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 et al. 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 1 H nuclear Overhauser effect spectroscopy (NOESY) NMR cross peaks between ketoconazole and PAA confirmed the existence of drug−polymer interactions in D 2 O. 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.

Amorphous solid dispersions (ASDs) can potentially increase the apparent solubility and thereby the oral bioavailability of poorly soluble compounds. However, their physical instability, i.e., potential to crystallize, is a major concern. Our objective was to explore methods for rapid assessment of the physical stability of ASDs. Ketoconazole ASDs were prepared with each of the three polymers, poly­(acrylic acid) (PAA), poly­(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP). The physical stability of these ASDs was evaluated after exposure to 90% RH (25 °C) in an automated water sorption analyzer. The onset time for ketoconazole crystallization, induced by water sorption, was rank ordered as PAA > PHEMA > PVP. Additionally, the ability of the polymers to inhibit crystallization on contact with aqueous medium was studied by powder X-ray diffractometry using synchrotron radiation. In this case, the rank ordering was PAA ∼ PHEMA > PVP. To check the validity of our approach, the long-term stability of ketoconazole in ASDs was evaluated in the glassy state, both at 25 and at 40 °C, and was rank ordered as PAA > PHEMA > PVP. Crystallization, accelerated by water vapor sorption, can serve as an effective preliminary screening tool to rapidly evaluate and rank order the physical stability of ASDs.

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We present a new approach for characterizing drug–polymer interactions in aqueous media, using sedimentation velocity analytical ultracentrifugation (AUC). We investigated the potential interaction of ketoconazole (KTZ), a poorly water-soluble drug, with polyacrylic acid (PAA) and a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus) in aqueous buffers. The effect of the polymer on the sedimentation coefficient of the drug was the observable metric. The drug alone, when subjected to AUC, exhibited a very narrow sedimentation peak at 0.2 Svedberg (S), in agreement with the expectation for a monomeric drug with a molar mass < 1000 Dalton. Conversely, the neat polymers showed broad profiles with higher sedimentation coefficients, reflecting their larger more heterogeneous size distributions. The sedimentation profiles of the drug–polymer mixtures were expectedly different from the profile of the neat drug. With KTZ-Soluplus, a complete shift to faster sedimentation times (indicative of an interaction) was observed, while with KTZ-PAA, a split peak indicated the existence of the drug in both free and interacting states. The sedimentation profile of carbamazepine, a second model drug, in the presence of hydroxypropyl methyl cellulose acetate succinate (HPMCAS, another polymer) revealed multiple “populations” of drug–polymer species, very similar to the sedimentation profile of neat HPMCAS. The interactions probed by AUC were compared with the results from isothermal titration calorimetry. In vitro dissolution tests performed on amorphous solid dispersions prepared with the same drug–polymer pairs suggested that the interactions may play a role in prolonging drug supersaturation. The results show the possibility of characterizing drug–polymer interactions in aqueous solution with high hydrodynamic resolution, addressing a major challenge frequently encountered in the mechanistic investigations of the dissolution behavior of amorphous solid dispersions.