Donepezil Hydrochloride BCS Class Ambiguity: Relevant Aspects to be Considered in Drug Classification.

Donepezil hydrochloride (DH) is the most used anti-Alzheimer's disease drug, however, its classification according to the Biopharmaceutics Classification System (BCS) is not clear in the literature. BCS is one of the accepted criteria used to grant biowaiver (waiver of in vivo bioequivalence studies) of new drug products. So, the purpose of this work was to elucidate the BCS classification of DH and to raise the discussion about the possibility of biowaiver for new medicines containing it. The polymorphic form was previously identified as form III of DH. The drug showed high solubility in the entire pH range evaluated (1.2 to 6.8, at 37 °C) with a pH-dependent solubility profile. The effective permeability (Peff) values obtained with different DH concentrations, using in situ closed-loop perfusion model were statistically similar (p > 0.05), even when compared to high permeability control used (ketoprofen), demonstrating that DH has high permeability which, associated with its high solubility, allows to classify DH as BCS class 1. Relevant data to evaluate for granting a biowaiver for new medicines were also reviewed from the literature. Based on information reunited new immediate-release drug products containing DH should be eligible for BCS-based biowaiver.

A sustainable UPLC-UV method for quantification of donepezil hydrochloride in biorelevant media applied to dissolution profile comparison.

Donepezil hydrochloride is one of the most prescribed anti-Alzheimer's drugs, despite being available for more than two decades, chromatographic methods for the quantification of the drug in biorelevant media that mimics pH physiological conditions in vivo (pH 1.2, 4.5, and 6.8) are not available in the literature. These media are used in the dissolution test, an important tool, for registration and quality control of medicines. Considering the need for methods with this purpose, this work aimed to develop and validate a sustainable UPLC-UV method for quantification of donepezil hydrochloride in tablets, specifically on assay and dissolution profile, with reduced environmental impacts. The proposed method has a run time of 2 min and requires for each run, only 0.8 mL of solvents, providing excellent green analysis. The method proved to be selective, linear, precise, accurate, robust in the range of 2-14 µg/mL. Three products (reference, similar, and generic) were analyzed and showed very rapid dissolution. The average content varied from 100.2 ± 0.6% to 109.5 ± 2.1%. Using dissolution efficiency (DE), the drug release profiles were compared in different biorelevant media.

Polymorphic and Quantum Chemistry Characterization of Candesartan Cilexetil: Importance for the Correct Drug Classification According to Biopharmaceutics Classification System.

The recommended method for the biopharmaceutical evaluation of drug solubility is the shake flask; however, there are discrepancies reported about the solubility of certain compounds measured with this method, one of them is candesartan cilexetil. The present work aimed to elucidate the solubility of candesartan cilexetil by associating others assays such as stability determination, polymorphic characterization and in silico calculations of intrinsic solubility, ionized species, and electronic structures using quantum chemistry descriptors (frontier molecular orbitals and Fukui functions). For the complete biopharmaceutical classification, we also reviewed the permeability data available. The polymorphic form used was previously identified as the form I of candesartan cilexetil. The solubility was evaluated in biorelevant media in the pH range of 1.2-6.8 at 37.0°C according to the stability previously assessed. The solubility of candesartan cilexetil is pH dependent and the dose/solubility ratios obtained demonstrated the low solubility of the prodrug. The in silico calculations supported the found results and evidenced the main groups involved in the solvation, benzimidazole, and tetrazol-biphenyl. The human absolute bioavailability reported demonstrates that candesartan cilexetil has low permeability and when associated with the low solubility allows to classify it as class 4 of the Biopharmaceutics Classification System.