Assessing the Efficacy of Poly(<i>N</i>‑isopropylacrylamide) for Drug Delivery Applications Using Molecular Dynamics Simulations

All-atom molecular dynamic simulations (AA-MD) are performed for aqueous solutions of hydrophobic drug molecules (phenytoin) with model polymer excipients, namely, (1) N-isopropylacrylamide, (pNIPAAm), (2) pNIPAAm-co-acrylamide (Am), and (3) pNIPAAm-co-dimethylacrylamide (DMA). After validating the force field parameters using the well-known lower critical solution behavior of pNIPAAm, we simulate the polymer–drug complex in water and its behavior at temperatures below (295 K) and above the LCST (310 K). Using radial distribution functions, we find that there is an optimum comonomer molar fraction of around 20–30% DMA at which interaction with phenytoin drug molecules is strongest, consistent with recent experimental findings. The results provide evidence that molecular simulations are able to provide guidance in the optimization of novel polymer excipients for drug release

Assessing the Efficacy of Poly(<i>N</i>‑isopropylacrylamide) for Drug Delivery Applications Using Molecular Dynamics Simulations

All-atom molecular dynamic simulations (AA-MD) are performed for aqueous solutions of hydrophobic drug molecules (phenytoin) with model polymer excipients, namely, (1) <i>N</i>-isopropylacrylamide, (pNIPAAm), (2) pNIPAAm-<i>co</i>-acrylamide (Am), and (3) pNIPAAm-<i>co</i>-dimethylacrylamide (DMA). After validating the force field parameters using the well-known lower critical solution behavior of pNIPAAm, we simulate the polymer–drug complex in water and its behavior at temperatures below (295 K) and above the LCST (310 K). Using radial distribution functions, we find that there is an optimum comonomer molar fraction of around 20–30% DMA at which interaction with phenytoin drug molecules is strongest, consistent with recent experimental findings. The results provide evidence that molecular simulations are able to provide guidance in the optimization of novel polymer excipients for drug release

Unraveling Dynamics of Entangled Polymers in Strong Extensional Flows

The traditional Doi–Edwards tube model, applied to extensional flows at strain rates above the inverse Rouse time, predicts that the tube deforms affinely, which implies that the extensional stress reaches its plateau as soon as the chain has become locally fully stretched, even if the chain is still folded, and far from being completely unraveled. By starting from a state in which the chain is in a locally fully stretched, but folded, state, we develop an “entangled kink dynamics algorithm” that predicts the final unraveling of an ensemble of mutually entangled, folded chains, driven by a combination of drag forces and chain tension, with negligible Brownian motion. Equations for motions of both entangled folds and unentangled folds in which two chains hook together at a single fold point are derived and solved, including the effects of constraint release that occurs when the end of one chain passes through the fold at which that chain is entangled. This model predicts that the stress approaches its final plateau stress only after complete chain unraveling, which for long chains is at much higher strains than in the tube model

Multiscale Modeling of Sub-Entanglement-Scale Chain Stretching and Strain Hardening in Deformed Polymeric Glasses

Using both coarse-grained (CG) and fine-grained (FG) simulations we show how strain hardening in polymeric glasses under uniaxial extension arises from highly stretched strands that form as the polymer chains deform subaffinely on increasing length scales as strain increases. The coarse-grained simulations are performed using the hybrid Brownian dynamics method (HBD) [Zou, W.; Larson, R. G. Soft Matter 2016, 3, 3853–3865] with 10–30 coarse-grained springs per polymer chain, while the fine-grained simulations employ the Kremer-Grest bead–spring model with 600 beads per chain. We find that the HBD model accurately predicts how the MD chain configurations evolve during deformation despite being a single-chain-in-mean-field model that does not account for entanglements or monomer-level structure. We show using both models that the glassy strain hardening modulus GR is much larger than the melt plateau modulus GN because chain segments become highly stretched at modest Hencky strain (ϵ < ∼1) owing to the high interchain friction in the glass. HBD model predictions of strain hardening match those of the MD simulations in shape and magnitude, relative to the flow stress, which is the stress just beyond the yield point, for several deformation protocols, and also capture the increase in strain hardening with increasing chain length that saturates in the long chain limit. As deformation proceeds, chains begin to form kinks or folds (starting at a Hencky strain ϵ ≈ 1.0) analogous to those produced in extensional flows of dilute and entangled polymer solutions. We identify “entangled kinks” in the MD simulations; these do not appear to strongly influence strain hardening but may be important in delaying fracture. Motivated by these results, we improve upon HBD’s ability to accurately capture stress–strain curves at small strains through yielding and strain softening by extending the theory to multiple segmental relaxation modes, whose strain-dependent relaxation times are obtained from small-molecule probe relaxation experiments by Ediger and co-workers [Bending, B.; Ediger, M. D. J. Polym. Sci. B 2016, 54, 1957–1967]. This produces excellent agreement between the HBD model and experimental stress–strain curves through the yield point but requires segmental relaxation data for each experiment. Future work should aim at developing a constitutive equation for the segmental relaxation