Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

Abstract

Highly soluble cocrystals can improve the bioavailability of poorly soluble drugs by inducing supersaturation when absorption is limited by drug dissolution. Enrofloxacin (ENR) is a concentration-dependent fluoroquinolone antibacterial with poor solubility. In this study, two new ENR salts, 3,5-dihydroxybenzoic acid (ENR-3,5-DHBA) and 2,6-dihydroxybenzoic acid (ENR-2,6-DHBA•1/2H 2 O), were prepared, and their physicochemical properties were evaluated for suitability in formulation development.Results showed that the solubility of the two new salts enhanced. Although ENR-3,5-DHBA had a much higher solubility than ENR, it underwent rapid precipitation during dissolution, forming the poorly soluble ENR•6H 2 O in aqueous form. This negated the potential high-solubility advantage of the new salt, which might have enhanced its dissolution rate and in vivo bioavailability. To solve this problem, we systematically evaluated suitable crystallization inhibitors that could maintain the supersaturation generated by cocrystal/salt dissolution for a prolonged period. At 37 °C, the solubility and mean AUC 0−24h of ENR-3,5-DHBA increased by about 4.7 and 1.5 times, respectively (compared with ENR), when ENR-3,5-DHBA was dosed with 2.0 mg/mL methacrylic acidethyl acrylate copolymer (ME) solution instead of an active pharmaceutical ingredient. This study demonstrates that using a highly soluble salt and an appropriate crystallization inhibitor is a potentially effective formulation strategy for improving the oral bioavailability of poorly soluble drugs.