Tautomeric asymmetric self–inhibition: an underexploited pH–dependent strategy to enhance berberrubine solubility

Cocrystals and co‑amorphous systems are widely used to enhance drug solubility, yet they invariably rely on exogenous coformers; even those listed as Generally Recognized as Safe (GRAS) carry residual safety concerns that are difficult to eliminate. Here we present an additive‑free alternative built on tautomeric asymmetric self‑inhibition. Two novel hydrated polymorphs of berberrubine (BRB)-Form A (C19H22ClNO7, triclinic, P-1) and Form B (C19H20ClNO6, monoclinic, P21/c)-obtained via keto-enol tautomerism, serve as a proof of concept. A chemically counterintuitive solubility behavior emerged: Form A maintains a nearly constant solubility across pH 1.2-7.4, whereas Form B, comparable to Form A under strongly acidic or basic conditions, surges to roughly ten‑fold higher solubility at the pH where both tautomers coexist. Using quantum chemical calculations and complementary analyses, we traced this striking phenomenon to an asymmetric self‑inhibition mechanism. A quantitative model, the Inhibition Efficiency Index (IEI), was further developed to evaluate asymmetric self‑inhibition, and it accurately predicts the observed pH‑dependent solubility dichotomy. These results demonstrate that tautomerism‑driven crystal engineering can synergistically improve the dissolution rate and physical stability of poorly soluble drugs, helping to overcome bioavailability constraints. The insight also lays a rational foundation for formulating tautomeric drugs, berberrubine included, to achieve predictable and enhanced oral absorption.