Mechanism of formation governs the mechanism of release of antibiotics from calcium phosphate nanopowders and cements in a drug-dependent manner.

The kinetics of drug release from hydroxyapatite (HAp) cements could be tuned by controlling the kinetics of crystallization of their HAp precursor powders during synthesis. Here it is shown that this history of formation affects not only the kinetics, but also the mechanism of release. Cements composed of two HAp powders precipitated under different conditions, one (HAp2) taking twice longer to transform from the amorphous to the crystalline state than the other (HAp1), were mixed at different ratios to tune their drug release kinetics and tested for the release mechanism in conjunction with compositional and microstructural analyses. While the cement component converting to the amorphous phase during gelation (HAp2) exhibited a faster, but also more anomalous, non-Fickian mechanism of release of vancomycin, the cement component retaining its crystalline state all throughout gelation, setting and hardening (HAp1) stabilized at the ideal, Fickian diffusion case corresponding to the Korsmeyer-Peppas exponent value of 0.45 ± 0.02. This effect got reversed for the other antibiotic studied as a drug, ciprofloxacin, in which case HAp2 exhibited the ideal, Fickian diffusion with n = 0.45 ± 0.02 and the increase in the content of the cement component retaining its crystallinity during gelation, setting and hardening (HAp1) steadily shifted the mechanism of release to more anomalous, non-Fickian types. This has indicated that the molecular structure of the drug is an essential determinant of the mechanism of release and that the design of a carrier for a universally tunable release of drugs based on the passive transport is likely impossible. Preliminary assays involving the addition of chitosan or gelatin as polymeric components to HAp led to the inclusion of swelling and erosion as additional effects by which the drug escapes the carrier and shifted the release toward less diffusional and more multimodal mechanisms. With regard to the microstructural and compositional effects governing the release mechanism and kinetics, the retention of a finite concentration of slit-like pores of the amorphous precursor in HAp2 and its lower surface energy and lesser drug binding potential in the gelled, amorphous state, but also its possibly less stable and more diffusive particle surface and higher structural water content were elaborated as potential reasons explaining the distinct rates and mechanisms of release from the two HAp powders with different histories of formation.