Study of the interaction and hydrolysis of furosemide with cyclodextrins in solution and in the solid states

Furosemide, a potent diuretic, has been found to give a low bioavailability profile when administered orally which potentially could be due to its insoly. in water, and hydrolysis of the drug prior to absorption.  Complex formation of furosemide and both α-​cyclodextrin and β-​cyclodextrin in soln. was studied by phase soly. and spectral shift methods.  The values of the apparent stability const., Kc, by these techniques, were 625 M^-​1 and 485 M^-​1 with α-​cyclodextrin and were 1015 M^-​1 and 1377 M^-​1 with β-​cyclodextrin, resp.  Binary systems of furosemide with α-​CyD and with β-​CyD were prepd. using the phys. mixt., co-​grinding and copptn. methods.  The interaction in the solid state was investigated by DSC, IR spectroscopy, x-​ray powder diffractometry (XPD) and a dissoln.-​rate method.  The main conclusion arising from these studies has been a high interaction between drug and carrier, linked to a clear increase in the amorphous nature of the drug in these systems, specially in the co-​ground system.  As expected, the dissoln. rate of CyDs complexes was much faster than that of the pure drug.  This might be attributed to the amorphous state, the increased wettability of the drug and the inclusion complex formation at the liq. and solid state.  On the other hand, an in-​vitro kinetic study was performed to elucidate the effect of pH and temp. in absence and presence of α- and β-​CyDs on the kinetics and hydrolysis mechanism of furosemide as a function of pH and temp.