Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control.

Autor: Sluggett GW; Analytical Research & Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA. Electronic address: gregory.w.sluggett@pfizer.com., Zelesky T; Analytical Research & Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA., Hetrick EM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Babayan Y; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Baertschi SW; Baertschi Consulting, LLC, Carmel, IN, 46033, USA.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical and biomedical analysis [J Pharm Biomed Anal] 2018 Feb 05; Vol. 149, pp. 206-213. Date of Electronic Publication: 2017 Oct 29.
DOI: 10.1016/j.jpba.2017.10.035
Abstrakt: Accelerated stability studies of pharmaceutical products are commonly conducted at various combinations of temperature and relative humidity (RH). The RH of the sample environment can be controlled to set points using humidity-controlled stability chambers or via storage of the sample in a closed container in the presence of a saturated aqueous salt solution. Herein we report an unexpected N-nitrosation reaction that occurs upon storage of carvedilol- or propranolol-excipient blends in a stability chamber in the presence of saturated sodium nitrite (NaNO 2 ) solution to control relative humidity (∼60% RH). In both cases, the major products were identified as the corresponding N-nitroso derivatives of the secondary amine drugs based on mass spectrometry, UV-vis and retention time. These degradation products were not observed upon storage of the samples at the same temperature and humidity but in the presence of saturated potassium iodide (KI) solution (∼60% RH) for humidity control. The levels of the N-nitrosamine derivatives varied with the pH of various NaNO 2 batches. The presence of volatile NOx species in the headspace of a container containing saturated NaNO 2 solution was confirmed via the Griess assay. The process for formation of the N-nitrosamine derivatives is proposed to involve volatilization of nitric oxide (NO) from aqueous nitrite solution into the headspace of the container followed by diffusion into the solid drug-excipient blend and subsequent reaction of NOx with the secondary amine.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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