Geometrical and Structural Dynamics of Imatinib within Biorelevant Colloids.

Solubilization of lipophilic drugs is essential for efficient uptake. We detail the solubilization of imatinib in simulated gastrointestinal fluids containing taurocholate (TC) and lecithin (L) and reflecting fasted versus fed states using NMR spectroscopy, X-ray diffractometry, transmission electron microscopy, and dynamic light scattering analysis. Imatinib concentration impacted colloidal geometries and molecular dynamics in a fasted state. At drug substance concentrations up to 250 µM, imatinib was mainly engulfed within the core of >110 nm in diameter vesicles. At higher drug concentrations, the colloids collapsed to <40 nm, and imatinib migrated into the shell of the micelles, mainly being associated with the lipophilic face of TC but not with L. Simulating the fed state resulted in the formation of small micelles independent of the drug concentration. Furthermore, a hydrogel was formed, effectively keeping the drug substance in an amorphous state even when stressed by drying. In conclusion, this study detailed the fascinating dynamics of colloidal structures and molecular assembly as a function of imatinib concentration in biorelevant conditions. This approach may provide a blueprint for the rational development of future pharmaceutical formulations, taking the molecular interactions with bile salts/phospholipids into account.

14N-1H HMQC solid-state NMR as a powerful tool to study amorphous formulations - an exemplary study of paclitaxel loaded polymer micelles.

Amorphous drug-polymer formulations are complex materials and often challenging to characterize, even more so if the small molecule component itself is increasingly complex. In this work, we present 14N-1H HMQC magic-angle spinning (MAS) NMR experiments in the solid state as a promising tool to study amorphous formulations. Poly(2-oxazoline) based polymer micelles loaded with different amounts of the cancer drug paclitaxel serve to highlight the possibilities offered by these experiments: while the dense core of these polymeric micelles prevents NMR spectroscopic analysis in solution and the very similar 15N chemical shifts hamper a solid-state NMR characterization based on this nucleus, 14N is a very versatile alternative. 14N-1H HMQC experiments yield well-separated signals, which are spread over a large ppm range, and provide information on the symmetry of the nitrogen environment and probe 14N-1H through-space proximities. In this way, the overall complexity can be narrowed down to specific N-containing environments. The results from the experiments presented here represent a valuable puzzle piece, which helps to improve the structural understanding of drug-polymer formulations. It can be straightforwardly combined with complementary NMR spectroscopic experiments and other analytical techniques.