Ethanol-based solubility-enabling oral drug formulation development: Accounting for the solubility-permeability interplay

Noa Fine-Shamir, Arik Dahan

Research output: Contribution to journalArticlepeer-review

Abstract

The aim of the current work was to investigate the key factors that govern the success/failure of an ethanol-based solubility-enabling oral drug formulation, including the effects of the ethanol on the solubility of the drug, the permeability across the intestinal membrane, the drug's dissolution in the aqueous milieu of the gastrointestinal tract (GIT), and the resulting solubility-permeability interplay. The concentration-dependent effects of ethanol-based vehicles on the solubility, the in-vitro Caco-2 permeability, the in-vivo rat permeability, and the biorelevant dissolution of the BCS class II antiepileptic drug carbamazepine were studied, and a predictive model describing the solubility-permeability relationship was developed. Significant concentration-dependent solubility increase of CBZ was obtained with increasing ethanol levels, that was accompanied by permeability decrease, both in Caco-2 and in rat perfusion studies, demonstrating a tradeoff between the increased solubility afforded by the ethanol and a concomitant permeability decrease. When ethanol absorption was accounted for, an excellent agreement was achieved between the predicted permeability and the experimental data. Biorelevant dissolution studies revealed that minimal ethanol levels of 30 % and 50 % were needed to fully dissolve 1 and 5 mg CBZ dose respectively, with no drug precipitation. In conclusion, key factors to be accounted for when developing ethanol-based formulation include the drug's solubility, permeability, the solubility-permeability interplay, and the drug dose intended to be delivered. Only the minimal amount of ethanol sufficient to solubilize the drug dose throughout the GIT should be used, and not more than that, to avoid unnecessarily permeability loss, and to maximize overall drug absorption.

Original languageEnglish
Article number123893
JournalInternational Journal of Pharmaceutics
Volume653
DOIs
StatePublished - 25 Mar 2024

Keywords

  • Drug delivery
  • Ethanol
  • Intestinal permeability
  • Low solubility
  • Oral absorption/bioavailability
  • Solubility-enabling formulation
  • Solubility-permeability interplay

ASJC Scopus subject areas

  • Pharmaceutical Science

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