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
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.
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Materials
CEL was received as a sample from AARTI Drugs Ltd., Mumbai, India. Microcrystalline cellulose beads (VIVAPUR® MCC Spheres 700), used as the coating substrate, were purchased from JRS Pharma (Weissenborn, Germany). Polyvinylpyrrolidone (PVP K30) and EC aqueous dispersion (Surelease® E−7-19040) were kindly donated by Colorcon (West Point, PA, USA). TPN was synthesized using soluble corn starch, methacrylic acid (MAA), N,N′-methylenebisacrylamide (MBA), sodium thiosulfate, potassium persulfate, and sodium dodecyl sulfate (SDS ), purchased from Sigma–Aldrich (Oakville, ON, Canada), and polysorbate 80 (PS80) (Tween 80-LQ-(CQ)), donated by Croda (Edison, NJ, USA). Crystalline CEL formulation, Celebrex® capsules (100 mg), purchased for research purposes from Rexall Pharmacy (Mississauga, ON, Canada).
Jamie Anne Lugtu-Pe, Xuning Zhang, Sako Mirzaie, Hao Han R. Chang, Nour AL-Mousawi, Kuan Chen, Yongqiang Li, Anil Kane, Daniel Bar-Shalom, Xiao Yu Wu, 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, Acta Pharmaceutica Sinica B, Volume 14, Issue 6, 2024, Pages 2669-2684, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2024.03.026.
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