An emerging terpolymeric nanoparticle pore former as an internal recrystallization inhibitor of celecoxib in controlled release amorphous solid dispersion beads: Experimental studies and molecular dynamics analysis

Research output: Contribution to journalJournal articleResearchpeer-review

  • Jamie Anne Lugtu-Pe
  • Xuning Zhang
  • Sako Mirzaie
  • Hao Han R. Chang
  • Nour AL-Mousawi
  • Kuan Chen
  • Yongqiang Li
  • Anil Kane
  • Bar-Shalom, Daniel
  • Xiao Yu Wu

Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate. However, most new chemical entities exhibit poor water solubility, and hence are exempt from such benefits. Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility, like other supersaturating systems, the problem of drug recrystallization has yet to be resolved, particularly within the dosage form. Here, we explored the potential of an emerging, non-leachable terpolymer nanoparticle (TPN) pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion (CRASD) beads comprising a poorly soluble drug (celecoxib) reservoir and insoluble polymer (ethylcellulose) membrane. Compared to conventional pore former, polyvinylpyrrolidone (PVP), TPN-containing membranes exhibited superior structural integrity, less crystal formation at the CRASD bead surface, and greater extent of celecoxib release. All-atom molecular dynamics analyses revealed that in the presence of TPN, intra-molecular bonding, crystal formation tendency, diffusion coefficient, and molecular flexibility of celecoxib were reduced, while intermolecular H-bonding was increased as compared to PVP. This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.

Original languageEnglish
JournalActa Pharmaceutica Sinica B
ISSN2211-3835
DOIs
Publication statusAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

    Research areas

  • Controlled release amorphous solid dispersion, Drug-polymer interactions, Effect of pore formers, Internal recrystallization, Membrane-reservoir coated beads, Molecular dynamics simulation, Poorly soluble drug, Terpolymer nanogel

ID: 390356542