Detection of low-dose of piroxicam polymorphs in pharmaceutical tablets by surface-enhanced Raman chemical imaging and multivariate analysis

Abstract

In the pharmaceutical industry, the detection and the identification of polymorphic forms of an active pharmaceutical ingredient (API) is an important concern during the drug development and the manufacturing process. The necessity to detect polymorphic forms especially at low concentrations is an area of particular interest in pharmaceutical applications due the difference of physico-chemical properties exhibited by the polymorphs. The polymorphic behavior of drugs can affect the therapeutic efficacy of the drug substance and can also have an impact from an intellectual property (IP) standpoint. Indeed, much effort are expended by the regulatory authorities to determine if the polymorph present in the final product is covered by a patent for IP rights aspects. Various analytical techniques can be used for polymorph detection and characterization such as X-ray powder diffraction (XRPD), solid-state nuclear magnetic resonance spectroscopy (ssNMR) and vibrational spectroscopy. Despite low sensitivity and long image acquisition times, Raman microscopy is well suited to the analysis of polymorphic forms since it enables the acquisition of spectral and spatial information at the same time. This technique can be combined with surface-enhanced Raman scattering (SERS), resulting in surface-enhanced Raman chemical imaging (SER-CI). SER-CI is a promising tool for the detection and the visualization of low-dose compounds or impurities in tablets taking account of the high sensitivity of this technique. Consequently, we firstly focused on the development of a reproducible spray-coating method to control the deposition of SERS nanoparticles on pharmaceutical samples in order to fully exploit the potential of SER-CI. Besides, this spraying technique, coupled with SER-CI, was applied to model tablets consisting of one excipient and a 10% (w/w) API concentration. Piroxicam, a non-steroidal anti-inflammatory drug which presents three polymorphic forms was used as a model API. The model formulation was a binary mixture of the form β and the form α2 polymorphs of piroxicam. Using SER-CI and multivariate analysis, it was possible to detect the β form polymorph in these model tablets below 1% (w/w) while reducing the image acquisition time. To conclude, the combination of the spray-coating method and SER-CI enabled the detection of low-dose of piroxicam polymorphs in model pharmaceutical formulations. This approach can serve as a potential way for the development of methods validation for semi-quantitative and quantitative analyse