1*Department of Pharmaceutics, Modern College of Pharmacy, Savitribai Phule Pune University, Pune, Maharashtra, INDIA
Email: santoshab5528@gmail.com
Nitrosamine impurities represent a major regulatory concern because of their carcinogenic potential and very low acceptable intake limits. Varenicline, an amine-containing drug substance used for smoking cessation therapy, is susceptible to nitrosation under acidic and/or moisture-rich conditions in the presence of trace nitrite, forming N‑nitroso‑varenicline. Here, we compare two mechanistically distinct, formulation-relevant mitigation concepts: (i) polymer-matrix shielding of the nitrosatable secondary amine within a hydroxyl-rich maltodextrin solid dispersion and (ii) a small-molecule interaction model using cysteine as a comparator. A varenicline–maltodextrin solid dispersion was prepared using rotavapor-assisted solvent evaporation to promote intimate molecular mixing while minimizing prolonged water exposure, followed by direct-compression tablet development using low-nitrite excipients and sodium citrate to maintain a microenvironmental pH > 6. AutoDock Vina was modified into a physicochemical association model (molecular docking), and used to determine drug-excipient interactions. The varenicline-maltodextrin complex which scored the highest had a positive docking affinity score of -2.66 kcal/mol and a hydrogen bond of 2.84 Å between the amine group of varenicline and the hydroxyl groups of maltodextrins. A similar docking score was obtained with cysteine (−2.65 kcal/mol) and hydrogen-bond formation (representative distance of approximately 2.55 Å), indicating the possibility of hydrogen-bond formation, but not polymeric encapsulation. In general, the synergistic interaction-based shielding, decreased solid dispersion mobility, pH regulation, and excipient nitrite reduction offer a logical, multilayer model proposed to reduce the risk of nitrosation in varenicline solid dosage forms.
Keywords: Varenicline; N-nitroso-varenicline; mitigation of nitrosamine; solid dispersion; maltodextrin; cysteine; molecular docking.
How to cite this article: Bhende S, Phatak A, Chaudhari P. Drug-Excipient Interaction Guided Design Of A Solid Dispersion System For Nitrosation Risk Reduction In Varenicline. Int J Drug Deliv Technol. 2026;16(6s): 515-521; DOI: 10.25258/ijddt.16.6s.76
Source of support: None
Conflict of interest: None