Comparative Investigation on Mono- and Disalts of Osimertinib and Sulfonic Acid: Preparation, Characterization, Solubility, and Hygroscopicity Evaluation

Salt formation proved to be the most effective solid-state form for insoluble drugs in terms of improving solubility, crystallinity, stability, and/or bioavailability. A salt form of a drug where two ions of the same type are associated with one drug molecule further improves solubility and overall drug performance. However, a systematic comparison of these forms for a given drug combination remains scarce. This is achieved by the drug having at least two sites that can ionize, allowing it to form ionic bonds with a counterion. Osimertinib (OSTN), characterized by poor solubility and bioavailability, is a highly selective kinase inhibitor approved by the FDA, which is indicated for treatment of locally advanced or metastatic nonsmall cell lung cancer. In the present study, a multicomponent system based on OSTN’s diprotic base was prepared and characterized by various methods. This system comprises mono- and disalts derived from three sulfonic acids: methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Although the powder diffractions of OSTN mesylate (OSTN-MSA-A and OSTN-MSA-B) and OTSN tosilate (OSTN-TsOH) have been reported, and the crystal structure of OSTN-MSA-B was solved by using synchrotron X-ray powder diffraction data and optimized using density functional techniques, our study marks the inaugural report of their crystallographic structures. Three new solid forms (OSTN-BES, OSTN-2BES, and OSTN-2TsOH) were initially identified and subjected to a comprehensive characterization through thermal analysis, X-ray diffraction, X-ray photoelectron spectroscopy (XPS) techniques, etc. In addition, their hygroscopicity and solubility were determined and compared, combining with the respective molecular conformation, their inter- and intramolecular interactions, and packing arrangement. Notably, OSTN disalt exhibited superior dissolution performance when compared to that of monosalt. The comparative study offers valuable guidance for the development of salt screening for insoluble drugs with two sites that can ionize.