Norfloxacin - polymorphs, solvates, salts, complexes and co-crystals

2 Norfloxacin - polymorphs, solvates, salts, complexes and co-crystals 

Norfloxacin forms metal ion complexes with many di- and trivalent ions including Ca +, Mg +, Zn +, Fe and Al + [28]. Formation constants for these complexes have been measured using potentiometric titrations between pH 2 and 11 (pATaS are 6.3 and 8.5 for the carboxylic acid and piperazinyl amine, respectively). Complexation occurs at the carbonyl-carboxylate site initially and subsequently at the piperazinyl amine as the pH increases, with these sites of interaction elucidated by single crystal structure determination [39-41]. At pH 6.5 the largest formation constant is found with AP+ and decreases according to the following trend Al + Fe + Zn + Mg + Ca +. 

In an open, randomized, crossover study in mixed breed dogs, 12mgkg norfloxacin in 0.01 M HCl was given alone or co-administered with equimolar amounts of a metal chloride salt. Differences in the Cmax and AUC were observed and found to follow the same rank order as the complex formation constants. A follow up study looking at the effect of five different doses of Mg + (0.25, 0.5, 1, 2 and 4 1 Mg + norfloxacin), from MgCl2, showed that increasing the available Mg + resulted in a rank order decrease in the oral absorption of norfloxacin, most likely because more of the active compound is tied up as the metal ion complex. 

In contrast to these studies where decreases in oral bioavailability are correlated with complex formation, increasing the solubility of norfloxacin using speciflc solubility enhancers has been shown to increase the oral bioavailability [29, 42, 43]. Both EDTA (p.srai 1-7) and sodium caprate (caprylic acid pA a 5) were thought to act as chelating agents to increase the dissolution of norfloxacin into aqueous media [42]. The combinations of norfloxacin and either EDTA or sodium caprate were dosed as mixed powders in capsules. While both excipients increased the oral bioavailability of norfloxacin in rabbits, sodium caprate was more effective than EDTA (sodium 

Recently, several organic salts and a co-crystal of norfloxacin were prepared. Salts were formed with ascorbic [35] = 4.17), lactic [36] (p.sra = 3.89), succinic [34] 

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