The
objective of this study is to achieve a fundamental understanding
of polymorphic interconversion during the tableting process, including
during compaction, dwell, decompression/unloading, and ejection using
an in situ mechanical Raman spectroscopy. The fit-for-purpose in situ mechanical Raman spectroscopy developed herein can
provide simultaneous measurement of Raman spectra and densification
for the powder compacts. Chlorpropamide (CPA), an antidiabetic drug,
was selected as a model pharmaceutical compound because of its mechanical
shear-induced polymorphic conversions. The results confirm that CPA
polymorph A (CPA-A) was transformed to CPA polymorph C (CPA-C) under
different compaction stresses. We also observed that the converted
polymorph CPA-C could be reverted to the CPA-A due to the elastic
recovery of powder compacts as detected during dwelling and unloading.
This study is the first depiction of the dynamics of CPA polymorphic
interconversion during compression, dwell, unloading, and ejection.
Mechanistically, this study illustrates a correlation between the
change in the powder compact’s relative density and polymorphic
interconversion of the drug substance in different solid-state forms.
The present research suggests that the process-induced polymorph conversion
is a complicated dynamic process, which could be affected by the compaction
pressure, the elasticity/plasticity of the material, the level of
elastic recovery, and the dissipation of residual stress. In summary,
this study demonstrates that the in situ mechanical
Raman spectroscopy approach enables the simultaneous detection of
mechanical and chemical information of the powder compact throughout
the tableting process.