Use of Bead Mixtures as a Novel Process Optimization Approach to Nanomilling of Drug Suspensions

Gulenay Guner, Manisha Kannan, Matthew Berrios, Ecevit Bilgili

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Purpose: We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)–yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, effective production of drug nanosuspensions during wet stirred media milling (WSMM). Methods: Aqueous suspensions of 10% fenofibrate (FNB, drug), 7.5% HPC-L, and 0.05% SDS were wet-milled at 3000–4000 rpm and 35%–50% volumetric loading of CPS:YSZ bead mixtures (CPS:YSZ 0:1–1:0 v:v). Laser diffraction, SEM, viscometry, DSC, and XRPD were used for characterization. An nth-order model described the breakage kinetics, while a microhydrodynamic model allowed us to gain insights into the impact of bead materials. Results: CPS beads achieved the lowest specific power consumption, whereas YSZ beads led to the fastest breakage. Breakage followed second-order kinetics. Optimum conditions were identified as 3000 rpm and 50% loading of 0.5:0.5 v/v CPS:YSZ mixture from energy–cycle time–heat dissipation perspectives. The microhydrodynamic model suggests that YSZ beads experienced more energetic/forceful collisions with smaller contact area as compared with CPS beads owing to the higher density–elastic modulus of the former. Conclusions: We demonstrated the feasibility of CPS–YSZ bead mixtures and rationalized its optimal use in WSMM through their modulation of breakage kinetics, energy utilization, and heat dissipation.

Original languageEnglish (US)
Pages (from-to)1279-1296
Number of pages18
JournalPharmaceutical Research
Issue number7
StatePublished - Jul 2021

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)


  • bead mixtures
  • poorly water-soluble drugs
  • process modeling
  • process optimization
  • wet stirred media milling


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