Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study

Abstract

Nitrosamines, in the absence of toxicological data, are regarded as potential mutagens and need to be controlled at nanogram levels in drug products. Recent high profile product withdrawals have increased regulatory scrutiny of nitrosamine formation assessments for marketed products and for new drug applications. Formation of nitrosamine in drug product is possible when nitrite and vulnerable amines are present. Nitrite is often present as an impurity in excipients at ppm levels, whereas vulnerable amines, if present, stem mainly from the drug substance or its major impurities. In the event a drug product were to contain a major source of vulnerable amines (such as a moiety in the drug substance), it would be desirable to have an inhibitor which could be added to the formulation to minimize nitrosamine formation. This work demonstrates, for the first time, that the inhibition of nitrosamine formation in oral solid dosage forms is indeed feasible with suitable inhibitors. Five inhibitors investigated (ascorbic acid, sodium ascorbate, α-tocopherol, caffeic acid, and ferulic acid) showed >80% inhibition when spiked at ∼1 wt% level. This work has also shown the potential use of amino acids (glycine, lysine, histidine) as inhibitors of nitrosamine formation in solution.

Keywords: Drug product; Inhibition; Nitrosamine formation.