Influence of Air Temperature and Humidity on Dehydration Equilibria and Kinetics of Theophylline

The effect of hygrothermal conditions (air temperature and relative humidity) on the dehydration of theophylline monohydrate was investigated. Firstly, the equilibrium states of theophylline were investigated. The data from gravimetric analysis at constant temperature and humidity were reported as desorption isotherms. The PXRD analysis was used to identify the different polymorphic forms of theophylline: the monohydrate, the metastable anhydrate, and the stable anhydrate. Solid-solid phase diagrams for two processing times were proposed. Secondly, the dehydration kinetics were studied. The water content evolutions with time were recorded at several temperatures from 20°C to 80°C and several relative humidities from 4% to 50%. Different mathematical models were used to fit the experimental data. The spatially averaged solution of 2D Fickian transient diffusion equation best represented the water mass loss versus time experimental relationship. The dehydration rate constant was found to increase exponentially with air temperature and to decrease exponentially with air relative humidity. 1. Introduction Theophylline (C7H8N4O2: 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione) is widely used as a bronchodilator in asthma therapy. Its hydration behaviour and solid-state transitions have been extensively studied and presently the compound is known to exist as a monohydrate (M) and four anhydrous polymorphs (I, II, III, and IV) [1–3]. The M form has been shown to lose water in low relative humidity (or water activity for solvents) to produce form II which is the most prevalent form and has been long considered as the only stable form at room temperature [4, 5]. Form I is produced by heating form II [2, 6] and is reported to be the stable form at higher temperatures. Form III is a highly metastable form and converts easily to form II during storage [3, 7]. This form can be only produced as an intermediate during dehydration of the monohydrate and was never found as an intermediate during hydration of the stable anhydrous form according to Phadnis and Suryanarayanan [8]. Form IV has been identified recently [9]. It occurs as a result of slow, solvent-mediated conversion from form II, and is now claimed as the most thermodynamically stable anhydrous polymorph of theophylline. However, in subsequent sections of the paper the term “stable anhydrate” will refer only to form II as this form is the most commonly encountered and discussed in the literature and the one which was obtained in the dehydration experiments reported here. The dehydration kinetics of theophylline