New Hydroxybenzoic Acid Salts of Nintedanib with Improved Aqueous Solubilities

Nintedanib is a kinase inhibitor used primarily for the treatment of idiopathic pulmonary fibrosis and nonsmall cell lung cancer. It exhibits poor aqueous solubility and low oral bioavailability (∼4.7%). To address the poor aqueous solubility, we have prepared several new crystalline salts of the drug with hydroxybenzoic acid coformers. We have also prepared new crystalline salts with compounds nicotinic acid, vanillic acid, p-fluorobenzoic acid, p-aminobenzoic acid, and 2-chloro-4-nitrobenzoic acid with reported anticancer activities for exploring new anticancer combinations of nintedanib. All crystalline salts were thoroughly characterized, and their aqueous solubility was determined in the study. The physical stability of the anhydrous nintedanib salts was studied under ambient and accelerated conditions. The amorphous phases of some of these crystalline Nin salts were also prepared by milling, and their kinetic solubilities were compared. Further, the amorphous solid dispersions of the amorphous 2,6-dihydroxybenzoate salt (showing the highest kinetic solubility) were prepared with polymers PVP-K-30 and Eudragit-L-100 in different w/w ratios, and the physical stability and in vitro powder dissolution profile were studied.