In the present study, bulk measurements and chemometric modeling have obvious limitations when the targeted component is present at low levels in a multi-component tablet. A two-step Raman mapping approach was developed herein to investigate salt disproportionation in tablets with a low drug loading (5% w/w).

Utilizing the proposed two-step mapping approach, we successfully observed the presence of PIO free base in a model tablet exposed at ambient conditions, which could not be detected by Raman bulk measurements.

Finding of this paper suggests that the proposed two-step Raman mapping approach has the potential to detect minor species in a multi-component tablet matrix. Moreover, this finding also indicates that magnesium stearate could lead to the disproportionation of PIO-HCl even at ambient conditions (below the reported critical R.H.).

To the best of our knowledge, this is the first time that Raman mapping has been employed to study salt disproportionation in a multi-component tablet matrix. The success of applying Raman microcopy to detect the product of disproportionation, which is a minor component embedded in a tablet, will help formulation scientists better understand in situ drug-excipients compatibility.