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.