Microenvironmental pH-Modulated Vitamin B6 Ternary Eutectics for BCS Class IV Drug Delivery

Abstract

Abstract The essence of developing multicomponent solid formulations for drugs with poor physicochemical and pharmacokinetic properties is rapidly evolving to cut short the consumption of resources and time. Quite a few commercially available binary drug formulations in the public domain serve as a prime illustration of the field’s success. However, the design and utilization of ternary or higher-order drug formulations can be more efficacious in terms of enhancing such properties of the drug as well as providing humidity resistance and controlling unexpected phase transitions during drug development. Low-soluble and low-permeable BCS IV class drugs continuously present a barrier by lowering their absorption in the body. Drugs mesalamine (MSA) and acetazolamide (ACZ) from the same BCS class were chosen to enhance properties by introducing the binary and ternary solid formulation approach. Soluble and acceptable co-partners, viz., vitamin B6 (pyridoxine hydrochloride, PRDHCl) and p-Aminobenzoic acid (PABA), were carefully chosen. The grinding of MSA and ACZ with p-aminobenzoic acid (PABA) resulted in a physical mixture (MSA·PABA) and a cocrystal (ACZ·PABA), respectively, due to the mismatch of functional moieties and shape. Interestingly, the addition of PRDHCl to the two binary systems generated two ternary eutectic solids, viz., PRDHCl·MSA·PABA and PRDHCl·ACZ·PABA. The thermal and spectroscopic analyses suggested that PRDHCl·MSA·PABA is a mixture of PRDHCl, MSA and PABA. However, PRDHCl·ACZ·PABA exists as a combination of the cocrystal ACZ·PABA and PRDHCl. The conversion of different binary solids to ternary eutectic solids showed a notable impact on the pH-dependent solubility and membrane permeability of both drugs, MSA and ACZ. Microenvironmental pH (MpH) and different microspecies (neutral, ionic, and zwitterionic) generated at the solid−liquid interface are accountable for the altered and improved pH-dependent solubility and membrane permeability of the solids.

The authors' abstract, as published at the source. Crystal Growth & Design, 2026 · DOI ↗