Fluorescence-Based High-Throughput Salt Screening

The present study reports a high-throughput screening method for the salt formation of amine-containing active pharmaceutical ingredients (APIs) based on fluorescence measurements. A free form amine API was alkynylated by a solid-vapor reaction using propargyl bromide, and a fluorescent compound was produced by a subsequent reaction using 9-azidomethylanthracene. In contrast, salts were inert to propargyl bromide; thus, no fluorescence was observed. Samples for salt screening were prepared by grinding haloperidol with various counter acids, and these mixtures were derivatized in a 96-well microplate to determine whether the salt formation had occurred between haloperidol and the counter acids. Samples that turned into fluorescent and nonfluorescent were confirmed to be free form and salt form, respectively, using powder X-ray diffraction and Raman spectroscopy. In conclusion, our method adequately functions as an indicator of the salt formation of amine APIs. Further, this method allows for the rapid evaluation of the salt formation of APIs using 96-well microplates without the need for special reagents or techniques; thus, it is valuable for the discovery of an optimal salt form of newly developed amine APIs in the pharmaceutical industry.