A comprehensive approach toward concomitant triclabendazole polymorphism in pharmaceutical products

Abstract

Triclabendazole (TCB) is a highly effective and low-cost anti-parasitic active pharmaceutical ingredient (API) used in the treatment of fascioliasis, a neglected tropical disease caused by Fasciola hepatica. It belongs to Class II/IV in the Biopharmaceutics Classification System, where API dissolution results in the limiting step for its absorption. TCB exhibits tautomeric and conformational polymorphism, where Form I contains different conformations of tautomer A, and Form II is a 1:1 conglomerate of tautomers A and B, each in a single conformation. Since both forms may precipitate concomitantly during the preparation of the API, the control of polymorphic quality is critical for this anti-parasitic agent. A comprehensive approach was developed to address the determination of the polymorphic quality of drug-products when pure solid forms are not available, such as the case of concomitant crystallization of TCB I and II. First, both solid forms of the drug were isolated and characterized (digital optical microscopy, differential scanning calorimetry, hot stage microscopy, mid-infrared, near-infrared and solid-state 13C nuclear magnetic resonance). Next, lab-scale crystallization of Forms I and II was optimized, following a smart approach (green solvent and robust procedures), in order to obtain standards for calibration. A strategy based on NIR spectroscopy coupled to PLS was developed and validated to assess the polymorphic composition of drug-products. The new method was successfully applied to formulated products. The intrinsic dissolution rate of the pure forms demonstrated that Form II dissolves up to 60% faster than Form I, reinforcing the need for polymorphic control to assure the lot-to-lot equivalence. Thus, NIR-PLS emerges as a unique tool able to control the risk of polymorphic changes and their impact on bioavailability in formulated products.