J Pharm Innov (2011) 6:97106

DOI 10.1007/s12247-011-9107-5

RESEARCH ARTICLE

Important Factors in the Size Reduction of Polymer-Stabilized

Drug Particle Suspensions Using High-Pressure Homogenization
Francis S. Romanski & Eric Jayjock &
Fernando J. Muzzio & Maria Silvina Tomassone

Published online: 3 June 2011

# Springer Science+Business Media, LLC 2011

Abstract In recent years, high-pressure homogenization has

been used with increasing frequency to reduce the size of
pharmaceutical suspensions to the micron, submicron, and
nano scales with the goal of increasing the dissolution rate of
the drug, and consequently, the in vivo bioavailability. As
particle suspensions become smaller in size, increased
concentrations of surfactants and stabilizers are required to
prevent particle agglomeration. Recently, relatively high
concentrations of biocompatible polymers have been used to
stabilize suspensions by imparting surface-active steric
stability as well as kinetic stability through an increase in
suspension viscosity and/or a transition to non-Newtonian
rheological properties. While the benefits of stable suspensions are known, little is known about the effect of the high
polymer concentration on the actual breakup of the particles in
suspension. In this work, designed experiments were used to
identify the key parameters that govern the final particle size
of a drug suspension following homogenization. In particular,
drug loading, operating pressure, and polymer concentration
were all found to be statistically significant factors in
determining the resulting size of particles in suspension. In
addition, it was found that an optimal polymer concentration
of 2% (w/w) was required to adequately stabilize the particle
suspension while simultaneously avoiding a decrease in
homogenizer performance. Concentrations higher than 2%
(w/w) resulted in size reduction limitations due to the
increased viscosity (>10 cP) and the transition to nonNewtonian behavior.

F. S. Romanski : E. Jayjock : F. J. Muzzio : M. S. Tomassone (*)

Rutgers Chemical and Biochemical Engineering,
98 Brett Rd.,
Piscataway, NJ 08854, USA
e-mail: silvina@soemail.rutgers.edu

Keywords High-pressure homogenization .

Drug suspensions . Agglomeration

Introduction
High-pressure homogenization is a common process used
in many food and pharmaceutical processes including
emulsification, sterilization, and particle size reduction. In
high-pressure homogenization, droplet, particle, and cell
breakdown is conducted through a combination of shear,
grinding, and cavitation. Recently, the process of highpressure homogenization has been used with growing
frequency to reduce the size of pharmaceutical suspensions,
in particular, poorly water-soluble drugs [1]. Micro- and
nanoscale suspensions of drug particles have been shown to
increase the solubility rate of poorly water-soluble drugs [2]
and, as a consequence, may increase the in vivo bioavailability, which has been attributed to an increased surface
area-to-volume ratio and a higher dissolution pressure [3].
However, an unfortunate side effect of decreasing particle
size is that particles on the micro and nano scales tend to
irreversibly agglomerate, caused by attractive van der
Waals forces between small particles which intensify
greatly as particles become smaller. Fortunately, many
amphiphillic compounds, commonly referred to as surfactants, can be used to interact with the surface of the small
particles to stabilize them through a combination of
electrostatic, steric, and kinetic interactions [4].
Imparting steric interactions into a suspension of smaller
particles can be accomplished by adding non-ionic surfactants that essentially coat the surface of the small
particles, preventing particle contact, and also requiring
the surfactant to be removed before the particles can either
grow, ripen, or agglomerate; this is referred to as steric

