Gelation during\nRing-Opening Reactions of Cellulosics\nwith Cyclic Anhydrides: Phenomena and Mechanisms

Cellulose esters are used in Food and Drug Administration-approved\noral formulations, including in amorphous solid dispersions (ASDs).\nSome bear substituents with terminal carboxyl moieties (e.g., hydroxypropyl\nmethyl cellulose acetate succinate (HPMCAS)); these ω-carboxy\nester substituents enhance interactions with drug molecules in solid\nand solution phases and enable pH-responsive drug release. However,\nthe synthesis of carboxyl-pendent cellulose esters is challenging,\npartly due to competing reactions between introduced carboxyl groups\nand residual hydroxyls on different chains, forming either physically\nor covalently cross-linked systems. As we explored ring-opening reactions\nof cyclic anhydrides with cellulose and its esters to prepare polymers\ndesigned for high ASD performance, we became concerned upon encountering\ngelation. Herein, we probe the complexity of such ring-opening reactions\nin detail, for the first time, utilizing rheometry and solid-state <sup>13</sup>C NMR spectroscopy. Gelation in these ring-opening reactions\nwas caused predominantly by physical interactions, progressing in\nsome cases to covalent cross-links over time.