Cocrystals and Salts of Milrinone with Fluoro Coformers: Improving Drug Dissolution and Diffusion and Calculating Normalized Diffusion for Pharmaceutical Cocrystals

Milrinone (MRN) is a second-generation bipyridine phosphodiesterase inhibitor that improves cardiac function and peripheral vasodilation in acute decongested heart failure patients. Due to its poor aqueous solubility and high permeability, it is classified as a biopharmaceutical classification system class II drug. The present study aimed at screening binary cocrystals of MRN with different coformers containing fluoro-substitution. Four cocrystals were obtained with 4-fluorobenzoic acid (4-FBA), 2,5-difluorobenzoic acid (25-DFBA), 3,4,5-trifluorobenzoic acid, and 2,3,4,5-tetrafluorobenzoic acid and a salt with 5-fluoro-2-hydroxybenzoic acid (5F-2-HBA). These binary crystalline products were characterized by powder X-ray diffraction, single-crystal X-ray diffraction, IR spectroscopy, differential scanning calorimetry, and thermogravimetry analysis. Their crystal structures were analyzed in terms of hydrogen bonding, supramolecular synthons such as carboxylic acid–pyridine, amide–amide dimer, hydroxyl–pyridine, and weak intermolecular interactions. The polar hydrogen bonding and nonpolar hydrophobic interactions in the crystal structures were partitioned by a Hirshfeld surface analysis. The solubility, dissolution rate, and diffusion/permeability of the MRN cocrystal/salt were studied in a physiological medium of pH 7.0. Fluorinated coformers resulted in faster dissolution and higher diffusion in all cases; specifically, MRN-4-FBA exhibited the highest drug concentration (58 mg/L) and MRN-25-DFBA the highest diffusion (130 mg/L) across dialysis membrane-135 in a pH 7.0 buffer. In addition to bioavailability, which is calculated as solubility × permeability and is a measure of the overall drug concentration in the medium, we propose calculation of drug diffusion normalized for the differences in drug concentration for the different cocrystals/salts in the experimental medium (Diffnorm = Diff/Diss), as a corrected parameter to quantitatively measure the change in drug diffusion effects of cocrystals and salts relative to the reference drug concentration.