Physical chemical drug-drug interactions from drug discovery to registration: New opportunities for the pharmaceutical scientist to impact drug development

摘要

Drug discovery efforts frequently yield molecules with challenging physicochemical attributes that affect formulation, product development, and robustness of drug absorption across patient populations. Low aqueous solubility and/or low permeability rates have been conveniently classified via the Biopharmaceutical Classification System (BCS).1 Within the solubility axis, drugs frequently exhibit pH-dependent solubility, where the potential for extensive drug dissolution may vary dramatically as a function of pH over the course of the gastrointestinal (GI) tract. For example weakly basic drugs may be sufficiently soluble in the stomach under standard conditions, yet these same drugs may rapidly become insufficiently soluble once exiting the stomach into the higher pH duodenum or later. For patients with limited gastric acid secretion (hypochlorhydria, or achlorhydria), their stomach pH may be higher than standard conditions, and for these individuals, drug absorption may be significantly lower (for weak base drugs) or higher (for weak acid drugs). Further, patients taking acid-reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids), which elevate gastric pH, are similarly prone to the interaction of variable gastric pH affecting the extent of drug dissolution or precipitation in the GI tract. This special edition of Molecular Pharmaceutics focuses specifically on physicochemical DDI effects and formulation approaches as well as in vivo and in silico methodologies to support robust product development despite the challenges presented by undesirable physicochemical properties.