464851 Assessing the Efficacy of Thermo-Responsive Poly(N-isopropylacrylamide) in Phenytoin Solid Dispersion Formulation Using Atomistic Molecular Dynamics Simulations

Friday, November 18, 2016: 12:50 PM
Continental 4 (Hilton San Francisco Union Square)
Soroush Moghadam, Mechanical Engineering, University of Michigan, Ann Arbor, MI and Ronald G. Larson, Chemical Engineering, University of Michigan, Ann Arbor, MI

Abstract for AICHE Annual Meeting 2016

Submission Deadline: May 9th, 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~32oC), 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


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