A challenged spectral overlap resolution of oromucosal spray: A comparative study of PCR, PLS, and siPLS algorithms with sustainability assessment

Three novel multivariate spectrophotometric methods namely Principal Component Regression (PCR), Partial Least Squares (PLS), and synergy intervals Partial Least Squares (siPLS) were developed for the successful resolution of spectrally overlapping signals of a quaternary mixture of benzocaine, benzydamine hydrochloride, cetalkonium chloride, and benzydamine hydrochloride official impurity (Impurity C). This work represents the first reported application of chemometric techniques to resolve this specific quaternary mixture in both its pure form and co-formulated dosage form.

The methods demonstrated good linearity and accuracy in analyzing the aforementioned compounds in laboratory-prepared mixtures and oromucosal spray. Linearity of the developed methods was found to be (3.00–15.00, 1.50–7.50 and 1.50–3.50 μg/mL) for benzocaine, benzydamine hydrochloride, and benzydamine hydrochloride impurity C (1-benzyl-1H-indazol-3-ol), correspondingly. The developed models were validated using internal and external data sets. Furthermore, statistical analysis did not reveal any substantial differences between our findings and those of the reported methods.

A comprehensive sustainability assessment, employing metrics such as Analytical Eco-Scale (AES), Green Analytical Procedure Index (GAPI), Analytical GREEnness metric (AGREE), Red-Green-Blue model (RGB12), and Blue Applicability Grade Index (BAGI), highlighted the advantages of the developed methods over conventional HPLC with respect to cost, time, and environmental impact. The developed methods achieved the following scores of 79, 0.69, 89.4, and 70 for AES, AGREE, RGB12, and BAGI, respectively.

These findings suggest that the proposed multivariate assisted spectrophotometric methods could offer a valuable alternative to HPLC for rapid and efficient quality control analysis of these compounds in pharmaceutical formulations.