Detailed insight into the internal structure of drug‐loaded polymeric micelles is scarce, but important for developing optimized delivery systems. We observed that an increase in the curcumin loading of triblock copolymers based on poly(2‐oxazolines) and poly(2‐oxazines) results in poorer dissolution properties. Using solid‐state NMR spectroscopy and complementary tools we propose a loading‐dependent structural model on the molecular level that provides an explanation for these pronounced differences. Changes in the chemical shifts and cross‐peaks in 2D NMR experiments give evidence for the involvement of the hydrophobic polymer block in the curcumin coordination at low loadings, while at higher loadings an increase in the interaction with the hydrophilic polymer blocks is observed. The involvement of the hydrophilic compartment may be critical for ultrahigh‐loaded polymer micelles and can help to rationalize specific polymer modifications to improve the performance of similar drug delivery systems.
Bile
colloids containing taurocholate and lecithin are essential
for the solubilization of hydrophobic molecules including poorly water-soluble
drugs such as Perphenazine. We detail the impact of Perphenazine concentrations
on taurocholate/lecithin colloids using analytical ultracentrifugation,
dynamic light scattering, small-angle neutron scattering, nuclear
magnetic resonance spectroscopy, coarse-grained molecular dynamics
simulations, and isothermal titration calorimetry. Perphenazine impacted
colloidal molecular arrangement, structure, and binding thermodynamics
in a concentration-dependent manner. At low concentration, Perphenazine
was integrated into stable and large taurocholate/lecithin colloids
and close to lecithin. Integration of Perphenazine into these colloids
was exothermic. At higher Perphenazine concentration, the taurocholate/lecithin
colloids had an approximately 5-fold reduction in apparent hydrodynamic
size, heat release was less exothermic upon drug integration into
the colloids, and Perphenazine interacted with both lecithin and taurocholate.
In addition, Perphenazine induced a morphological transition from
vesicles to wormlike micelles as indicated by neutron scattering.
Despite these surprising colloidal dynamics, these natural colloids
successfully ensured stable relative amounts of free Perphenazine
throughout the entire drug concentration range tested here. Future
studies are required to further detail these findings both on a molecular
structural basis and in terms of in vivo relevance.
Predicting biopharmaceutical characteristics
and food effects for
drug substances may substantially leverage rational formulation outcomes.
We established a bile and lipid interaction prediction model for new
drug substances and further explored the model for the prediction
of bile-related food effects. One hundred and forty-one drugs were
categorized as bile and/or lipid interacting and noninteracting drugs
using 1H nuclear magnetic resonance (NMR) spectroscopy.
Quantitative structure–property relationship modeling with
molecular descriptors was applied to predict a drug’s interaction
with bile and/or lipids. Bile interaction, for example, was indicated
by two descriptors characterizing polarity and lipophilicity with
a high balanced accuracy of 0.8. Furthermore, the predicted bile interaction
correlated with a positive food effect. Reliable prediction of drug
substance interaction with lipids required four molecular descriptors
with a balanced accuracy of 0.7. These described a drug’s shape,
lipophilicity, aromaticity, and hydrogen bond acceptor capability.
In conclusion, reliable models might be found through drug libraries
characterized for bile interaction by NMR. Furthermore, there is potential
for predicting bile-related positive food effects.
Physically loaded polymeric micelles - from bulk properties to a molecular level understanding: In this work, solid-state NMR complemented by PXRD and quantum chemical calculations is used to learn about the short range order and structural arrangement in polymeric micelles formed by amphiphilic triblock copolymers. From changes in chemical shift and line widths, we could observe that at higher loadings, not just the micellar core but also the hydrophilic corona is involved in coordination of poorly soluble guest molecules, which can explain the poorer dissolution properties. This can serve as a platform for the future, targeted modification of such polymers. <br>
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