Sustainable Mechanochemical Preparation of Carboxylated Cellulose Nanocrystals for Scalable Tablet Production and Evaluation of Gut Microbiota Safety

The clinical application of cellulose nanocrystals (CNCs) as pharmaceutical excipients has been hindered by the low yields (<50%) of traditional acid hydrolysis and unclear comprehensive safety evaluations regarding the gut microbiota. Herein, we report a green mechanochemical synergistic strategy utilizing l-malic acid (l-MA)-assisted high-shear hydrolysis to overcome these bottlenecks. This process achieved an exceptional yield of 91.51% while endowing the CNCs with high crystallinity (80.16%) and abundant surface carboxyl groups via in situ esterification. When employed as a direct compression excipient, the CNCs formed a unique “interlocking inlay” microstructure, resolving the long-standing trade-off between tablet hardness and disintegration. The resulting tablets exhibited more superior hardness (>29 N) and minimal friability (<0.31%) than commercial microcrystalline cellulose and starch, yet achieved ultrarapid disintegration (∼3 s) driven by enhanced hydrophilicity and capillary action. Furthermore, life cycle assessment (LCA) demonstrated significant reductions in carbon footprint and energy consumption. Crucially, an in vitro gut microbiota model confirmed the biological safety of the CNCs, showing no adverse effects on the growth kinetics of core intestinal bacteria. This work provides a sustainable, scalable paradigm for next-generation pharmaceutical excipients.