Vol. 69, No. 181
Chem. Pharm. Bull. 69, 81–85 (2021)

Regular Article

Development of Novel Bead Milling Technology with Less Metal
Contamination by pH Optimization of the Suspension Medium
Hironori Tanaka,*,a,b Yuya Ochii,a Yasushi Moroto,a Tetsuharu Ibaraki,c and Ken-ichi OgawarabaFormulation R&D Laboratory, CMC R&D Division, Shionogi & Co., Ltd.; 3–1–1 Futaba-cho, Toyonaka, Osaka
561–0825, Japan: b Laboratory of Pharmaceutics, Kobe Pharmaceutical University; 4–19–1 Motoyamakita-machi,
Higashinada-ku, Kobe 658–8558, Japan: and c Hiroshima Metal & Machinery Co., Ltd.; 1–2–43 Hiroshiratake, Kure,
Hiroshima 737–0144, Japan.
Received August 4, 2020; accepted October 16, 2020
To develop novel contamination-less bead milling technology without impairing grinding eﬃciency, weinvestigated the eﬀect of the formulation properties on the grinding eﬃciency and the metal contamination
generated during the grinding process. Among the various formulations tested, the combination of polyvinylpyrrolidone and sodium dodecyl sulfate was found to be suitable for eﬃciently pulverizing phenytoin.
However, this stabilization system included a relatively strong acid, which raised the concern of possible
corrosion of the zirconia beads. An evaluation of the process clearly demonstrated that acidic pH promoted
bead dissolution, suggesting that this could be suppressed by controlling the pH of the suspension. Amongthe various pH values tested, the metal contamination generated during the grinding process could be signiﬁcantly reduced in the optimized pH range without signiﬁcant diﬀerences in the particle size of the phenytoin
suspension after pulverization. In addition, the contamination reduction by pH optimization in the presenceof physical contact among the beads was approximately 10-times larger than that without bead contact,suggesting that pH optimization could suppress not only bead dissolution but also the wear caused by beadcollisions during the grinding process. These ﬁndings show that pH optimization is a simple but eﬀective approach to reducing metal contamination during the grinding process.
Key words

Introduction

nanosized particle; bead mill; contamination; pH optimization

Recently, it has become possible to ﬁnd a larger numberof excellent drug candidate compounds in a shorter period oftime thanks to the progress of various technologies, such as
combinatorial chemistry and high-throughput screening technology.1) However, approximately 40–70% of such drug candidate compounds have been discontinued due to their poor
solubility.2,3) Therefore, new technologies to overcome poor
drug solubility have been actively investigated.4)
For poorly soluble drugs, pharmaceutical technologies toimprove their dissolution rate and apparent solubility are essential to achieving higher bioavailability. The Noyes–Whitney equation5) and the Ostwald–Freundlich equation6) are
well-known for describing the dissolution rate and apparent
solubility of a drug, respectively. Based on these equations,increasing the surface area or solubility of a drug is considered to be eﬀective for improving its dissolution rate.7)
Further, pulverization is one useful technology for obtaining nanosized particles to improve the dissolution rate of adrug by increasing its surface area.8) Nanosized particles canbe prepared by bottom-up or breakdown techniques, such as
pulverization, bead milling,9–13) high-pressure homogenizing,14–19) and liquid antisolvent precipitation.20) Among them,bead milling, a breakdown technique, oﬀers high grinding efﬁciency and is superior to other technologies in terms of scalability and reproducibility.21) Therefore, bead milling is currently one of the most widely used wet grinding techniques.22)
In the bead mill grinding method, a grinding medium, suchas yttria-stabilized zirconia beads, is often used to grind anddisperse drugs. Therefore, the risk of metal contamination,such as from the zirconium due to collision of the grinding
beads, has been a major concern.23–26) Although zirconium
toxicity was conﬁrmed to be moderately low by histological or cytological studies,27) it is essential to minimize andcontrol undesirable contamination by impurities, particularly
for pharmaceutical products. Therefore, various methods toreduce metal contamination in the grinding process have beenstudied, but the outcomes remain unsatisfactory.
The mainstream approach to reducing contamination by thecollision of grinding beads is optimization of the grinding medium or grinding parameters of the milling equipment. As an
example of the former, smaller-sized zirconia beads have beenreported to reduce the amount of contamination.28) In addition, materials such as dry ice,26) sugars,29) and salts,30) which
are considered safe, have been used as grinding media. As an
example of the latter, the wear of the grinding media is considered to be suppressible by using a lower rotation speed andlower media ﬁlling.31) Although the abovementioned approaches can reduce the amount of contamination generated during
the grinding process, they are known to impair the grinding
eﬃciency. Therefore, in the present study, we attempted toﬁnd a novel approach to reduce metal contamination without
impairing the grinding eﬃciency.

