Precise analysis of thyroxine enantiomers in pharmaceutical formulation by mobility difference based on cyclodextrin

Identification and determination of chiral pharmaceutical residues is still a challenging analytical puzzle. In this work, a simple, rapid, and effective method for chiral D/L-tetraiodothyronine (T4) separation and quantitative was developed based on host-guest recognition using ion mobility spectrometry-mass spectrometry (IMS-MS). The D/L-T4 enantiomers were mobility separated by their diastereomeric complexes through mixing with cyclodextrin (CD) and metal ions. D/L-T4 was first separated by complexing with host molecule (a-, p-, c-CD), observing weak peak-to-peak resolution (Rp-p) by the formed binary complex [CD + D/L-T4-H]+, and the Rp-p decreased with the CD size increasing. However, the separation effect of D/L-T4 was much improved with the addition of divalent metal ions (G2+) by the formed ternary complex [CD + D/L-T4 + G]2+. In comparison, a-CD related complexes can possess the best separation effect for D/L-T4 in most cases. Considering the high selectivity, non-toxic, and chemically stable of p-CD, [p-CD + D/L-T4 + Ca]2+ was selected for D/L-T4 analysis (RP-P = 0.764). Whereafter, chemical theoretical conformations for [p-CD + D/L-T4 + H]+ and [p-CD + D/L-T4 + C a]2+ were optimized, discovering similar micro-interaction modes between [p-CD + D-T4 + H] + and [p-CD + L-T4 + H]+; while with the addition of Ca2+, significantly different interaction modes were observed between [p-CD + D-T4 + Ca]2+ and [p-CD + L-T4 + Ca]2+. And theo-retical collision cross section (CCS) trends for the complexes were consistent with that of the exper-imental results. Additionally, calibration curves were linear within 1.00 to 104 ng mL-1 with coefficient (R2 > 0.99), gaining the limit of detection (LODs) calculation of 0.11 ng mL-1, and the detection range between D-T4 and L-T4 of 45.6:1 to 1:59.8. Finally, the method was applied for D/L-T4 detection in Levothyroxine tablets, the detection content has good consistency on drug labeling. Because the proposed method exhibited good analytical performance in terms of speed, selectivity, sensitivity, and reproducibility of the measurements, that can be a promising strategy for effective D/L-T4 detection in pharmaceutical industries or other practical samples.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).