The amphipathic bioactive compounds curcumin, resveratrol, and mitomycin C, which have similar solubility parameter component distributions, have been studied for encapsulation under batch conditions into core−shell nanocarriers composed of external hydrophobically functionalized polyelectrolytes and an inner matrix of polyesters or polyester blends: poly(Llactide), poly(lactide-co-glycolide), and/or poly(ethylene succinate). Our contribution comprises determining the influence of process parameters on the properties and quality of the final products, namely core−shell nanoparticles loaded with appropriate drugs, according to process analysis technologymanagement. The crucial roles of the organic phase dosing rates and process temperatures were carefully investigated. Moreover, a technically feasible method of removing organic solvents from aqueous dispersions�stripping with inert gas�was employed and evaluated via FT-IR studies. The experiments were supported by the calculation and analysis of solubility parameters (δ) and dispersion (δ d ), polar (δ p ), and hydrogen bond (δ h ) components utilizing HSPiP software. The payload locus and sample morphology were studied via atomic force microscopy and X-ray photoelectron spectroscopy analyses with Ar + sputtering. It was demonstrated that dosing rates of organic phases not exceeding ca. 0.5 mL/min per 1 L of aqueous dispersion of hydrophobically functionalized polyelectrolytes made it possible to obtain core−shell nanoparticles of ca. 100−150 nm with a very narrow polydispersity (PdI < 0.2). The locus of amphipathic payloads in nanocarriers, mostly within the core polymeric structure, was in good agreement with the results of solubility parameter component studies: water-insoluble polyesters with both polar and nonpolar interactions between chains serve as good host materials for amphipathic drugs.