Solid-state transition mechanism in carbamazepine polymorphs by time-resolved terahertz spectroscopy.

Preprint, the communication has been published in ChemPhysChem 8(13):1924-1927 (doi:10.1002/cphc.200700261). Polymorphism of molecular crystals is a phenomenon in solid-state chemistry where a compound is able to exhibit more than one crystal structure. It is of wide importance in an industrial context as key physicochemical properties, such as solubility, are strongly dependent on the crystal structure. [1] Carbamazepine (CBZ, 5H-dibenz[b,f ]azepine5-carboxamide), a drug used for the treatment of epilepsy is known to exhibit at least four anhydrous polymorphic modifications. [2] At room temperature the P-monoclinic modification (form III) is the thermodynamically most stable of the four polymorphs. It converts to the triclinic form I by melting and subsequent crystallization upon heating. In addition, at temperatures below the melting point of form III a solid-state conversion occurs which was reported to follow a two step mechanism via the gas phase. [3] The study of the mechanism was solely based on the phenomenological observations by hot stage microscopy. However, this two step process was neither detected nor considered in previous structural or spectroscopic studies of the conversion kinetics. [4]–[6] Here, we present a study that for the first time shows the ability to resolve the mechanism spectroscopically and take it into account for the kinetics of the phase transition. Terahertz pulsed spectroscopy (TPS) is very sensitive to subtle differences in structure by directly probing the lattice dynamics of molecular crystals in the far-infrared. [7] Earlier work demonstrated that form I and III of CBZ show distinct spectral features in the terahertz range between 2 and 130 cm−1 and that these differences can be used to monitor the phase transition between the two forms. [8] The assignment of spectral features in the terahertz range is still subject to scientific debate and several approaches are currently discussed. [9] For the fairly rigid molecule of CBZ, that forms dimers in all its polymorphic modifications, we have made some tentative assignments based on force-field lattice dynamics calculations. [9] 2 0 3 0 4 0 5 0 6 0 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 0 m i n 6 0 m i n 1 2 0 m i n 1 8 0 m i n 2 4 0 m i n 3 0 0 m i n A