Temperature Cycling Induced Deracemization of p-Synephrine in the Presence of Degradation

Abstract

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 p-synephrine hydrochloride salt. The pilot study demonstrates that a maximum enantiomeric excess of 86% R-(-)-p-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.

Scheme 1. Racemization Reaction Scheme of R-(-)-p-Synephrine in Acidic Media

Scheme 2. Elimination Reaction to Form Di-Synephrine Ether Dihydrochloride (Dimer)

Figure 1

Dynamic development of the enantiomeric excess for pilot study experiments PT-01 to PT-08 (see Section 4.2 for experimental details). SD: initial enantiomeric excess, samples collected 10 min after enantiopure R-(-)-p-synephrine freebase addition.

Figure 2

Dynamic development of the enantiomeric excess and solid-state forms for pilot study experiments PS-01 to PS-04 (see Section 4.2 for experimental details). (A) Enantiomeric excess. (B) Melting point. (C) Enthalpy of fusion. IS: RS-SYNHCl salt slurry; SA: RS-SYNHCl salt slurry resuspended with 0.5 mL of salt buffer solution ([3g of RS-SYNHCl salt]/[mL of 4 M HCl/KCl buffer]); SD: initial enantiomeric excess samples, collected 10 min post enantiopure R-(-)-p-synephrine freebase addition.

Figure 3

PXRD diagrams from pilot study experiments PS-01 to PS-04 (see Section 4.2 for experimental details). The sample collected (A) immediately after resuspending the RS-SYNHCl salt slurry with 0.5 mL RS-SYNHCl salt buffer solution ([3g RS-SYNHCl salt]/[mL 4 M HCl/KCl buffer]), (B) at 10 min after adding enantiopure R-(-)-p-synephrine freebase, and (C–F) immediately after completing the sixth, eighth, and tenth cycles and thirty-third cycle (∼24 h), respectively. SATDOH: simulated PXRD pattern derived from R-(-)-p-synephrine hydrochloride salt. Dimer: simulated PXRD pattern of disynephrine ether dihydrochloride from the SC-XRD data (Sections 4.3.2 and 4.4.4).

Figure 4

Synephrine depletion kinetics at 50 °C (see Section 4.3.1; Supporting Information, Note 2B). The concentration of p-synephrine hydrochloride salt buffer solution was 3g of RS-SYNHCl salt per mL of 4 M HCl/KCl buffer. The temperature was 50 °C. (A) Transmission recorded in Crystal 16. (B) Synephrine concentration measured by HPLC over time.