Hydrophobic ion pairing: encapsulating small molecules, peptides, and proteins into nanocarriers

Hydrophobic ion pairing has emerged as a method to modulate the solubility of charged hydrophilic molecules ranging in class from small molecules to large enzymes. Charged hydrophilic molecules are ionically paired with oppositely-charged molecules that include hydrophobic moieties; the resulting uncharged complex is water-insoluble and will precipitate in aqueous media. Here we review one of the most prominent applications of hydrophobic ion pairing: efficient encapsulation of charged hydrophilic molecules into nano-scale delivery vehicles - nanoparticles or nanocarriers. Hydrophobic complexes are formed and then encapsulated using techniques developed for poorly-water-soluble therapeutics. With this approach, researchers have reported encapsulation efficiencies up to 100% and drug loadings up to 30%. This review covers the fundamentals of hydrophobic ion pairing, including nomenclature, drug eligibility for the technique, commonly-used counterions, and drug release of encapsulated ion paired complexes. We then focus on nanoformulation techniques used in concert with hydrophobic ion pairing and note strengths and weaknesses specific to each. The penultimate section bridges hydrophobic ion pairing with the related fields of polyelectrolyte coacervation and polyelectrolyte-surfactant complexation. We then discuss the state of the art and anticipated future challenges. The review ends with comprehensive tables of reported hydrophobic ion pairing and encapsulation from the literature.