Dehydration kinetics and crystal water dynamics of carbamazepine dihydrate

To investigate the dehydration of carbamazepine dihydrate, combining kinetics and crystal water dynamics with electronic structure calculations.

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.

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 .

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.