Poor aqueous solubility is a major hurdle in the pipeline of developing new drugs. This lowers drug effectiveness and results in limited drug bioavailability. Crystallization inhibitors have been employed as excipients in amorphous solid dispersions in order to form metastable, supersaturated drug formulations with enhanced solubility. Olefin cross-metathesis has successfully provided an array of new and multifunctional cellulose-based derivatives for amorphous solid dispersion polymer matrices. Several of these derivatives, as well as endogenous bile salts, effectively extend nucleation induction times of hydrophobic therapeutics in physiologically similar settings. In this study, cellulose ether derivatives are appended to bile salt mimics to yield conjugates that may act synergistically as drug-crystallization inhibitors while also increasing drug solubility. Conjugate hydrophilicity is enhanced via selective modification of bile salt mimics and by choice of cellulosic backbones (hydroxypropyl and hydroxyethyl cellulose). Increased hydrophilicity enhances the ability of these conjugates to achieve supersaturation. Here we report, the synthesis of these novel conjugates and characterization by NMR spectroscopy, DSC, SEC and FTIR. Amorphous solid dispersion candidacy is evaluated via aqueous stability, solubility, and retention of amorphous properties of these novel candidates, as well as induction time studies in biologically relevant conditions.

Design of synergistic drug crystallization inhibitors via olefin cross-metathesis of hydrophilic cellulose ethers and bile acid derivatives

255th National Meeting (2018)

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