Experimental

Materials Phenytoin was purchased from Shizuoka Caffeine Industries (Japan), polyvinylpyrrolidone (PVP K-25),
and sodium dodecyl sulfate (SDS) from BASF Japan Ltd.
(Japan), hydroxypropyl methylcellulose (HPMC TC-5E) from
Shin-Etsu Chemical Co., Ltd. (Japan), hydroxypropyl cel-* To whom correspondence should be addressed. e-mail: hironori.tanaka@shionogi.co.jp© 2021 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.

lulose (HPC-SSL) from Nippon Soda Co., Ltd. (Japan), andyttria-stabilized zirconia beads with a diameter of 500 µm(YTZ-0.5) from Nikkato Corporation (Japan). Hydrochloric
acid (HCl), trisodium citrate, citric acid, sodium dihydrogen
phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, sodium carbonate, and sodium hydrogen carbonate,used to prepare buﬀers of various pH, and 1 N sodium hydroxide (NaOH), used to adjust the pH, were purchased from
Kanto Chemical Co., Inc (Japan). All other chemicals and solvents were of analytical reagent grade, and puriﬁed water wasused throughout the study.
Formulation Study Using a Rotation–Revolution Mixer
Phenytoin at 5% (w/w) in puriﬁed water was stabilized with
1% (w/w) polymer and 0.1% (w/w) SDS. Phenytoin wasdispersed in a dispersion medium with a stirrer and thensonicated to form a suspension. An amount of 2 mL of suspension and 4 g of zirconia beads, 500 µm in diameter, wereplaced into a zirconia vessel, followed by milling at 2000 rpm
for 4 min with a chamber temperature of 5 °C using a rotation–revolution mixer (NP-100, Thinky Corp., Japan). The
same cycle was repeated 9 times, for a total of 36 min of
milling. The temperature of the milling chamber was maintained at 4–7 °C during grinding. Particle size distributions
as Z-averages were measured using dynamic light scattering(DLS; Zetasizer Nano, Malvern Panalytical Ltd., Japan). The
Z-average was determined by taking the refractive index
value of 1.61 for phenytoin particles and 1.33 for the measurement medium (water). To measure the particle size, water wasused to dilute the drug to maintain the drug concentration of
0.4 mg/mL.
Evaluation of the pH-Dependent Dissolution of Zirconia
Beads A pH 1 buﬀer was prepared using 0.1 N HCl. The
pH 3–5 buﬀer was prepared using 100 mM citrate buﬀer, pH
6–8 buﬀer using 100 mM phosphate buﬀer, and pH 9 and 10
buﬀers using 100 mM carbonate buﬀer. An amount of 9.25 gof yttria-stabilized zirconia beads of 500-µm diameter wasplaced into a metal-free container. The sample was inverted 5
times for homogenization with 5 mL of each pH buﬀer. Thesesamples were incubated at 25 °C for 24 h, and the supernatant
was obtained after 5 repeats of inversion at predetermined
times. The obtained sample was evaluated for metal contamination using inductively coupled plasma-mass spectrometry(ICP-MS, iCAPQ, Thermo Fisher Scientiﬁc, U.S.A.).
Procedure for Wet Milling with Dyno-Mill Phenytoin
at 5% (w/w) in puriﬁed water was stabilized with 3% (w/w)
PVP K-25 and 0.25% (w/w) SDS. Phenytoin was dispersed ina dispersion medium with a stirrer and then sonicated to forma suspension. For pH adjustment, 1 N of NaOH was added
until the target pH was reached. After adjusting the pH, stirring was conducted with a stirring bar for 90 min, then 150 gof suspension was prepared, and 100 g was used. Wet milling
was performed using a Dyno-mill Research Lab apparatus(Willy A. Bachofen AG, Germany). For all experiments, themilling chamber was ﬁlled with beads at a ratio of 70 % (v/v).
The rotation speed of the accelerator was set to 4 m/s for 90 min
for the grinding process. Yttria-stabilized zirconia beads witha diameter of 500 µm were used as the grinding medium. The
process was performed in the recirculation mode. The grinding chamber was connected to an external cooling device
BH-302 (Yamato Scientiﬁc Co., Ltd., Japan) to dissipate theheat generated during milling. Samples were taken from theoutlet of the grinding chamber for particle size measurement
and metal contamination determination at diﬀerent time intervals. Particle size distributions as D50 were measured using
DLS (UPA150, Nikkiso Corp., Japan) after milling times offrom 5 to 90 min. The volumetric median particle size D50
was determined by taking a refractive index value of 1.61 forthe phenytoin particles and 1.33 for the measurement medium(water). To measure the particle size, water was used to dilutethe drug to maintain the drug concentration of 0.4 mg/mL.
Determination of Metal Contamination in the Nanosized Particle Suspension The metal contamination in thenanosized particle suspension was determined by elemental
analysis. Both the solid and dissolved components in the suspension were quantiﬁed by ICP-MS. An amount of 0.5 g of thesample was placed into a metal-free chamber, and an internal
standard substance (Co) and the NMP/HCl/HNO3 mixture(90 : 5 : 5) were added. The samples were completely dissolved
by ultrasonic irradiation. Elemental analysis was performed
with four diﬀerent calibration solutions and an internal standard. The range of the calibration was 0.5–2.0 ppm.

