Optimizing N,N,N-trimethyl chitosan synthesis: A design of experiments (DoE) approach

This study aimed to optimize the synthesis of trimethyl chitosan (TMC) with a high degree of N,N,N-trimethylation (DTM) through a one-step procedure, minimizing reagent use, reaction time, and avoiding O-methylation, using the Design of Experiments (DoE) approach. Initially, sequential designs were done. Following the determination of the initial conditions a Fractional Factorial Design was used, investigating methyl iodide (MeI) and NaHCO₃ molar ratios, temperature, and reaction time on DTM. MeI and NaHCO₃ molar ratios were found to be significant (p-values equal to 0.02 and 0.02, respectively), the reaction temperature (p = 0.04) displayed a non-linear effect, while the reaction time was found to be non-significant (p = 0.93). Finally, a Full Factorial Design was done to optimize temperature and base addition methods. Incremental addition of the base was determined to be feasible without affecting the DTM, thereby preventing any viscosity-related problems. DTM was achieved up to 72 % in a one-step procedure, with no O-methylation. These optimized conditions offer a cost-effective, one-step synthesis method for TMC production, holding significant promise for industrial applications by avoiding multistep reactions, ensuring minimal reagent use, and preventing O-methylation. The findings mark a substantial advancement in TMC synthesis, presenting a streamlined and efficient approach with substantial practical implications for process development.