Purpose: To investigate the dehydration of carbamazepine dihydrate, combining kinetics and crystal water dynamics with electronic structure calculations.
Methods: Thermal microscopy, moisture sorption, and thermogravimetric analysis (TGA) were applied to evaluate the effects on relative humidity (RH) and temperature, while crystal water dynamics were monitored by 2D-FTIR correlation spectroscopy (2DCOS) and the nature of the H-bonding network was investigated by 3D-periodic DFT calculations.
Results: It was found that the dihydrate is unstable below 40% RH and/or above the glass transition temperature (T g ∼ 53°C). At room temperature, amorphous carbamazepine is formed at RH ∼ 0%, form I at RH ∼ 10%, and mixtures of forms I and III at higher RH. Above the T g , the dehydration yields partially crystalline mixtures of forms I and IV between 50–100°C, and form I above 100°C. In all cases, the amorphous product crystallizes to form IV. Thermal analysis and 2DCOS revealed a biphasic dehydration process. Kinetic modelling suggests a diffusion-controlled dehydration below T g and reaction interface-controlled kinetics above T g .
Conclusions: The dehydration consists of two overlapping water removal processes, with the water molecule attached to the amide C=O departing faster, probably due to the destabilizing effect of anti-bonding interactions between the water H1s and the carbonyl O2p orbital.