(774b) Assessing the Efficacy of Thermo-Responsive Poly(N-isopropylacrylamide) in Phenytoin Solid Dispersion Formulation Using Atomistic Molecular Dynamics Simulations

Abstract for AICHE Annual
Meeting 2016

Submission Deadline: May 9^th,
2016

Session: 26004 Amorphous
Solid Dispersion for Drug Product

Category: Pharmaceutical
Discovery, Development, and Manufacturing Forum

Assessing the Efficacy of Thermo-Responsive
Poly(N-isopropylacrylamide) in Phenytoin Solid
Dispersion Formulation Using Atomistic Molecular Dynamics Simulations

Soroush Moghadam¹ and Ronald G. Larson²

¹Department of
Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109

²Department of Chemical
Engineering, University of Michigan, Ann Arbor, MI, 48109

For an active
pharmaceutical ingredient (API) to be absorbed from the gastro-intestinal tract
into the bloodstream, it must be sufficiently soluble in the GI fluid. However,
more than 40% of new chemical entities in the pharmaceutical industry are
poorly soluble, leading to drug aggregation and crystallization, which
necessitates the use of an excipient to stabilize and increase the solubility.
Solid dispersions can maintain the API in an amorphous form and result in a
supersaturated API solution upon its dissolution in the GI tract. As the
hydrophilic component, thermo-sensitive poly(N-isopropylacrylamide), namely
pNIPAAm, has been suggested to provide desired controlled release properties due
to its lower critical solution temperature (LCST~32^oC),
biocompatibility and also large design space for its functional groups. Although
many simulation studies analyzed the LCST behavior of pNIPAAm chains in water, to
date there has not been a computational analysis of how pNIPAAm interacts with
drug molecules at molecular levels as a function of temperature and how we can
tune these properties to reach desired stability of polymer-drug complex. In
this study, we performed
all-atom molecular dynamic (AA-MD) simulations to model
pNIPAAm and a drug candidate, phenytoin, in an explicit water environment. AMBER forcefield and
solvated ensemble averaging of partial charges have been implemented. After
validating the forcefield parameters using the well-known lower critical
solution behavior of pNIPAAm, we simulated the polymer-drug complex in water
and its behavior at temperatures below (295K) and above the LCST (310K). The
effect of copolymerization with hydrophilic elements (e.g. Dimethylacylamide
(DMA)) on the excipient behavior has been studied. We found that existence of
hydrophilic comonomers in a pNIPAAm chain dramatically affects its temperature
transition dependence. However, It affects affinity of the excipient functional
groups to interact with drug molecules as well. Using radial distribution
functions, we found that there is an optimum comonomer molar fraction of around
20-30% DMA at which interaction with phenytoin drug molecules is strongest. Furthermore,
maintaining the weight percents of the components, using shorter polymer chains
close to pNIPAAm reported persistence lengths can significantly influence the
drug-polymer interaction upon heating. Although the length and time scales of
our simulations are not high enough to be conclusive, this study provides
insights to help optimizing the composition of pNIPAAm for any given drug.

KEYWORDS: Polymer Drug
Aggregates, Molecular Dynamics, pNIPAAm