• Carolina Morales Moraes, Priscila Abrami, Eneida de Paula, Angélica F A Braga, and Leonardo Fernandes Fraceto.
• Faculty of Pharmacy, University of Sorocaba, Cidade Universitária, Rodovia Raposo Tavares, Km 92,5, 18023-000 Sorocaba, SP, Brazil.
• Int J Pharm. 2007 Feb 22; 331 (1): 99-106.

AbstractLocal anesthetics are substances able to induce pain relief by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of nervous impulses. S(--) bupivacaine (S(--) bvc) is an amide type local anesthetic widely used in surgery and obstetrics for sustained peripheral and central nerve blockade. The present work focuses on the characterization of an inclusion complex of S(--) bvc in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The complexation with HP-beta-CD has been investigated using reversed-phase liquid chromatography and solubility isotherms. The retention behavior was analyzed on a reversed phase C18 column and the mobile phase used was acetonitrile-phosphate buffer pH 7.4 (10mM), (45/55, v/v), in which HP-beta-CD was incorporated as a mobile phase additive. The decrease in the retention times with increasing concentration of HP-beta-CD enables the determination of the complex apparent stability constants by HPLC as a function of temperature. The solubility isotherms were studied as a function of pH (7.4 and 10.5) and temperature. The pH study showed that S(--) bvc reaches a concentration at least 1.5 and 4.5 times higher (pH 7.4 and 10.5, respectively) than the one presented by the free drug in water. The calculated values for the apparent stability constant (K) are 13.1+/-2.8 and 95.4+/-11.8M(-1) for pH 7.4 and 10.5, respectively, thus indicating the formation of a stable complex. In addition, the study of the apparent stability constant by HPLC and solubility isotherm gives thermodynamics information about the interaction between S(--) bvc and HP-beta-CD. The application of the continuous variation method indicated the presence of a complex with 1:1 S(--) bvc:HP-beta-CD stoichiometry. This is an important study for the characterization of potential formulations to be used as therapeutic options for the treatment of pain.

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