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Separation and Characterization of Novel Degradation and Process Related Impurities of Bedaquiline Bulk Drug.

ABSTRACT: Bedaquiline (BDQ) is a new drug approved by United States Food and Drug Administration (USFDA) in 2012 for the treatment of drug-resistant tuberculosis, which has become a major threat globally. The manuscript presents the development of three liquid chromatography (LC) based analytical methods. The first is a stability indicating RP-HPLC (reverse phase-high performance liquid chromatography) method to analyze the BDQ in presence of its degradation products. Another UPLC/ESI-MS (ultra-performance liquid chromatography/electron spray ionization-mass spectrometry) method was developed for the identification of different degradation based and process related impurities and the third, preparative HPLC method was developed for the isolation of major degradation products. Eleven degradation products and one process related impurity were identified using UPLC/ESI-MS whereas preparative HPLC was used to isolate two degradation products and their chemical structure was elucidated using nuclear magnetic resonance, mass and infra-red spectral data.

SUBMITTER: Vanavi PJ

PROVIDER: S-EPMC9439945 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Separation and Characterization of Novel Degradation and Process Related Impurities of Bedaquiline Bulk Drug.

Vanavi Pragati J PJ Rajput Sadhana J SJ

Journal of chromatographic science 20220901 7

Bedaquiline (BDQ) is a new drug approved by United States Food and Drug Administration (USFDA) in 2012 for the treatment of drug-resistant tuberculosis, which has become a major threat globally. The manuscript presents the development of three liquid chromatography (LC) based analytical methods. The first is a stability indicating RP-HPLC (reverse phase-high performance liquid chromatography) method to analyze the BDQ in presence of its degradation products. Another UPLC/ESI-MS (ultra-performanc ...[more]

PMID: 34607340

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Project description:Therapeutic oligonucleotides such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA) are among the most remarkable modalities in modern medicine. ASOs and siRNA are composed of single- or double-stranded 15-25 mer synthesized oligonucleotides, which can be used to modulate gene expression. Liquid chromatography-mass spectrometry (LC/MS) is a necessary technique for the quality control of therapeutic oligonucleotides; it is used to evaluate the quantities of target oligonucleotides and their impurities. The widely applied oligonucleotide therapeutic quantitation method uses both ultraviolet (UV) absorbance and the MS signal intensity. Peaks separated from the main peak, which contains full-length product, are generally quantitated by UV. However, coeluting impurities, such as n - 1 shortmers, abasic oligonucleotides, and PS → PO (phosphorothiate to phosphodiester) oligonucleotides, are quantitated by MS. These coeluting impurities can also be comprised of various isomers with the same modification, thus increasing the difficulty in their separation and relative quantitation by LC/MS. It is possible that a specific isomer with a certain structural form induces toxicities. Therefore, characterization of each isomer separation is in high demand. In this study, we separated and characterized oligonucleotide isomers by employing a cyclic ion mobility mass spectrometry (cyclic IMS) system, which allows the separation of ions with the same m/z ratio based on their structural differences. Patisiran antisense and sense strands and their n - 1 and abasic isomers were used as sample sequences, and their ratio characterization was achieved by cyclic IMS. In addition, we evaluated the PS → PO conversion isomers of the antisense strand of givosiran, which originally contained four PS modification sites. The PS → PO isomers exhibited specific and distinguishable mobiligram patterns. We believe that cyclic IMS is a promising method for evaluating therapeutic oligonucleotide isomers.

Dataset Information

Separation and Characterization of Novel Degradation and Process Related Impurities of Bedaquiline Bulk Drug.

Publications

Separation and Characterization of Novel Degradation and Process Related Impurities of Bedaquiline Bulk Drug.

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