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Updated: Jun 21, 2026
07:38
A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s
Published on: September 25, 2017
Recrystallization can stop nitrosamine formation in ranitidine hydrochloride
Jianchao Xu1, Yijing Huang1, Jon Selbo2
1Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, 47907, USA.
Journal of Pharmaceutical Sciences
|June 19, 2026
Summary
Controlling crystal quality by recrystallization can significantly reduce N-nitrosodimethylamine (NDMA) formation in ranitidine hydrochloride. High-quality crystals with fewer reactive species inhibit NDMA, offering a new strategy against drug contamination.
Area of Science:
- Pharmaceutical Sciences
- Chemical Engineering
- Materials Science
Background:
- Nitrosamines, including N-nitrosodimethylamine (NDMA), are carcinogenic contaminants found in various products.
- NDMA is a significant concern in pharmaceuticals like ranitidine hydrochloride due to its carcinogenicity.
- Solid-state reactive species (SSRS), such as crystal defects, drive NDMA formation in solid-state ranitidine hydrochloride.
Purpose of the Study:
- To investigate the impact of crystal quality on NDMA formation in ranitidine hydrochloride.
- To demonstrate the efficacy of recrystallization in inhibiting NDMA formation.
- To explore the role of oxygen in the degradation of ranitidine hydrochloride.
Main Methods:
- Recrystallization of ranitidine hydrochloride to control crystal quality.
- Storage of different ranitidine hydrochloride samples (as-received, cryoground, recrystallized) under controlled conditions (60°C, <2% RH).
- Assessment of NDMA formation under varying oxygen concentrations (vacuum, nitrogen, air, oxygen-rich).
Main Results:
- Well-controlled recrystallization yielding high-quality crystals significantly reduced NDMA formation compared to as-received material.
- Cryoground samples exhibited increased reactivity, while subsequent recrystallization restored stability.
- NDMA formation was minimal under vacuum/nitrogen, elevated in air, and highest in an oxygen-rich environment.
Conclusions:
- Reducing SSRS through well-controlled crystallization is a highly effective method to inhibit nitrosamine formation in ranitidine hydrochloride.
- This approach offers a potential alternative or complementary strategy to antioxidants and pH modification for minimizing nitrosamine contamination.
- Crystal quality is a critical factor influencing the stability and degradation pathways of drug substances like ranitidine hydrochloride.
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