Tuning Caco-2 permeability by cocrystallization: Insights from molecular dynamics simulation

Noopur Pandey, Nimmy Kumari, Parag Roy, Susanta Kumar Mondal, Abhishek Thakur, Changquan Calvin Sun, Animesh Ghosh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Emerging evidence suggests that intestinal permeability can be potentially enhanced through cocrystallization. However, a mechanism for this effect remains to be established. In this study, we first demonstrate the enhancement in intestinal permeability, evaluated by the Caco-2 cell permeability assay, of acetazolamide (ACZ) in the presence of a conformer, p-aminobenzoic acid (PABA), delivered in the form of a 1:1 cocrystal. The binding strength of ACZ and PABA with the Pgp efflux transporter, either alone or as a mixture, was calculated using molecular dynamics simulation. Results show that PABA weakens the binding of ACZ with Pgp, which leads to a lower efflux ratio and elevated permeability of ACZ. This work provides molecular-level insights into a potentially effective strategy to improve the intestinal permeability of drugs. If the same cocrystal also exhibits higher solubility, oral bioavailability of BCS IV drugs can likely be improved by forming a cocrystal with a Pgp inhibitor.

Original languageEnglish (US)
Article number123666
JournalInternational journal of pharmaceutics
StatePublished - Jan 25 2024

Bibliographical note

Publisher Copyright:
© 2023 Elsevier B.V.


  • Acetazolamide
  • All-atom molecular dynamics
  • Caco-2 cell
  • Cocrystallization
  • Efflux
  • P-glycoprotein
  • Permeability

PubMed: MeSH publication types

  • Journal Article


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