Accelerating Pharmaceutical Process Development with an Acoustic Droplet Ejection-Multiple Reaction Monitoring-Mass Spectrometry Workflow

Fast-paced pharmaceutical process developments (e.g., high-throughput experimentation, directed evolution, and machine learning) involve the introduction of fast, sensitive, and accurate analytical assays using limited sample volumes. In recent years, acoustic droplet ejection (ADE) coupled with an...

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Bibliographic Details
Published in:Analytical chemistry (Washington) 2024-01, Vol.96 (3), p.1138-1146
Main Authors: Hu, Hang, Singh, Andrew N., Lehnherr, Dan, Mdluli, Velabo, Chun, Stephanie W., Makarewicz, Amanda M., Gouker, Joseph R., Ukaegbu, Ophelia, Li, Shasha, Wen, Xiujuan, McLaren, David G., Velasquez, Juan E., Moore, Jeffrey C., Galanie, Stephanie, Appiah-Amponsah, Emmanuel, Regalado, Erik L.
Format: Article
Language:English
Subjects:
Acoustics
Assaying
Catalysts
Chemical reactions
Cross coupling
Directed evolution
Droplets
Drug Development
Ejection
Liquid chromatography
Machine learning
Mass spectrometry
Mass Spectrometry - methods
Mass spectroscopy
Mathematical analysis
Monitoring
Peptides
Pharmaceuticals
R&D
Research & development
Sampling
Scientific imaging
Screening
Workflow
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Summary:Fast-paced pharmaceutical process developments (e.g., high-throughput experimentation, directed evolution, and machine learning) involve the introduction of fast, sensitive, and accurate analytical assays using limited sample volumes. In recent years, acoustic droplet ejection (ADE) coupled with an open port interface has been invented as a sampling technology for mass spectrometry, providing high-throughput nanoliter analytical measurements directly from the standard microplates. Herein, we introduce an ADE-multiple reaction monitoring-mass spectrometry (ADE-MRM-MS) workflow to accelerate pharmaceutical process research and development (PR&D). This systematic workflow outlines the selection of MRM transitions and optimization of assay parameters in a data-driven manner using rapid measurements (1 sample/s). The synergy between ADE sampling and MRM analysis enables analytical assays with excellent sensitivity, selectivity, and speed for PR&D reaction screenings. This workflow was utilized to develop new ADE-MRM-MS assays guiding a variety of industrial processes, including (1) screening of Ni-based catalysts for C–N cross-coupling reaction at 1 Hz and (2) high-throughput regioisomer analysis-enabled enzyme library screening for peptide ligation reaction. ADE-MRM-MS assays were demonstrated to deliver accurate results that are comparable to conventional liquid chromatography (LC) experiments while providing >100-fold throughput enhancement.
ISSN:0003-2700
1520-6882
DOI:10.1021/acs.analchem.3c04211