Distinguishing Pharmaceutical Salts and Cocrystals by Fluorescence Lifetime Mapping and Quantum Crystallography
4 affiliations
- 1Department of Chemistry
- 2Indian Institute of Technology Delhi
- 3The University of Queensland – IIT Delhi Research Academy (UQIDRA)
- 4IIT Delhi
Abstract
Distinguishing between salt and cocrystal forms of a drug remains challenging in multicomponent systems with ambiguous proton transfer, particularly during bulk production in the pharmaceutical industry. Here, we address this challenge by combining fluorescence lifetime imaging microscopy (FLIM) for rapid bulk-phase discrimination with Hirshfeld atom refinement (HAR) for single-crystal-level validation. This integrated FLIM–HAR approach was applied to 11 multicomponent solids derived from the pharmaceutical drugs niflumic acid, mefenamic acid, and sulfamethazine. Owing to its sensitivity to the local electronic environment and crystal-field effects, FLIM provided spatially resolved lifetime signatures that clearly distinguished salts from cocrystals, with salts consistently exhibiting longer fluorescence lifetimes. HAR unambiguously located the transferred protons, as evidenced by difference Fourier maps, thereby validating the salt–cocrystal assignments. Analysis of intermolecular interactions using the HAR models further revealed stronger interactions and tighter crystal packing in the salts, primarily arising from charge-assisted hydrogen bonding, consistent with the observed lifetime differences. The correlation between fluorescence lifetime and HAR-determined protonation state demonstrates that lifetime provides a sensitive probe of proton transfer in pharmaceutical solids. The integrated FLIM–HAR methodology therefore provides a rapid and reliable strategy for distinguishing pharmaceutical salts and cocrystals, with particular potential for bulk-phase characterization.
Related
- Pharmaceutical residues in food samples: occurrence, toxicity, fluorescence quenching mechanisms, and analysis using carbon dot-based fluorescent probes
- Addition-Fragmentation-Transfer Monitored by Fluorescence Lifetime Imaging Microscopy.
- Unlocking delafloxacin fluorescence with 9-fluorenyl methyl chloroformate: A sensitive spectrofluorimetric method for pharmaceutical and plasma analysis with greenness and whiteness assessment
- Simultaneous quantification of duloxetine and 1-naphthol in pharmaceutical and biological matrices using a sensitive and eco-friendly synchronous fluorescence technique
- Virtual screening, synthesis, solid state characterization, evaluation for solubility, dissolution, and stability of gallic acid-based cocrystals of glimepiride
BibTeX
@misc{kumar2026distinguishing,
title = {{Distinguishing Pharmaceutical Salts and Cocrystals by Fluorescence Lifetime Mapping and Quantum Crystallography}},
author = {Amit Kumar and Aditya Kumar Prajapati and Sofia Arefeen Khan and Monika Gupta and Sajesh P. Thomas},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15009733/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009733/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Distinguishing Pharmaceutical Salts and Cocrystals by Fluorescence Lifetime Mapping and Quantum Crystallography
AU - Amit Kumar
AU - Aditya Kumar Prajapati
AU - Sofia Arefeen Khan
AU - Monika Gupta
AU - Sajesh P. Thomas
PY - 2026
DA - 2026/10/01
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009733/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009733/v1
AB - Distinguishing between salt and cocrystal forms of a drug remains challenging in multicomponent systems with ambiguous proton transfer, particularly during bulk production in the pharmaceutical industry. Here, we address this challenge by combining fluorescence lifetime imaging microscopy (FLIM) for rapid bulk-phase discrimination with Hirshfeld atom refinement (HAR) for single-crystal-level validation. This integrated FLIM–HAR approach was applied to 11 multicomponent solids derived from the pharmaceutical drugs niflumic acid, mefenamic acid, and sulfamethazine. Owing to its sensitivity to the local electronic environment and crystal-field effects, FLIM provided spatially resolved lifetime signatures that clearly distinguished salts from cocrystals, with salts consistently exhibiting longer fluorescence lifetimes. HAR unambiguously located the transferred protons, as evidenced by difference Fourier maps, thereby validating the salt–cocrystal assignments. Analysis of intermolecular interactions using the HAR models further revealed stronger interactions and tighter crystal packing in the salts, primarily arising from charge-assisted hydrogen bonding, consistent with the observed lifetime differences. The correlation between fluorescence lifetime and HAR-determined protonation state demonstrates that lifetime provides a sensitive probe of proton transfer in pharmaceutical solids. The integrated FLIM–HAR methodology therefore provides a rapid and reliable strategy for distinguishing pharmaceutical salts and cocrystals, with particular potential for bulk-phase characterization.
ER -