Gao, Yi; Olsen, Kenneth W.
Drug-Polymer Interactions at Water-Crystal Interfaces and Implications for Crystallization Inhibition: Molecular Dynamics Simulations of Amphiphilic Block Copolymer Interactions with Tolazamide Crystals

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 50ns 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 (10ns) and strongly (total interaction energy of -121.1kJ/mol/monomer) than that with the (010) face (approximate to 35ns, -85.4kJ/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. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2132-2141, 2015


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