Results and Discussion

Suspension Formulation Design for Bead Milling Prior
to this study, the suspension formulation was optimized tostabilize the dispersion of phenytoin. It has been reported thatthe formulation of a polymer and surfactant is useful for stabilizing the dispersion of a drug.32) In this study, we selected
HPMC, HPC, and PVP as the polymer candidates. In addition,
SDS was used as a surfactant to prepare a combination formulation with a polymer. Subsequently, phenytoin was dispersed
in water with these additives and then subjected to grinding
with zirconia beads using a rotation–revolution mixer. The
eﬀects of the dispersion medium on the phenytoin particle size
are shown in Fig. 1. The grinding process was continued until
the particle size reduction transition reached equilibrium. The
grinding eﬃciency was evaluated by measuring the particle
size reduction of phenytoin in the suspension at each grinding time. The particle size at the pulverization equilibrium
diﬀered depending on the type of polymer used, with thesmallest being in the suspension with PVP and SDS. This
result was similar to that of a previous study in which the size
reduction of phenytoin was successfully promoted throughthe combinatorial use of 0.5% PVP and 0.1% SDS.33) Furthermore, earlier reports have suggested that a PVP-based layering

Fig. 1.

Eﬀect of Polymer and Surfactant on Particle Size of Phenytoin

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Vol. 69, No. 1 (2021)83

structure with SDS would surround drug particles with static
barriers and eﬀectively suppress their aggregation.34,35) Therefore, PVP and SDS were selected to stabilize the dispersionof phenytoin to maintain high grinding eﬃciency throughout
this study.
Eﬀect of Additives on the Suspension pH Zirconia
beads, which are commonly used in the bead milling method,
are partially stabilized by yttrium oxide and aluminum oxide,
which are added to aid sintering.36) However, in zirconia ceramics, the phase transition from tetragonal to monoclinic,
which is considered to be the cause of microcracks, has beenreported to progress more vigorously in water than in air.37) It
has also been suggested that these oxides can corrode depending on temperature and pH,38,39) and the dissolution of yttrium
from yttria-stabilized zirconium oxide powders has been observed at low pH.40) Therefore, we focused on the eﬀect of thesuspension pH on the metal contamination generated during
the grinding process.
The eﬀects of various additives on the pH of the disperTable 1.

