Solid phase transitions induced by direct compression : the case of caffeine and carbamazepine
The purpose of this study was to improve the understanding of process induced transformations (PITs) in the field of the pharmaceutical industry. This present study is focused on the direct compression process applied to two model active molecules named caffeine and carbamazepine. Experimental characterization methods of phase transitions in the tablets were developed. Densities inside the tablets were measured by X-ray computed micro-tomography and by micro-indentation at the surface. Thermal methods for DSC and TGA were applied in order to estimate transformation degrees of tablet parts. Low frequencies micro-Raman Spectroscopy (MRS) was used for the first time as a way for polymorphs mapping. Raman spectroscopy was also developed in the high frequencies range to increase the analyzed part area and to computerize the spectra treatment. Caffeine form I is transformed naturally toward caffeine form II but this transition can take many years at room temperature. Our investigations have shown that the direct compression process induced a partial transition of caffeine I toward caffeine II. Phase transition degree stayed higher in the tablet than in the non-compressed powder during two years. Quantification process was set up for DSC and low frequencies MRS. It was found that the pressure level did not influenced the transition degree. Moreover, both polymorphs coexist at the micrometer scale in all caffeine particles. Caffeine formulated with micro-crystalline cellulose exhibits a plastic behavior under compaction. X-ray tomography revealed higher densities zones next to the tablet slides but any impact on the transition degree was detected. The use of calibrated caffeine particles led to a more brittle behavior and seemed to decrease the transition degree. The investigations on carbamazepine dihydrate did not show any phase transformation of this active molecule induced by direct compression