Studies regarding the induced thermal degradation, kinetic analysis and possible interactions with various excipients of an osseointegration agent: zoledronic acid

Abstract

Zoledronic acid is a nitrogen-containing bisphosphonate agent that suppresses farnesyl diphosphate synthase, i.e., inhibits bone resorption and bone remodeling activity. Our current study evaluates the thermal behavior of zoledronic acid and performs a kinetic analysis of the main degradation process and compatibility studies between the active agent and various excipients. The thermal behavior of zoledronic acid is characterized by two thermally induced events; a dehydration process with a rate maximum at 133 °C, respectively, a complex multistep process of a deep oxidative degradation that covers a range of temperature starting at 225 °C. Kinetic parameters were determined according to ICTAC 2000 Protocol recommendations and using four kinetic methods to determine the kinetic triplet: Friedman, Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose and modified nonparametric kinetic method. The thermal behavior of zoledronic acid monohydrate and of its binary mixture in 1:1 mass ratio with talc, silica, mannitol, sorbitol, hydroxyethyl cellulose and magnesium stearate, respectively, were studied by thermal analysis under nonisothermal conditions. Talc and silica were used as standard inert excipients in the binary mixture. The polyhydroxylic compounds mannitol and sorbitol and the polysaccharide hydroxyethyl cellulose have similar thermal behavior, decomposing from 300 °C. Thus, they can be used in solid formulations of zoledronic acid. Magnesium stearate is recommended to be avoided in solid formulations, due to its low thermal stability.