Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives.

The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.

Norfloxacin, a fluoroquinolone antibacterial agent. Classification, mechanism of action, and in vitro activity.

Norfloxacin is an orally absorbed fluoroquinolone antibacterial with a fluorine at position 6 and a piperazine ring at position 7. These changes have resulted in a marked enhancement (compared with that of the older quinolones) of in vitro antibacterial activity. Specifically, the antibacterial spectrum of norfloxacin includes Pseudomonas aeruginosa, as well as enteric pathogens. Norfloxacin is also active against both penicillin-susceptible and penicillin-resistant strains of Neisseria gonorrhoeae. Relative to its activity against gram-negative bacteria, norfloxacin is somewhat less active against gram-positive cocci. In general, the staphylococci are more susceptible to the drug than are the streptococci. As with all fluoroquinolones, norfloxacin's activity against anaerobic bacteria is poor. For urinary tract bacterial isolates, the following Bauer-Kirby disk diffusion zone-size breakpoints have been proposed: greater than or equal to 17 mm, susceptible; 13 to 16 mm, intermediate; less than or equal to 12 mm, resistant. Bacteria with minimal inhibitory concentrations (MICs) less than or equal to 16 micrograms/ml are considered susceptible; those with MICs greater than or equal to 32 micrograms/ml are considered resistant to norfloxacin. The mechanism of action of norfloxacin involves inhibition of the A subunit of the important bacterial enzyme DNA gyrase, which is essential for DNA replication. Plasmid-mediated resistance to the fluoroquinolones is not encountered. Further, although some cross-resistance within the fluoroquinolone class has occurred, there is little cross-resistance between norfloxacin and antibiotics of other classes.