The phase-inversion hydrothermal synthesis of alendronate and Ca(ii) promotes the formation of a coordination complex whose solid-state, stability, particle size and cytotoxicity were assessed and optimized to potentiate its biomedical applications.

Formation of several materials denominated as bisphosphonate-based coordination complexes (BPCCs), resulted from the reaction between clinically employed bisphosphonate, zoledronate (ZOLE) and bioactive metals (M2+ = Ca2+, Mg2+ and Zn2+) salts....

Coordination of clinically employed bisphosphonate, risedronate (RISE), to bioactive metals, Ca 2+ , Mg 2+ , and Zn 2+ , allowed the formation of bisphosphonate-based coordination complexes (BPCCs). Three RISE-based BPCCs, RISE-Ca, RISE-Mg, and RISE-Zn, were produced, and their structures were elucidated by single crystal X-ray diffraction. Interestingly, the addition of an auxiliary ligand, etidronic acid (HEDP), resulted in the recrystallized protonated form of the ligand, H-RISE. The pHdependent structural stability of the RISE-based BPCCs was measured by means of dissolution profiles under neutral and acidic simulated physiological conditions (PBS and FaSSGF, respectively). In comparison to RISE (Actonel), the complexes showed a lower equilibrium solubility (∼70−85% in 18−24 h) in PBS, while a higher equilibrium solubility (∼100% in 3 h) in acidic media. The results point to the capacity to release this BP in a pH-dependent manner from the RISE-based BPCCs. Subsequently, the particle size of RISE-Ca was reduced, from 300 μm to ∼350 d.nm, employing the phase inversion temperature (PIT)-nanoemulsion method, resulting in