Integrated Approach to Study the Dehydration Kinetics of Nitrofurantoin Monohydrate

There is a need for thorough knowledge of solid-state transformations in order to implement quality by design (QbD) methodology in drug development. The present study was aimed at gaining a mechanistic understanding of the dehydration of nitrofurantoin monohydrate II (NF-MH). The dehydration was studied using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), and variable temperature X-ray powder diffraction (VT-XRPD). Isothermal TGA data were used to study dehydration kinetics using model-fitting and model-free approaches. Model-fitting analysis indicated a good fit for several models derived from nucleation growth and/or geometric contraction mechanisms. However, based on visual observations during HSM, Avrami-Erofeyev equations A3 and A4, indicating nucleation growth phenomenon, were found to be the most suitable kinetic models. HSM showed initiation of dehydration with random nucleation, and nuclei coalesced with the progress of dehydration reaction. VT-XRPD revealed formation of anhydrate p form on dehydration of NF-MH. The phenomenon of random nucleation is justified based on the crystal structure of NF-MH, which showed presence of water molecules in an isolated manner, prohibiting directional dehydration. It was found that supplementary information from HSM and VT-XRPD can be valuable to gain a better understanding of dehydration from formal solid-state kinetics analysis. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3966-3976, 2010