Distinguishing Pharmaceutical Salts and Cocrystals by Fluorescence Lifetime Mapping and Quantum Crystallography
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Authors: Amit Kumar, Aditya Kumar Prajapati, Sofia Arefeen Khan, Monika Gupta, Sajesh P. Thomas
Language: English
Subfield: Physical and Theoretical Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: Arthritis National Research Foundation, National Research Foundation, Department of Science and Technology, Ministry of Science and Technology, India, University Grants Commission, Indian Institute of Technology Delhi, Principal Scientific Adviser to the Government of India, Science and Engineering Research Board
OpenAlex ID: W7215038732