Towards a holistic view of tablet quality, an extensive study on paracetamol tablets with nuclear magnetic resonance using similarity calculations, differential NMR and hierarchical cluster analysis

Abstract

The ¹H NMR spectra obtained from 56 different paracetamol tablets were thoroughly investigated to analyse and quantify besides paracetamol, the excipients and eventual minor components present in the formulations. In the NMR spectra the amide-iminol tautomerism of paracetamol was observed, with the iminol form present at a quantity of only 0.80% of the amide form. Furthermore, seventeen different components of the tablets were identified, ranging from major excipients like starch and polyvinylpyrrolidone (PVP) to minor components like different parabens, sorbate and triacetin. The similarity from all spectra in relation to each of the other spectra was calculated and based on the similarity table a hierarchical cluster analysis (HCA) was performed. Each of the components of the DMSO extracts of the tablets was quantified, providing a component table, which also was used for HCA. The quantitative analysis of paracetamol was determined to have a precision of 0.2% using the residual solvent signals as internal standard. The HCA of the similarity data and the component table were compared with the HCAs obtained by analysis of the crude NMR data. This clearly shows the limitations of multivariate data analysis and the strength of similarity calculations combined with differential NMR, especially in relation to the analysis of trace components. In fact, the spectrum is not a series of unrelated variables, but a superposition of a limited number of component spectra, and the quantities of these components were determined.

Keywords: (1)H NMR; Differential NMR; Hierarchical cluster analysis; Paracetamol; Similarity; Tautomerism.