**Priveledge Mazonde, Sandile M. M. Khamanga and Roderick B. Walker**

Department of Pharmaceutics, Faculty of Pharmacy, Rhodes University, Makhanda 6140, South Africa; pmazonde@live.com (P.M.); S.Khamanga@ru.ac.za (S.M.M.K.) **\*** Correspondence: r.b.walker@ru.ac.za; Tel.: +27-46-603-8412

Received: 20 July 2020; Accepted: 13 August 2020; Published: 23 August 2020

**Abstract:** The formation, manufacture and characterization of low energy water-in-oil (w/o) nanoemulsions prepared using cold pressed flaxseed oil containing efavirenz was investigated. Pseudo-ternary phase diagrams were constructed to identify the nanoemulsion region(s). Other potential lipid-based drug delivery phases containing flaxseed oil with 1:1 *m*/*m* surfactant mixture of Tween® 80, Span® 20 and different amounts of ethanol were tested to characterize the impact of surfactant mixture on emulsion formation. Flaxseed oil was used as the oil phase as efavirenz exhibited high solubility in the vehicle when compared to other vegetable oils tested. Optimization of surfactant mixtures was undertaken using design of experiments, specifically a D-optimal design with the flaxseed oil content set at 10% *m*/*m*. Two solutions from the desired optimization function were produced based on desirability and five nanoemulsion formulations were produced and characterized in terms of in vitro release of efavirenz, physical and chemical stability. Metastable nanoemulsions containing 10% *m*/*m* flaxseed oil were successfully manufactured and significant isotropic gel (semisolid) and o/w emulsions were observed during phase behavior studies. Droplet sizes ranged between 156 and 225 nm, zeta potential between −24 and −41 mV and all formulations were found to be monodisperse with polydispersity indices ≤ 0.487.

**Keywords:** nanoemulsion(s); phase-behavior; DoE; D-optimal design; vegetable oils; non-ionic surfactants; efavirenz; flaxseed oil
