Effect of Norfloxacin Polymorphs Complexation with B-Cyclodextrin on Solubility

CLAUDIA GARNERO; JANET NAVARRO; LUCAS CHIERENTIN; HERIDA SALGADO; MARCELA LONGHI

Rosario

Congreso; 2° Reunión Internacional de Ciencias Farmacéuticas; 2012

Introduction The solid state properties of active pharmaceutical ingredients (APIs) are of great importance in the pharmaceutical field because the delivery of an API with the suitable solubility, bioavailability, and stability profiles depends on which crystal form of the drug is present. Norfloxacin (NOR) is a synthetic antibacterial fluoroquinolone related to nalidixic acid, but its potency has been increased [1, 2]. This agent exhibits a wide spectrum of activity, excellent therapeutic effect have been shown in the treatment of respiratory, biliary and urinary tract infections. NOR exists in several solid forms: three anhydrous polymorphs, and an amorphous form, a methanol solvate and several hydrated forms [3].Considering the polymorphic impact on the activity of the drug molecules, the objective of this study was investigate the effect of complexation with B-cyclodextrin (B-CD) on the solubility of polymorphs A, B and C of NOR. Materials and methods In order to investigated the influence of binary complexes on the solubility of three forms of NOR, phase solubility studies of each NOR polymorph were performed according to the method of Higuchi and Connors [4]. Different polymorphic NOR forms were obtained using different solvents. The solubility measurements were performed in aqueous and buffered aqueous solutions containing different concentrations of B-CD. Each NOR form in the absence of B-CD were used to determine their intrinsic solubility. The drug content was measured by UV-vis spectrophotometry. Results and discussion NOR is very slightly soluble in water and hence only 35-45% of orally administered drug is absorbed. In order to enhance the absorption, it is necessary to improve its solubility. Therefore, the effect of B-CD on the solubility was investigated at 25.0 ± 0.1 ºC in aqueous and buffered (pH 6.0 and 8.0) solutions. The interactions of the NOR A:B-CD, NOR B:B-CD and NOR C:B-CD systems both in aqueous and buffer solutions displayed different type solubility curves, revealing differences in solubility behaviors of the three polymorphs. In particular, the profiles in aqueous solutions for NOR A:B-CD and NOR B:B-CD systems were characteristic of A type, in contrast the curve for NOR C:B-CD was classified as B type. Also, these studies revealed similar intrinsic solubility in water of the polymorphs. It is interesting to note that NOR A:B-CD system showed the highest solubility value in buffer solutions of pH 8.0. Conclusions: Our results demonstrate the solubility differences between NOR polymorphs. Additionally, we can confirm the capability of B-CD to interact with each polymorph, generating binary complexes having different solubility behavior. Acknowledgments We thank Ferromet S.A. (agent of Roquette in Argentina) for their donation of B-cyclodextrin. References 1. Martindale, The Extra Pharmacopoeia, 30th ed., vol. I, The Pharmaceutical Press, London, 1993, pp. 188. 2. K. Florey, Analytical Profile of Drug Substances, vol. 20, Academic Press, New York, 1991, pp. 557-600. 3. Puigjaner, C.; Barbas, R.; Portell,A.; Font-Bardia, M.; Alcobe, X.; Prohens, R. Cryst. Growth Des. 10 (2010) 2948?2953. 4. T. Higuchi, K.A. Connors, Phase-solubility techniques, in: C.N. Reilly (Ed.), in: Advances in Analytical Chemistry and Instrumentation, Wiley-Interscience, New York, 1965, pp. 117?212.