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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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.

OriginalsprogEngelsk
TidsskriftActa Pharmaceutica Sinica B
ISSN2211-3835
DOI
StatusAccepteret/In press - 2024

Bibliografisk note

Funding Information:
This study was supported in part by an Ontario Research Fund-Research Excellence (ORF-RE) grant (Ontario, Canada) in partnership with Patheon by Thermo Fisher Scientific, Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grant and Equipment Grants to Xiao Yu Wu, University of Toronto (Canada), Leslie Dan Faculty of Pharmacy Dean's Fund to Jamie Anne Lugtu-Pe, University of Toronto (Canada), Mitacs Accelerate Internship sponsored by Candoo Pharmatech Company Inc. to Xuning Zhang (Canada), NSERC CREATE ContRoL program support to Sako Mirzaie and Hao Han R. Chang (Canada), Ontario Graduate Scholarship (OGS) to Hao Han R. Chang (Canada), and Pharmaceutical Sciences graduate department scholarships to Hao Han R. Chang and Kuan Chen, University of Toronto (Canada). The authors also sincerely thank Dr. Ping Lee for the use of DSC and polarized light microscope, University of Toronto (Canada), Dr. David Dubins for the use of the fluid bed coater in the Patheon Pharmaceutics Teaching Laboratory, University of Toronto (Canada), Colorcon for providing samples of PVP and Surelease\u00AE EC, Croda for donating PS 80, and Florent Vilotte (Colorcon) for providing technical advice on coating conditions.

Publisher Copyright:
© 2024 The Authors

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