Process induced transformations during tablet manufacturing: phase transition analysis of caffeine using DSC and low frequency micro-Raman spectroscopy

The phase transition of a model API, caffeine Form I, was studied during tableting process monitored with an instrumented press. The formulation used had a plastic flow behavior according to the Heckel model in the compression pressure range of 70-170 MPa. The quantitative methods of analysis used were Differential Scanning Calorimetry (DSC) and low frequency Micro Raman Spectroscopy (MRS) which was used for the first time for the mapping of polymorphs in tablets. They brought complementary contributions since MRS is a microscopic spectral analysis with a spatial resolution of 5 μm³ and DSC takes into account a macroscopic fraction (10 mg) of the tablet. Phase transitions were present at the surfaces, borders and center of the tablets. Whatever the pressure applied during the compression process, the transition degree of caffeine Form I toward Form II was almost constant. MRS provided higher transition degrees (50-60%) than DSC (20-35%). MRS revealed that caffeine Form I particles were partially transformed in all parts of the tablets at a microscopic scale. Moreover, tablet surfaces showed local higher transition degree compared to the other parts.