Temperature Cycling Induced Deracemization of <i>p</i>-Synephrine in the Presence of Degradation

The acquisition of enantioenriched organic molecules is crucial in processes where the enantiomeric purity of active ingredients impacts efficacy and safety. Temperature cycling-induced deracemization (TCID) can achieve deracemization, but its effectiveness can be hindered by degradation reactions that influence the kinetics and the achievable enantioenrichment. This work characterizes the impact of degradation on the dynamic development of enantiomeric excess during the TCID process for the <i>p</i>-synephrine hydrochloride salt. The pilot study demonstrates that a maximum enantiomeric excess of 86% <i>R</i>-(-)-<i>p</i>-synephrine can be achieved at an intermediate batch time among all tested conditions. Degradation promoted the crystallization of a dimer with novel solid-state form, disynephrine ether dihydrochloride, which led to a substantial decrease in the slurry density of synephrine, potentially contributing to the observed decline in enantiomeric excess during the TCID process. Batch-to-batch variability in process dynamics and maximum attainable enantiomeric excess was observed, potentially attributable to the sensitivity of the process to uncontrolled initial conditions. These findings underscore the importance of accounting for degradation kinetics in the design and optimization of TCID processes for enantioenrichment.