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.
Microbial, mammalian,
and plant cells produce and contain secondary
metabolites, which typically are soluble in water to prevent cell
damage by crystallization. The formation of ion pairs, for example,
with carboxylic acids or mineral acids, is a natural blueprint to
maintain basic metabolites in solution. Here, we aim at showing whether
the mostly large carboxylates form soluble protic ionic liquids (PILs)
with the basic natural product papaverine resulting in enhanced aqueous
solubility. The obtained PILs were characterized by
1
H–
15
N HMBC nuclear magnetic resonance (NMR) and in the solid
state using X-ray powder diffraction, differential scanning calorimetry,
and dissolution measurements. Furthermore, their supramolecular pattern
in aqueous solution was studied by means of potentiometric and photometrical
solubility, NMR aggregation assay, dynamic light scattering, zeta
potential, and viscosity measurements. Thereby, we identified the
naturally occurring carboxylic acids, citric acid, malic acid, and
tartaric acid, as being appropriate counterions for papaverine and
which will facilitate the formation of PILs with their beneficial
characteristics, like the improved dissolution rate and enhanced apparent
solubility.
Interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz as model drug, the triblock copolymers Pluronic F-127 (PF127) and poly(2-oxazolin) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was observed if EFV was involved. The formulations showed multi-facetted concentration and composition dependent aggregation. This demonstrates that separate evaluation of polymers or drugs in biorelevant media is not sufficient and their mixtures need to be carefully studied.<br>
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