BCS-BASED BIOWAIVER MONOGRAPH FOR HYDROCHLOROTHIAZIDE

The Biopharmaceutical Classification System (BCS) is used to classify a drug substance based on its solubility and intestinal permeability. This system forms the basis for the development of a risk-based tool for international medicines regulatory authorities (MRAs), which is used when considering the waiver of in vivo bioequivalence studies during the development of generic formulations. Since the BCS classification of a drug substance is the primary precursor when considering a biowaiver, it is of utmost importance that a drug is classified correctly. However, after an in-depth literature review on the BCS classification of hydrochlorothiazide (HCTZ), several inconsistencies have been detected, with the primary inconsistency being the classification thereof. It has been found to be classified as a Class I, II, III, and/or IV drug. Furthermore, another detected inconsistency was the agreement of the polymorphic behaviour of HCTZ. Therefore, the focus of this publication was to evaluate the eligibility of HCTZ in immediate release (IR) solid oral dosage forms to qualify for a BCS-based biowaiver based on the available literature and additional generated experimental data, with the focus of this risk assessment being on solubility, permeability, dissolution, excipient impact, therapeutic window, dosage form and polymorphic behaviour of HCTZ. In this study, a proposed classification for HCTZ was given based on quality assured experimental data, as well as an in-depth literature review. In addition, the potential risk of the polymorphism of HCTZ to alter the bioavailability, product performance, and stability of HCTZ was explored. Additionally, the risk associated with the waiver of in vivo bioequivalence studies was explored and a recommendation was made. Finally, a computational simulation was performed using GastroPlus[R] to evaluate the impact of the experimentally determined solubility on the BCS classification of HCTZ, with respect to the intestinal permeability after the administration of different doses. This simulation presented results that were remarkably comparable to those obtain in vivo. KEYWORDS Hydrochlorothiazide, biopharmaceutical classification system, solubility, permeability, biowaiver, dissolution, excipients.
Introduction The Biopharmaceutical Classification System (BCS) is used to classify a drug substance based on its solubility and intestinal permeability. This system forms the basis for the development of a [...]