Tracing the origin of paracetamol tablets by near-infrared, mid-infrared, and nuclear magnetic resonance spectroscopy using principal component analysis and linear discriminant analysis.

Most drugs are no longer produced in their own countries by the pharmaceutical companies, but by contract manufacturers or at manufacturing sites in countries that can produce more cheaply. This not only makes it difficult to trace them back but also leaves room for criminal organizations to fake them unnoticed. For these reasons, it is becoming increasingly difficult to determine the exact origin of drugs. The goal of this work was to investigate how exactly this is possible by using different spectroscopic methods like nuclear magnetic resonance and near- and mid-infrared spectroscopy in combination with multivariate data analysis. As an example, 56 out of 64 different paracetamol preparations, collected from 19 countries around the world, were chosen to investigate whether it is possible to determine the pharmaceutical company, manufacturing site, or country of origin. By means of suitable pre-processing of the spectra and the different information contained in each method, principal component analysis was able to evaluate manufacturing relationships between individual companies and to differentiate between production sites or formulations. Linear discriminant analysis showed different results depending on the spectral method and purpose. For all spectroscopic methods, it was found that the classification of the preparations to their manufacturer achieves better results than the classification to their pharmaceutical company. The best results were obtained with nuclear magnetic resonance and near-infrared data, with 94.6%/99.6% and 98.7/100% of the spectra of the preparations correctly assigned to their pharmaceutical company or manufacturer.

Fingerprint spectra for drug formulations using a DOSY filter: Pros and cons.

It is often difficult to trace back drugs to the manufacturer, even though this can be important, especially when fake or low quality drugs are circulating. Drug formulations contain of the active pharmaceutical ingredient (API) and excipients and the finished products from different manufacturers usually differ. Hence, the characterization of the component composition is challenging. Here, we present an 1H NMR method which is able to look at both by diffusion-ordered spectroscopy (DOSY). Using a DOSY filter, the signals of the solvents and the API can be attenuated, whereas the excipient signals are visible. This way, the overlap of the API and excipient signals is substantially reduced, which is advantageous when one of the components is present in excess.

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.

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.

Distinguishing paracetamol formulations: Comparison of potentiometric "Electronic Tongue" with established analytical techniques.

Fast and inexpensive analytical tools for identification of the origin of pharmaceutical formulations are important to ensure consumers safety. This study explores the potential of potentiometric multisensor systems ("electronic tongues") in this type of application. 72 paracetamol samples purchased in different countries and produced by various companies were studied via infrared spectroscopy (IR), near infrared spectroscopy (NIR), nuclear magnetic resonance spectroscopy (NMR) and multisensor system (ET). A variety of chemometric tools was applied to explore and compare the information yielded by these methods. It was found that ET is capable of distinguishing paracetamol formulations from different producers. The chemical information derived from potentiometric sensor responses has something in common with that derived from NIR and IR; however, it is orthogonal to that from NMR. ET can be a valuable tool in express quality assessment of drugs.

Diffusion ordered NMR spectroscopy measurements as screening method of potential reactions of API and excipients in drug formulations.

In the development of new pharmaceutical formulations it is important to consider the possible interactions between the active pharmaceutical ingredient (API) and excipients which is a well-known problem. The objective of the work presented here was to investigate such reactions by means of diffusion ordered NMR spectroscopy (DOSY). The known reaction of 5-aminosalicylic acid (5-ASA) and the excipient citric acid was studied. Three reaction products have been verified by DOSY, 1H NMR and HPLC measurements. Despite a poor separation in the DOSY diagram, the reaction products could be assign due to the processing of thoughtful selected parts of the signals. The reaction of 5-ASA with formic acid and benzocaine with dibutyl phthalate was also studied by means of DOSY experiments.