Solubility Determination of Active Pharmaceutical Ingredients Which Have Been Recently Added to the List of Essential Medicines in the Context of the Biopharmaceutics Classification System-Biowaiver

Abstract

Since the publication of Lindenberg et al., which classified orally administered active pharmaceutical ingredients (APIs) on the 2004 Essential Medicines List (EML) of the World Health Organization according to the Biopharmaceutics Classification System (BCS), various APIs have been added to the EML. In this work, BCS classifications for 16 of the orally administered APIs which were added to the EML after 2004 were determined. To establish a reliable solubility classification for all these compounds, a miniaturized shake-flask method was introduced. This method enables a fast, economical determination of the BCS solubility class while reliably discriminating between "highly soluble" and "not highly soluble" compounds. Nine of the 16 APIs investigated were classified as "highly soluble" compounds, making them potential candidates for an approval of multisource drug products via the BCS-based biowaiver procedure. The choice of dose definition (which currently varies among the guidances pertaining to BCS-based bioequivalence published by various regulatory authorities) had no effect on the solubility classification of any of the 16 substances evaluated. BCS classification of the compounds was then completed using permeability data obtained from the literature. As several APIs decomposed at one or more pH values, a decision tree for determining their solubility was established.

Keywords: Biopharmaceutics Classification System (BCS); bioequivalence; pH; permeability; physicochemical properties; solubility.