Eﬀect of Additives on pH of the Dispersion Medium

Stabilizer

Additive

Surfactant
PolymerSDS(−)
PVP K-25
HPMC TC-5E
HPC-SSL

pH
(−)
6.15
3.81
6.72
5.41

(+)
6.05
3.89
6.94
5.48

sion medium are shown in Table 1. The pH of the dispersion medium was found to be aﬀected by the addition of thepolymer. Most importantly, the addition of PVP, a polymer
that is eﬀective for grinding phenytoin, shifted the pH of thedispersion medium to 3.81, which is relatively strongly acidic.
PVP has an aldehyde group at the end of its molecular structure.41) Some of the aldehyde group react with water to form acarboxylic acid, which could result in the aqueous solution becoming acidic. Meanwhile, when HPMC or HPC were added,
the pH of the dispersion medium shifted slightly from pH
6.15 to either more alkaline or acidic, respectively (Table 1).
The addition of SDS did not signiﬁcantly aﬀect the pH of thedispersion medium with or without the presence of polymers.
Evaluation of the pH-Dependent Dissolution of Zirconia
Beads The dissolution of the zirconia beads themselves atvarious pH values was evaluated without other additives, andthe dissolution amounts of zirconium, yttrium, and aluminumfrom the beads at each pH are shown in Fig. 2. The largest
dissolution was observed for zirconium, which is the main
component of zirconia beads. The dissolution amounts of yttrium and aluminum were also conﬁrmed. Interestingly, thedissolved amount of all metallic elements was minimized in
the pH range of 6–8. Zirconium oxide, which accounts for
95% of zirconia beads, has been reported to have increased
solubility under acidic or alkaline conditions.39) Therefore,
zirconia beads were suggested to dissolve depending on pH
and at least partly contribute to metal contamination in thegrinding process. Moreover, this result strongly indicates that
corrosion due to the dissolution of zirconia beads could be

Fig. 2.

pH-Dependent Dissolution of Zirconia Beads

Fig. 3.

Eﬀect of pH on Grinding Eﬃciency of Phenytoin

Fig. 4.

Eﬀect of pH Optimization on the Metal Contamination in the Grinding Process

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Chem. Pharm. Bull.

suppressed by controlling the pH of the suspension.
Eﬀects of pH on Grinding Eﬃciency Next, we evaluated the eﬀect of pH on the particle size of phenytoin in thegrinding process (Fig. 3). A previous study found that therotation speed was the most important parameter aﬀecting
metal contamination due to bead collision among the various process parameters of bead milling.42) To minimize themetal contamination generated during the grinding process,the rotation speed of the accelerator of the Dyno-mill was
set to 4 m/s, which is the lowest value that can be set. The
pH of the phenytoin suspension was adjusted to 6.67, 7.36,
or 8.14 before pulverization of the phenytoin suspension, andthe resulting particle sizes of phenytoin were measured overtime. The results are summarized in Fig. 3. For comparison,
the same evaluation was conducted for unadjusted pH (pH3.88) and alkali pH (pH 10.37). The particle sizes of phenytoin
decreased over time, and the size after 90 min of pulverization
was approximately 0.23–0.26 µm at all pH values. Although
there was a slight diﬀerence in the particle size of phenytoin
after pulverization for 0–30 min, the particle sizes considered
to have reached equilibrium after 90 min of pulverization weresimilar among the various pH values tested.
Eﬀects of pH Optimization on Metal Contamination
during the Grinding Process Among the various metal elements involved, we focused on the materials of the zirconia
beads and the grinding chamber of the Dyno-mill as possible
sources of metal contamination and measured the amounts ofcontaminating zirconium, yttrium, and aluminum after thegrinding process (Fig. 4). As expected, the metal contamination in the suspension tended to increase depending on thegrinding time. The highest contamination was observed withzirconium followed by aluminum and then yttrium. It is worth
noting that when the pH was adjusted in the range of pH
6.0–8.0, where the dissolution amounts of metallic elements
were found to be minimized (Fig. 2), the metal contamination
generated during the grinding process was also signiﬁcantly
reduced. Whereas, at pH 3.88 and 10.37, which are out of theTable 2. Contamination Reduction by pH Optimization with or without
Physical Contact among Zirconia Beads
Rotation speed (m/s)

pH

4

3.88
7.36
3.88
7.36

0

Fig. 5.

