Hydrophobic ion pairing: lipophilicity improvement of anionic macromolecules by divalent cation mediated complex formation

The aim of this study was to develop an alternative strategy to sufficiently increase the lipophilicity of anionic model macromolecules (MM) without the use of cationic counterions. Enoxaparin (ENO), insulin (INS) and poly-L-glutamic acid (PLG) were ion paired with anionic surfactants (sodium decanoate (DEC), sodium dodecyl sulfate (SDS), sodium stearate (SS) and sodium octadecyl sulfate (SOS)), mediated by divalent cations such as magnesium, calcium and zinc. Complexes were evaluated regarding their precipitation efficiency and logD_{n-butanol/water}. SEDDS were developed, loaded with the complexes and characterized for their size and stability. Finally, payloads and logD_{SEDDS/release medium} were determined. Divalent cation mediated ENO, INS and PLG complexes were successfully formed as underlined by high precipitation efficiencies above 90% in case of Zn²⁺-mediated complexes. Most pronounced increase in logD_{n-butanol/water} was achieved for ENO-Zn²⁺-SOS (1.85), INS-Zn²⁺-SOS (0.80) and PLG-Zn²⁺-SS (0.48) providing suitable solubilities in commonly used SEDDS components. Developed SEDDS displayed droplet sizes below 200 nm without major changes after loading with MM complexes. Payloads up to 18.72 mg/ml could be achieved in developed SEDDS for ENO-Zn²⁺-SOS, and 2.44 mg/ml and 6.93 mg/ml for INS-Zn²⁺-SOS and PLG-Zn²⁺-SS, respectively. In general, highest lipophilicity enhancement and thus solubility in SEDDS was obtained with Zn²⁺-mediated complexes among the investigated cations and particularly with the highly negatively charged polysaccharide ENO. The formation of complexes between anionic MM and anionic surfactants mediated by divalent cations, substituting normally used cationic counterions exhibiting higher toxicity, offers a promising alternative to enhance their lipophilicity for oral drug delivery.