated much less NDMA than ranitidine from other sources, despite identical polymorphic form (Form 2 HCl). The only reported difference appeared to be the final crystallization step.

Crystal defects—such as micro-cracks, dislocations, or lattice disorder—are already known to accelerate degradation in solid pharmaceuticals, whether introduced during crystallization or through post-processing like milling or compaction. These defects are not just inert blemishes. If sufficiently abundant, they can act as SSRs, creating reactive hot spots that may support chemical transformations that are kinetically unfavorable in a perfect crystal lattice.

The core evidence for this hypothesis comes from previously published work by the Munson lab in a peer-reviewed study. In that work, the researchers cryogenically milled ranitidine HCl, then stored it under highly accelerated conditions. They observed that more intensely milled (i.e., more defect-rich) samples produced NDMA more rapidly, and their chromatographic data showed a clear correlation between the extent of grinding and NDMA formation. The researchers also noted a gradual yellowing of samples—characteristic of NDMA accumulation.

Importantly, their data showed that particle size alone did not predict degradation rate. Larger particles with fewer defects proved more stable than smaller, defect-rich particles, suggesting that crystalline quality, rather than surface area, governs the rate of nitrosamine formation.

To probe potential mitigation strategies, Xu and colleagues presented unpublished EAS data on new recrystallized batches. Slow-growth crystallization techniques produced crystals with fewer defects, and those improved materials showed significantly reduced NDMA formation compared to more defect-rich samples made by rapid crystallization. While perfect crystals are not realistic in large-scale manufacturing, their data showed that carefully controlled crystallization could meaningfully suppress nitrosamine risk.

The team also discussed preliminary results under different storage atmospheres. According to their EAS presentation, storing defect-rich ranitidine under inert conditions (nitrogen or vacuum) appears to slow NDMA formation compared to storage in the presence of oxygen—suggesting an oxygen-promoted degradation pathway. However, these atmospheric-control findings remain preliminary and have not yet appeared in a peer-reviewed publication.

This work offers a compelling shift in how analytical chemists and pharmaceutical scientists might assess nitrosamine risk. Rather than focusing solely on chemical impurities or solution‑phase nitrosation, crystalline microstructure—and specifically, defect density—emerges as a potentially major factor. If validated and translated into manufacturing practices, this insight could open new avenues for mitigating nitrosamine contamination by refining crystallization processes and controlling storage atmospheres.