Furosemide:Maltodextrin interactions studied using Nuclear Magnetic Resonance

CLAUDIA GARNERO; MARCELA LONGHI; ANA KARINA CHATTAH

Alta Gracia, Córdoba

Jornada; Magnetic Resonance in a Cordubensis Perspective. New Developments in NMR; 2011

FAMAF - UNC

Furosemide (FUR) is a loop diuretic used in the oral treatment of edematous states associated with cardiac, renal, and hepatic failure and the treatment of hypertension.1 However, FUR is practically insoluble in water. An enhanced solubility of FUR is particularly important because its bioavailability is related to in vivo dissolution profile. In addition, seven polymorphic forms are known: four true polymorphs (I, II, III, IV), two solvates (IV—DMS and V—dioxane) and one amorphous form.2 Maltodextrins (MDs), products obtained from the partial hydrolysis of food grade starch with suitable acids and/or enzymes, have the capability of complexation to various classes of compounds, with the host-guest one being the most common interaction. Although, a strategy widely used to increase the solubility of drugs is the complex formation with cyclodextrins, the present work is focused to the investigation of the interaction of two polimorphs of FUR (I and II) with MD in solution and solid state, in order to provide an increasing in the solubility of the drug. Moreover, the characterization of pharmeceutical MDs complexes has not been reported in the literature. The solid samples were obtained by two different methods of preparation: kneading and physical mixture. In order to characterize these new systems, 13C solid-state NMR spectra were obtained to each bynary system and compared to the corresponding components and the physical mixture. In addition, proton spin-lattice relaxation time (T1) values were measured. Solubility measurements were performed according to the method of Higuchi and Connors.3 First, the polymorphs I and II were identified performing the assignments in the 13C solid state NMR spectra. Then, modifications of some signals of the FUR part of the spectrum in the complexes, gave evidence of FUR:MD molecular interaction in solid state. In addition, although the 1H T1 for the physical mixtures mantain time values similar to those measured in the components, in the complexes a new T1 value appear together with a value close to the FUR one, indicating that a certain degree of pure drug remains in the complex. Finally, 13C solid state spectra were edited using the T1 values. In addition, in the 1H-NMR solution spectra of FUR:MD, appreciable shifts were observed in the FUR signals, probably due to conformational changes as a result of interaction in solution. On the other hand, the solubility diagrams showed an increase in the solubility of each polymorph by the formation of soluble bynary complexes. This investigation demonstrates the capability of MDs to interact with FUR polymorphs, generating binary complexes both in solution and in solid state. REFERENCES: 1. Sweetman S, editor. Martindale: The complete drug reference. Electronic version, Pharmaceutical Press, 2009. 2. Latosinska J. N.; Latosinska M.; Medycki W.; Osuchowicz J. Chemical Physics Letters. 2006,127. 3.Higuchi T.; Connors K. A. Phase-Solubility Techniques. In Advances in Analytical Chemistry and Instrumentation, Wiley-Interscience: New York, Vol. 4, 1965, 117. CONICET, ANPCyT, SECyT-UNC