title: Integrated approach to study the dehydration kinetics of nitrofurantoin monohydrate.
abstract: 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 beta 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Vishal
authors.initials: V
authors.lastname: Koradia
authors.forename: Heidi Lopez
authors.initials: HL
authors.lastname: de Diego
authors.forename: Michiel Ringkjøbing
authors.initials: MR
authors.lastname: Elema
authors.forename: Jukka
authors.initials: J
authors.lastname: Rantanen
mesh_terms: D000892:Anti-Infective Agents, Urinary / Q000737:chemistry*; D003890:Desiccation; D007700:Kinetics; D009582:Nitrofurantoin / Q000737:chemistry*; D033362:Powder Diffraction; D013818:Thermogravimetry; D014867:Water / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D000892:Anti-Infective Agents, Urinary; D014867:Water; D009582:Nitrofurantoin