Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity

• Published in: Carbohydrate polymers Vol. 292; p. 119680
• Main Authors: Novo, Diana C., Gao, Chengzhe, Qi, Qingqing, Mosquera-Giraldo, Laura I., Spiering, Glenn A., Moore, Robert B., Taylor, Lynne S., Edgar, Kevin J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 15-09-2022
• Subjects: Amorphous solid dispersion; Bile-salts; Cellulose; Chemoselectivity; Enzalutamide; Olefin cross-metathesis; Bile-salts; Amorphous solid dispersion; Enzalutamide; Chemoselectivity; Cellulose; Olefin cross-metathesis
• ISSN: 0144-8617; 1879-1344
• DOI: 10.1016/j.carbpol.2022.119680

Crystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone.
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