Detection of low dose of piroxicam polymorph in pharmaceutical tablets by surface-enhanced Raman chemical imaging (SER-CI) and multivariate analysis

This study demonstrates, for the first time, the ability of surface-enhanced Raman chemical imaging (SER-CI) combined with multivariate analysis to detect low levels (0.1% (w/w)) of a polymorphic form in a pharmaceutical mixture. In the studied formulation, piroxicam was used as a model molecule to develop this approach. Piroxicam is a widely available non-steroidal anti-inflammatory drug, exhibiting an interesting case of polymorphism, with two most commonly observed forms (beta and alpha(2)). In this work, the SERS spectra of piroxicam polymorphic forms beta and alpha(2) are presented. These forms showed clear spectral differences in terms of band position and intensity. From a crystallographic point of view, the difference of exaltation between both forms was correlated with a preferred orientation of crystallites of form a alpha(2) making its SERS detection difficult compared to form beta. A preferred orientation of the (1k0) crystallographic planes of alpha(2) was demonstrated in samples, not promoting an appropriate molecular orientation onto the metallic surface. Additionally, a semi-quantitative approach using SER-CI combined with chemometric tools was developed enabling to detect crystallites of form beta below the detection limit of conventional Raman microscopy. The exaltation of the Raman signal in the presence of silver nanoparticles allowed a higher sensitivity and a reduction of the acquisition time by a factor of 6.