Phuong Bui ^a, Antonios Zavaliangos ^b

^a Department of Materials Science and Engineering, Drexel University

^b Department of Materials Science and Engineering, Drexel University

Purpose. During tablet compaction, crystalline forms of active pharmaceutical ingredients (APIs) may transform into another crystalline state (polymorph) depending on the local stresses. Prior studies on the polymorphic transformation in tablets typically reported the percent of transformation as a function of applied compaction pressure. However, the local stress history of compacts can also potentially influence these conversions. In this work, the heterogeneous transformation is mapped through the cross-section of tablet utilizing backscattering Raman spectroscopy. These experimental results are complemented with finite element analysis (FEA).

Methods. Chlorpropamide (CPM) is used as a model API with the potential transitions between stable form A (CPM-A) and metastable form C (CPM-C) during tableting. A CPM-C compact is split and polished using a special procedure to minimize the bias of the local transformation, which is quantified by Raman spectroscopy. The FEA simulates the prediction of local stress states and relative densities during tablet compaction.  

Results. The phase transformation mapping captured by Raman spectroscopy indicates a distinctive distribution of local conversion throughout the tablet’s cross-sectional surface, which is in agreement with the predicted densification from the FEA. Statistical comparisons of locations on the polished surface and the adjacent free surfaces show that the splitting and polishing procedure did not affect the conversions.

Conclusions. The spatial heterogeneity of polymorphic transformation is induced by the inhomogeneous densification, primarily due to friction between the tablet and die wall. A close correlation between the local stress states and transformation mapping can be demonstrated experimentally and rationalized by FEA.