title: Drug-polymer interactions at water-crystal interfaces and implications for crystallization inhibition: molecular dynamics simulations of amphiphilic block copolymer interactions with tolazamide crystals.
abstract: A diblock copolymer, poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA), modulates the crystal growth of tolazamide (TLZ), resulting in a crystal morphology change from needles to plates in aqueous media. To understand this crystal surface drug-polymer interaction, we conducted molecular dynamics simulations on crystal surfaces of TLZ in water containing PEG-b-PLA. A 130-ns simulation of the polymer in a large water box was run before initiating 50 ns simulations with each of the crystal surfaces. The simulations demonstrated differentiated drug-polymer interactions that are consistent with experimental studies. Interaction of PEG-b-PLA with the (001) face occurred more rapidly (≤10 ns) and strongly (total interaction energy of -121.1 kJ/mol/monomer) than that with the (010) face (∼35 ns, -85.4 kJ/mol/monomer). There was little interaction with the (100) face. Hydrophobic and van der Waals (VDW) interactions were the dominant forces, accounting for more than 90% of total interaction energies. It suggests that polymers capable of forming strong hydrophobic and VDW interactions might be more effective in inhibiting crystallization of poorly water-soluble and hydrophobic drugs in aqueous media (such as gastrointestinal fluid) than those with hydrogen-bonding capacities. Such in-depth analysis and understanding facilitate the rational selection of polymers in designing supersaturation-based enabling formulations.
authors.affiliation: Department of Chemistry, Loyola University Chicago, Chicago, Illinois, 60660.|Manufacturing Science and Technology, Operations, AbbVie, Inc., North Chicago, Illinois, 60064.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Chemistry, Loyola University Chicago, Chicago, Illinois, 60660.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Olsen
mesh_terms: D003460:Crystallization / Q000379:methods; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007773:Lactates / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D014042:Tolazamide / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D007773:Lactates; D011108:Polymers; C088513:poly(lactic acid-ethylene glycol); D014867:Water; D011092:Polyethylene Glycols; D014042:Tolazamide
keywords: crystallization; dissolution; drug-polymer interaction; hydrophobic interaction; molecular dynamics simulation; morphology; polymeric drug delivery systems; solubility; tolazamide; van der Waals interaction