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Enantiomeric Resolution of Pidotimod and Its Isomers in Pidotimod Oral Solutions Using Chiral RP-HPLC with Quadrupole Dalton Analyzer Detection

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Abstract

This study aimed to develop and validate a high-performance liquid chromatography system combined with a single-quadrupole Dalton mass detector for the separation and determination of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid) and its three isomers. The separations were achieved using a Lux Amylose-1 column operated at 40 °C using acetonitrile/0.1% trifluoroacetate (TFA) and isopropanol/0.1% TFA (90:10, v/v). The enantiorecognition mechanism was also elucidated using the ORCA 5 program. Four isomers were successfully separated with a resolution (Rs) > 1.5, with the method showing satisfactory linearity in the ranges of 0.2 to 3.5 μg·mL−1 (S,R; S,S) and 0.5 to 3.5 μg·mL−1 (R,S; R,R), along with good specificity, accuracy, and precision. Further, three batches of pidotimod oral solutions were evaluated and the S,S-isomer in each batch was detected at about 0.05%. Moreover, computational evaluations suggested that the sorbent-analyte interactions of amylose tris(3,5-dimethylphenycarbamate) can be used to successfully interpret and even predict the chromatographic separation results. The validated method showed high sensitivity and can potentially be used to analyze the isomer impurities of raw materials for quality control purposes.

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Funding

This work was supported by 2021 Project of Key Laboratory of Chemical Quality Research and Evaluation, Grant/Award Number: 1030050090128.

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Authors and Affiliations

  1. National Institutes for Food and Drug Control, Beijing, 102629, China

    Caiyu Zhang & Baoming Ning

  2. Beijing Institute of Petrochemical Technology, Beijing, 102627, China

    Wei Li

Authors
  1. Caiyu Zhang
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  2. Wei Li
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  3. Baoming Ning
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Contributions

All the authors contributed to the study conception and design. Material preparation, data collection, and analysis of HPLC-Qda were performed by CZ. WL performed the DFT calculations and analysis. The first draft was written by CZ and all the authors commented on previous versions of the manuscript. All the authors have read and approved the final manuscript. Conceptualization: CZ; methodology: CZ; formal analysis and investigation: CZ and WL; writing—original draft preparation: CZ; writing—review and editing: CZ; funding acquisition: CZ; resources: CZ, WL, and BN; supervision and project administration: BN.

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Correspondence to Baoming Ning.

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Zhang, C., Li, W. & Ning, B. Enantiomeric Resolution of Pidotimod and Its Isomers in Pidotimod Oral Solutions Using Chiral RP-HPLC with Quadrupole Dalton Analyzer Detection. Chromatographia 86, 55–62 (2023). https://doi.org/10.1007/s10337-022-04224-1

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