Dehydration of theophylline monohydrate—a two step process

Abstract

The physicochemical properties of theophylline monohydrate and anhydrous polymorphic form II were evaluated using crystallographic, calorimetric and computational methods. The heats of solution of theophylline monohydrate and its anhydrous form were 28.6 and 19.4 kJ/mol, respectively, and the heat of hydration of theophylline anhydrous was 12.2 kJ/mol, as determined by solution calorimetry. Dehydration of theophylline monohydrate was studied by DSC. Under closed, hermetic conditions, the heat of dehydration, 10.7 kJ/mol, was almost equal to the heat of hydration. Under open conditions, the measured heat of dehydration was 47.3 kJ/mol. The dehydration phenomenon was examined also by molecular modelling and the computed heat changes were equal to those determined experimentally. The obtained experimental and theoretical results indicated that the monohydrate-anhydrate transition of theophylline is energetically reversible. Under closed conditions and in the aqueous media, the reversible monohydrate-anhydrate transition comprised only the dehydration or hydration step and the heat of transitions were considerably lower than under open conditions. Under open conditions, the dehydration of theophylline monohydrate proceeds in two steps even though the steps are overlapping. The first step is dehydration and the second is evaporation of the loosened crystal water.