In an earlier report, ionic interactions between ketoconazole (KTZ), a weakly basic drug, and poly(acrylic acid) (PAA), an anionic polymer, resulted in a dramatic decrease in molecular mobility as well as reduced crystallization propensity of amorphous solid dispersion (ASD) in the solid state. On the other hand, weaker dipole-dipole interactions between KTZ and polyvinylpyrrolidone (PVP) resulted in ASDs with higher crystallization propensity (Mistry Mol Pharm., 2015, 12 (9), 3339-3350). In this work, we investigated the behavior of the ketoconazole (KTZ) solid dispersions in aqueous media. In vitro dissolution tests showed that the PAA ASD maintained the level of supersaturation for a longer duration than the PVP ASD at low polymer contents (4-20% w/w polymer). Additionally, the PAA ASDs were more resistant to drug crystallization in aqueous medium when measured with synchrotron X-ray diffractometry. Two-dimensional 1H nuclear Overhauser effect spectroscopy (NOESY) NMR cross peaks between ketoconazole and PAA confirmed the existence of drug-polymer interactions in D2O. The interaction was accompanied by a reduced drug diffusivity as monitored by 2D diffusion ordered spectroscopy (DOSY) NMR and enthalpy-driven when characterized by isothermal titration calorimetry (ITC). On the other hand, drug-polymer interactions were not detected between ketoconazole and PVP in aqueous solution, with NOESY, DOSY, or ITC. The results suggest that interactions that stabilize ASDs in the solid state can also be relevant and important in sustaining supersaturation in solution.
Keywords: DOSY; ITC; NMR; NOESY; amorphous solid dispersion; crystallization; dissolution apparatus IV; drug−polymer interactions; ketoconazole; synchrotron X-ray diffractometry.