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

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Abstract

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.

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Data Availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Abbreviations

a :

average frequency of drug particle compressions, Hz

c :

bead volume fraction (loading) in the milling chamber, −

CPS:

cross-linked polystyrene

d :

particle size, m

e :

restitution coefficient for the inelastic bead–bead collisions, −

E td50 :

specific energy consumed during td50, J/kg

E td90 :

specific energy consumed during td90, J/kg

F b n :

average maximum normal force during collision of two identical beads, N

g 0 :

radial distribution function, −

k :

apparent breakage rate constant, m1–n/s

K :

coefficient obtained from an empirical correlation, −

m D :

mass of drug, kg

n :

exponent of the nth-order breakage kinetic model, −

p :

probability for a single drug particle to be caught between the beads, −

P :

power applied by the mill stirrer (rotor), W

P w :

stirrer power per unit volume, W/m3

PSD:

particle size distribution

q :

exponent of the power-law viscosity model, −

q 3, Q 3 :

density distribution of volume fraction and cumulative volume fraction, −

R :

radius, m

R dis :

dissipation (effective drag) coefficient of the bead, −

R diss0 :

dissipation coefficient when relative motion of the bead–liquid is absent, −

t :

milling time, s

t d50 :

milling time required to attain a median drug particle size d50 of 0.25 μm, s

t d90 :

milling time required to attain a 90% passing size d90 of 0.5 μm, s

u b :

average bead oscillation velocity, m/s

V m :

volume of the milling chamber, m3

w i :

ith weighting coefficient in the merit score equation, −

WSMM:

wet stirred media milling

Y, Y* :

Young’s modulus and reduced elastic modulus for the bead–drug contact, Pa

YSZ:

yttrium-stabilized zirconia

α :

radius of the contact circle formed at the contact of two beads, m

ε coll :

energy dissipation rate due to partially inelastic bead–bead collisions, W/m3

ε ht :

power spent on shearing the milled suspension in the absence of beads, W/m3

ε m :

non-dimensional bead–bead gap thickness, −

ε visc :

energy dissipation rate due to the liquid–beads viscous friction and lubrication, W/m3

γ:

shear rate, 1/s

η :

Poisson’s ratio, −

θ :

granular temperature, m2/s2

μ :

apparent shear viscosity of the milled suspension, Pa·s

μ 0 :

parameter of the power-law viscosity model, Pa∙sq

ν :

frequency of single-bead oscillations, Hz

Π :

energy dissipation rate attributed to the deformation of drug particles, W/m3

Πσ y :

pseudo energy dissipation rate attributed to the deformation of drug particles, J2/m6s

ρ :

density, kg/m3

σ b max :

maximum bead contact pressure at the center of the bead contact circle, Pa

σ y :

contact pressure in a drug particle when the fully plastic condition is obtained, Pa

ω :

stirrer (rotational) speed, rpm

ψ :

volumetric fraction of drug particles in the drug suspension, −

b:

bead

L:

equivalent liquid (milled drug suspension)

m:

mixture of beads and milled suspension

p:

drug particle

10, 50, 90:

10%, 50%, and 90% passing size of the cumulative PSD

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Nisso for providing the materials free of charge. The corresponding author (E.B.) thanks Professor Dmitry Eskin for fruitful discussion on the microhydrodynamic model. G.G. acknowledges the NJIT Department of Chemical and Materials Engineering for the financial support, while E.B. acknowledges the Faculty Instrument Usage Seed Grant (FIUSG) by NJIT Otto H. York Center & the Materials Characterization Lab for characterization support. The authors report no conflict of interest.

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Authors and Affiliations

  1. Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, New Jersey, USA

    Gulenay Guner, Manisha Kannan, Matthew Berrios & Ecevit Bilgili

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  1. Gulenay Guner
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  2. Manisha Kannan
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  3. Matthew Berrios
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Contributions

Gulenay Guner: Conceptualization, Methodology, Software, Validation, Formal Analysis, Investigation, Writing - Original Draft, Visualization. Manisha Kannan: Investigation. Matthew Berrios: Investigation. Ecevit Bilgili: Conceptualization, Methodology, Writing - Review & Editing, Supervision, Project administration.

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Correspondence to Ecevit Bilgili.

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Guner, G., Kannan, M., Berrios, M. et al. Use of Bead Mixtures as a Novel Process Optimization Approach to Nanomilling of Drug Suspensions. Pharm Res 38, 1279–1296 (2021). https://doi.org/10.1007/s11095-021-03064-2

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