Contamination (ppm)
Zr

Y

Al

Total

2.52
0.79
0.03
0.00

0.49
0.29
0.13
0.01

0.66
0.29
0.08
0.03

3.67
1.37
0.24
0.04

Vol. 69, No. 1 (2021)

optimized pH range, metal contamination was larger, particularly for zirconium. Therefore, pH optimization of the phenytoin suspension would be a simple but eﬀective approachto reducing the metal contamination generated during thegrinding process (Figs. 2, 4) without impairing the grinding
eﬃciency (Fig. 3).
Elucidation of the Mechanisms of the Contamination
Reduction by pH Optimization The possible sources ofmetal contamination can be roughly categorized into the following: (i) dissolution of metals from metallic elements or(ii) wear generated by the collision of beads due to physicalcontact among beads. Based on these considerations, we tried
to estimate the contamination reduction by pH optimization
with and without physical contact among the beads (Table 2).
By setting the rotation speed of the Dyno-mill to 0 m/s, there
is no physical contact among beads, allowing evaluation of
only the dissolution process of the beads. Whereas, by setting
the rotation speed of the Dyno-mill to 4 m/s, not only the dissolution of the beads but also the wear caused by the physicalcontact among the beads could be evaluated. The contamination reduction by pH optimization was only 0.2 (0.24–0.04)
ppm with respect to the total amount of metal contamination
without physical contact among the beads. Meanwhile, thecontamination reduction by pH optimization with physicalcontact among the beads was approximately 2.3 (3.67–1.37)
ppm, which was approximately 10-times larger than that without bead contact. These results suggest that pH optimization
not only suppressed the dissolution amount of the beads, butalso prevented the wear caused by bead collisions during thegrinding process.
Proposed Mechanisms of Reduced Metal Contamination
by pH Optimization The binding strength of zirconiumoxide has been reported to dramatically change when thecontent of yttrium oxide changes, and microcracks can occur
on the surface of the sintered body due to crystal transition
from tetragonal to monoclinic.43) In addition, pre-damaged
zirconia beads were found to generate an increased amount ofwear.44) These ﬁndings together with the results obtained in
the present study led us to propose the following mechanism
for reduced metal contamination by pH optimization (Fig. 5).
First, the metal components of the zirconia beads dissolvefrom the surface. This generates microcracks on the surface ofthe zirconia beads, making the surface unstable. Finally, wear
due to collision of the beads occurs from the unstable surfaceof the zirconia beads. We consider that pH optimization reduces the dissolution of metal components and helps maintainstable and smooth surfaces of zirconia beads, leading to a
reduced amount of wear from bead collisions.

Schematic of the Proposed Mechanism of Metal Contamination from Zirconia Beads during the Bead Milling Process(a) Dissolution of metal components of zirconia bead from the surface; (b) Microcracks generated on the surface, making the surface unstable; (c) Wear due to bead collision easily occurs as a result of the unstable surface of the zirconia bead.

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Vol. 69, No. 1 (2021)85

Conclusion

To reduce metal contamination in the bead milling process,we focused on the pH-dependent dissolution of zirconia beads
in addition to the wear generated by bead collision. Basedon our ﬁndings, pH optimization appears to be a simple but
eﬀective approach to reduce the metal contamination generated during the grinding process without impairing thegrinding eﬃciency. This approach should be applicable to thepulverization of other drugs using bead milling technology.
Although further studies are necessary, the results reported
herein should provide valuable information to further optimize
contamination-less bead milling technology.
Acknowledgments The authors thank Daisuke Hirata(Hiroshima Metal & Machinery Co., Ltd.) for his excellent
technical assistance throughout this study.
Conﬂict of Interest
interest.

References

The authors declare no conﬂict of

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