Concise behavior of Curcumin in water-ethanol: Critical Water Aggregation Percentage and multivariate analysis of protolytic equilibria

Abstract Curcumin (CUR) is a promising natural product in the field of biomedical applications, having a range of pharmacological effects. Despite this, clinical trials have reported poor absorption, low bioavailability, and rapid metabolism, which reduce its effectiveness. In general, these problems are related to the highly hydrophobicity of CUR, a limiting factor not only in its applications but also in its characterization. In fact, the spectroscopic description of CUR in homogeneous/microheterogenous media has a range of controversies, mainly about its self-aggregation process and its pKa determinations. To solve these drawbacks, the present work describes the concise spectroscopic analysis of CUR in different water-ethanol mixtures. The Critical Water Aggregation Percentage (CWAP), i.e., the limit percentage in which monomers are predominant is 50% of water. The Multivariate Analysis that employs the chemometric tools (MASDA) by Q-mode method was efficient in demonstrating that above 75% (water: ethanol v/v) CUR exists predominantly in self-aggregated form. In addition, the molecular modeling conducted in the ORCA 4.2 using the Hartree-Fock method associated with MASDA demonstrated that even at 30% (water: ethanol v/v) CUR dimers are present (∼6%). From these conditions, the complex protolytic equilibria of CUR was evaluated in water-ethanol (30:70 v/v) with or without ionic strength. The pKa determination was also conducted by Multivariate Analysis. The obtained pKa values in the presence or absence of ionic strength control do not differ significantly. The protolytic equilibria can be represented in terms of the principal species: CUR0 ⇌ CUR−1 (enol/enolate), CUR−1 ⇌ CUR−2 (phenol/phenolate) and CUR−2 ⇌ CUR−3 phenol/phenolate). The chemometric also allows to obtain the spectra of the pure species and the molar absorptivity for each one. This set of results is especially important to complement the literature about the basic spectroscopy and physicochemical properties of CUR.