posted on 2018-10-30, 00:00authored byLaura
I. Mosquera-Giraldo, Carlos H. Borca, Andrew S. Parker, Yifan Dong, Kevin J. Edgar, Stephen P. Beaudoin, Lyudmila V. Slipchenko, Lynne S. Taylor
Amorphous
solid dispersions are widely used to enhance the oral
bioavailability of poorly water-soluble drugs. Polymeric additives
are commonly used to delay crystallization of the drug from the supersaturated
solutions formed upon ASD dissolution by influencing the nucleation
and growth of crystals. However, there is limited evidence regarding
the mechanisms by which polymers stabilize supersaturated drug solutions.
The current study used experiments and computational modeling to explore
polymer–drug interactions in aqueous solutions. Nucleation
induction times for supersaturated solutions of nine drugs in the
presence of five newly synthesized cellulose-based polymers were evaluated.
The polymers had carboxylic acids substituents with additional variations
in the side-chain structure: (1) one with a single side chain and
a carboxylic acid termination, (2) three with a branched side chain
terminated with a carboxylic and an alcohol group (varying the
cellulose linkage and the length of the hydrocarbon side chain), and
(3) one with a branched side chain with two carboxylic acid end groups.
The polymers with a short side chain and one carboxylic acid were
effective, whereas the polymers with the two carboxylic acids or a
long hydrocarbon chain were less effective. Atomic force microscopy
experiments, evaluating polymer adsorption onto amorphous drug films,
indicated that the effective polymers were uniformly spread across
the surface. These results were supported by molecular dynamics simulations
of a polymer chain in the presence of a drug aggregate in an aqueous
environment, whereby the effective materials had a higher probability
of establishing close contacts and more negative estimated free energies
of interaction. The insights provided by this study provide approaches
to design highly effective polymers to improve oral drug delivery.