Determination of bioequivalence between generic and reference drugs using laser-induced breakdown spectroscopy

Abstract

Background: In vitro bioequivalence studies are strictly limited to the comparison of dissolution performance to a reference drug. These studies are performed without considering the chemical similarity between the generic and reference drug formulations. This work has focused on developing a groundbreaking method based on the laser-induced breakdown spectroscopy (LIBS) technique for the in vitro bioequivalence determination of immediate-release solid oral dosage form generic drugs and as an alternative method for establishing the biowaiver of in vivo generic drug studies. Results: The novel LIBS-based methodology to determine in vitro bioequivalence is fast, easy to perform, and can be carried out without the requirement of tedious and complicated sample pre-treatment, nor expensive instrumentals and reagents, almost directly on the drug samples. Furthermore, the proposed methodology demonstrated that it is enough to identify the spectrochemical similarity of the formulation between generic drugs to a reference drug through the chemometric study of their LIBS spectra, based on the determination of the differentiation and similarity factors, f1 and f2, respectively, used in the pharmaceutical industry in this purpose. After analysing their LIBS spectra, the generic drugs selected for this work have all been shown to be in vitro bioequivalent, given their f1 values of less than 15 and f2 values greater than 50, according to the technical regulations on which the American and European medicines agencies are based for the approval of registration for generic immediate-release solid oral dosage form drugs. This has been evidenced even for drugs from Class III and Class IV of the biopharmaceutical classification system, whose active principle nominal concentration is very low as 0.1 and 0.25 mg/tablet, respectively. Significance: for the first time the LIBS technique has been successfully used in an advanced application for the pharmaceutical industry. The proposed method constitutes a reliable and specialized methodology for the establishment of formulation similarity between two drugs, without the requirement of separate identification of each of their components, which is a new and potential tool to determine the in vitro bioequivalence for generic immediate-release solid oral dosage form drugs.