Classification of polymorphic forms of fluconazole in pharmaceuticals by FT-IR and FT-NIR spectroscopy

Abstract

The main goal of this work was to test the ability of vibrational spectroscopy techniques to differentiate between different polymorphic forms of fluconazole in pharmaceutical products. These are mostly manufactured with fluconazole as polymorphic form II and form III. These crystalline forms may undergo polymorphic transition during the manufacturing process or storage conditions. Therefore, it is important to have a method to monitor these changes to ensure the stability and efficacy of the drug. Each of FT-IR or FT-NIR spectra were associated to partial least squares-discriminant analysis (PLS-DA) for building classification models to distinguish between form II, form III and monohydrate form. The results has shown that combining either FT-IR or FT-NIR to PLS-DA has a high efficiency to classify various fluconazole polymorphs, with a high sensitivity and specificity. Finally, the selectivity of the PLS-DA models was tested by analyzing separately each of three following samples by FT-IR and FT-NIR: lactose monohydrate, which is an excipient mostly used for manufacturing fluconazole pharmaceutical products, itraconazole and miconazole. These two last compounds mimic potential contaminants and belong to the same class as fluconazole. Based on the plots of Hotelling's T² vs Q residuals, pure compounds of miconazole and itraconazole, that were analyzed separately, were significantly considered outliers and rejected. Furthermore, binary mixtures consist of fluconazole form-II and monohydrate form with different ratios were used to test the suitability of each technique FT-IR and FT-NIR with PLS-DA to detect minimum contaminant or polymorphic conversion from a polymorphic form to another using also the plots of Hotelling's T² vs Q residuals.

Keywords: Classification; FT-IR spectroscopy; FT-NIR spectroscopy; Fluconazole; PLS-DA; Polymorphic forms.