Solid State Transformations Mediated by a Kinetically Stable Form

Abstract

The anhydrous forms of theophylline and the stability relationships with the monohydrate, Form M, are characterized. Form II, kinetically stable at room temperature and considered as the most stable form during the 70-year history of theophylline usage, is observed to act as an intermediary for conversions between other forms. Form IV, the thermodynamically stable form at room temperature, is shown to be enantiotropically related to Form II and undergoes a solid state transition on heating. The enantiotropic relationship between Forms II and I was investigated, and it was established that a Form II to I transition is observed only in samples generated using specific methods. Form III was found to be a high energy solid form which can only be generated by dehydration of the hydrate. Upon heating, Form III shows an exothermic transition to Form II. Upon rehydration, Form III is extremely hygroscopic and converts initially to Form II and then to Form M. The complexity of anhydrate–hydrate relationships is il...