Pharmaceutical Salts vs. Ionic Cocrystals: A Combined Structural and Solubility Study of Fluoxetine Multicomponent Crystals

Background/Objectives: The present work constitutes the comparative study of solubility and dissolution parameters of pharmaceutical salts and ionic cocrystals using the ternary system (fluoxetine:hydrochloric acid:fumaric acid) as an example. Methods: A multi-stage synthesis based on extraction of fluoxetine (FXT) free base into the diethyl ether layer was used to isolate two stable fumaric acid (FumAc) salts with (1:1) and (2:1) stoichiometry and a metastable polymorph of the (1:1) salt. The solvent-dependent solubility of FXT∙HCl, [FXT+FumAc] (1:1) salt and [FXT∙HCl+FumAc] (2:1) ionic cocrystal was rationalized in terms of acid–base equilibria, common ion effect, activity coefficients and surfactant-like activity of FXT supported by crystal packing analysis. Different kinetic models were applied to fit the experimental dissolution profiles in blank and supplemented biorelevant FaSSGF and FaSSIF media. Results: The crystal structure of fluoxetine hydrogen fumarate was found to feature the robust layered packing involving 2D hydrogen-bonded sheets separated by FXTH+ bilayers. The highest solubility advantage with respect to commercial FXT∙HCl in acidic media (4.8 times) was confirmed for [FXT+FumAc] (1:1) in pH 1.2 buffer solution, while the [FXT∙HCl+FumAc] (2:1) ionic cocrystal demonstrates the highest solubility (1.9 times) in blank FaSSIF medium (pH 6.5). The dissolution kinetic of studied solid forms was best modeled by zero-order and Korsmeyer–Peppas models. Conclusions: The solubility and dissolution rate were established to be inversely dependent on the solid form stability in specific media. The ionic cocrystal was observed to be the only solid form to demonstrate improved dissolution rate in complemented FaSSGF due to the un-ionized state of fumaric acid resulting in formation of mixed micelles with solubilizers. The [FXT+FumAc] (1:1) salt and the [FXT∙HCl+FumAc] ionic cocrystal can be recommended as soluble solid forms of fluoxetine, respectively, for gastro-soluble and enteric-coated formulations.