Amorphous solid dispersions (ASDs) are widely used to enhance the oral bioavailability of poorly water-soluble drugs. Polymeric additives are commonly used to delay crystallization of the drug from the supersaturated solutions formed upon ASD dissolution by influencing the nucleation and growth of crystals. However, there is limited evidence regarding the mechanisms by which polymers stabilize supersaturated drug solutions. The current study used experiments and computational modeling to explore polymer-drug interactions in aqueous solutions. Nucleation induction times for supersaturated solutions of nine model drugs in the presence of five newly synthesized cellulose-based polymers were evaluated. The polymers with a short side chain and one carboxylic acid were effective, whereas the polymers with the two carboxylic acids or a long hydrocarbon chain were less effective. Computed radial distribution functions and estimated free energies of interaction between a nucleus of drug molecules and a polymer chain model were useful to predict possible intermolecular interactions in solution. The tendency of the polysaccharides to interact at the amorphous drug-water interface was verified by AFM measurements, whereby computational predictions showed good agreement with experimental data. These approaches lend support to the hypothesis that polysaccharides that are effective crystallization inhibitors have a balance of hydrophobic and hydrophilic groups. Thus, effective polysaccharides interact with drug aggregates via hydrophobic interactions with backbone functionalities such as ethyl groups, while carboxylate groups associated with tethered substituents lead to an extended polymer conformation that in turn minimizes the tendency for intramolecular interactions. These results not only provide fundamental insight into mechanisms by which polymers modify nucleation rates, but also pave the way for the rational design of new materials for crystallization inhibition. These findings have been recently reported in Biomacromolecules.

Crystallization inhibition properties of cellulose esters and ethers for a group of chemically diverse drugs: Experimental and computational insight

2019 Spring National Meeting

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