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Eutectic mixtures can be formed by adding drugs other than nicotine (DOTNs) to nicotine‐based e‐liquids in electronic cigarettes (e‐cigarettes). Thus, the interaction between nicotine e‐liquids and DOTNs must be evaluated. Presented is the change in e‐cigarette aerosolization of nicotine and methadone alone versus a 1:1 nicotine:methadone mixture to evaluate the possible formation of a eutectic mixture that can result in an increase of drug delivery. E‐liquids were prepared in‐house using 1:1 propylene glycol (PG):vegetable glycerin (VG) as a base plus nicotine, methadone hydrochloride, or 1:1 nicotine:methadone hydrochloride. The e‐liquids were aerosolized via an automated vaping machine using parameters adopted from the Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) E‐cigarette Task Force method. Drug recovery was determined by capturing the aerosol from 15 puffs generated by the e‐cigarette. Concentrations of nicotine and methadone aerosolized were determined by gas chromatography–mass spectrometry using nicotine (n = 3), methadone (n = 3), and combined nicotine/methadone e‐liquids (n = 3), each prepared in‐house at 12 mg/ml. The concentration of nicotine and methadone in 15 puffs of the single drug e‐liquids were determined to be 1.60 ± 0.20 and 2.67 ± 0.12 mg, respectively. The concentration of nicotine and methadone in 15 puffs of the multidrug e‐liquid were determined to be 3.66 ± 0.49 and 3.65 ± 0.10 mg, respectively. The single nicotine and methadone e‐liquids had recoveries of 70 ± 0.1% and 84 ± 0.1%, respectively. In the 1:1 mixture, the recovery of both drugs increased. The development of a eutectic mixture can promote aerosolization of the drug and deliver a greater dose to the user. [ABSTRACT FROM AUTHOR]