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Development of an RP-HPLC Peptide Mapping Method for the Identification of a GLP-1 Receptor Agonist in Tablets

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Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2026, Tutores: Ángeles Sahuquillo Estrugo, Lara Pérez Martin

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In the pharmaceutical industry, the development of analytical methods capable of ensuring the identity, purity, potency and stability of a pharmaceutical product is a critical step in pharmaceutical product development. These methods ensure the quality and safety of the product prior to its commercialization.
This Final Degree Project presents the development, and analytical evaluation of an identification method for an active pharmaceutical ingredient (API) in a pharmaceutical product. The developed procedure is a qualitative peptide mapping method using reversed-phase high-performance liquid chromatography coupled with diode array detection (RP-HPLC-DAD). The primary objective is to confirm the unambiguous identity of a biologically derived drug by comparison with a laboratory standard of the API. The studied product is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated as an oral dosage form (tablets). The main challenge of this development lies in the extreme complexity of the drug matrix, which is heavily dominated by a gastric absorption enhancer (referred to as Excipient 1). This excipient protects the active pharmaceutical ingredient (API) from enzymatic degradation in vivo but severely interferes with the analytical stages.
The initial analytical strategy involved the selection of a suitable chromatographic system and selective enzymatic digestion of the peptide using Glu-C protease, designed to generate a characteristic profile of six peptide fragments. However, excipient 1 caused interferences with this process. Due to the presence of this compound, one of the peptide fragments was not detected. According to regulatory agencies like the European Medicines Agency (EMA), the recovery of all peptide fragments is a key aspect of this method, thus making this procedure unsuitable for routine quality control.
Various physical sample pre-treatment methodologies were systematically evaluated to isolate the API from the matrix prior to the digestion stage, but none provided satisfactory analyte recovery. Given the impossibility of achieving a robust physical separation, the research was reoriented towards the optimization of the digestion buffer strength and pH and the chemical stabilization of the excipient in solution via the controlled addition of a non-polar solvent. However, the addition of a non-polar solvent caused peak splitting and band broadening of the more polar and hydrophilic fragments.
The final resolution of the method was not achieved, but it will probably imply the chemical stabilization of excipient 1 through the addition of an organic solvent.
Although substantial improvements were achieved throughout the method development process and the major limitation of the initial procedure (the non-detection of a peptide fragment) was successfully addressed, the final method could not be further optimized or subjected to a comprehensive evaluation of its repeatability and validation parameters within the timeframe of this project.

# metadata.dc.title[].value
Development of an RP-HPLC Peptide Mapping Method for the Identification of a GLP-1 Receptor Agonist in Tablets

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Desenvolupament d’un mètode de peptide mapping mitjançant RP-HPLC per a la identificació d’un agonista del receptor GLP-1 en comprimits