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stabilization. Alternatively, if the continuous phase viscosity of a particle suspension is increased, the particle motion
becomes severely limited, which further reduces particle
particle interactions; this is termed kinetic stability [5].
Therefore, surfactants that can effectively coat all available
surface areas to add steric stability, while simultaneously
increasing the viscosity of the continuous phase adding
kinetic stability, are able to significantly limit or even
eliminate irreversible agglomeration. Unfortunately, the
addition of large concentrations of non-ionic surfactants to
suspensions tends to be very problematic, particularly in the
area of food and pharmaceuticals where cytotoxicity is a
primary concern. In addition, extremely high concentrations
of non-ionic surfactants are required to significantly affect
the continuous phase viscosity.
In recent years, research has begun to investigate the use
of biocompatible polymers to stabilize suspensions with
respect to agglomeration [1, 68]. Biocompatible polymers
have the distinct advantage of having a significantly lower
cytotoxicity; therefore, they can be used in much higher
concentrations than traditional anionic and non-ionic
surfactants. In addition, gel-forming biocompatible polymers such as hydroxypropyl methylcellulose (HPMC),
hydroxypropyl cellulose, gelatin, pullulan, and sodium
alginate can be used to sterically stabilize the suspensions.
These polymers also have a propensity to gel, which
increases the viscosity significantly and imparts kinetic
stability at proportionally lower concentrations than traditional non-ionic surfactants [9].
While the potential applications for biocompatible
polymers are numerous, the increased viscosity and
complex fluid rheology often associated with increased
concentrations can hinder the size reduction of pharmaceutical suspensions, limiting the utility of many size reduction
techniques. This has led formulators to first create an
appropriately sized suspension through milling or other
techniques (often containing high concentrations of traditional stabilizers), then subsequently increasing the viscosity of the suspension by the further addition of the
biocompatible polymer, which may result in poor stabilization, inadequate homogeneity, and the use of unnecessary
surfactants.
High-pressure homogenization presents a promising
alternative as it is well suited to deal with complex fluids.
Specifically, the piston gap high-pressure homogenizer
processes the fluid by segregating a small volume of fluid
and forcing it through a minute piston gap with a positive
displacement pump, thus allowing for high-viscosity and
non-Newtonian fluids to be processed easily and effectively.
Furthermore, high-pressure homogenizers can be scaled up
easily and without loss in performance, making them highly
advantageous from a manufacturing viewpoint [10]. The use
of high-pressure homogenization in conjunction with a

J Pharm Innov (2011) 6:97106

biocompatible polymer-based drug suspension should result

in a sterically and kinetically stable suspension that is easy
to process. Currently, biodegradable polymers are listed as
viable excipients for the production of stable nanosuspensions while using a Microfluidizer high-pressure homogenizer, including several currently manufactured and
patented formulations [11]. However, while the benefits of
using biocompatible polymers as excipients to stabilize
nanosuspension are known, little is known in the scientific
literature about how the high concentration of polymer
affects the actual breakup of the particle suspension during
homogenization. Specifically, it is not known within the
current literature whether the excess viscosity and/or complex
rheology of the polymer rich suspensions will enhance or limit
the particle breakup during homogenization.
Thus, the goal of this work was to identify the key
parameters that govern the breakup and final particle size
distributions of a polymer-rich drug suspension using highpressure homogenization. The significance of the polymer
concentration, operating pressure of the homogenizer, and
the concentration of particulate solids was explored using
designed experiments. HPMC was selected as the biocompatible polymer, known as a generally regarded as safe
film-forming polymer offered in a wide variety of pharmaceutical products. Griseofulvin, a common poorly watersoluble antifungal agent, was chosen to be the model solid
phase due to its lack of crystalline polymorphism and
resistance to mechanical grinding. The remainder of this
article is organized as follows: Materials and Methods
describes the materials and methods used in this study.
Results and Discussion discusses the effect of the
operating pressure, solid concentrations, and the biocompatible stabilizer concentration on the achievable minimum
particle size. Conclusions describes the key conclusions
of this work.

Materials and Methods

Materials
F50 Methocel brand HPMC was obtained from Dow
Chemical Co. (USA). Acetone, technical grade, purchased
from Fisher Scientific (USA), was used as received to
solubilize griseofulvin and clean the homogenizer apparatus. The griseofulvin used in this study was donated by
Johnson and Johnson Inc. (North Brunswick, NJ); it was
re-crystallized using the following anti-solvent crystallization technique: 2 L of acetone was pre-loaded with 30 mg/mL
griseofulvin using magnetic stirring and slight heating.
The resulting solution was slowly introduced to an equal
portion of deionized water at a rate of 100 mL/min. The
resulting crystal slurry was then vacuum-filtered using a

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99

Bchner funnel equipped with a Whatman 42 filter paper

(Fisher Scientific). All re-crystallized griseofulvin was
pooled, mixed, and stored in a single container. Figure 1
displays the particle size distribution for the griseofulvin
particles after re-crystallization (prior to homogenization).
Two optical microscope images representative of the
griseofulvin crystal size and habit after re-crystallization
are shown in Fig. 2.
Suspension Production
An Avestin Emulsiflex C-3 piston gap high-pressure
homogenization apparatus (Avestin Inc., Ottawa, Canada)
was used in these experiments; a schematic of the piston
gap high-pressure homogenizer is shown in Fig. 3. For all
experiments, the homogenizing valve was submerged in
50:50 ethylene glycol solution held at a constant 32C to
minimize heat generation. Two different approaches were
used for the particle size reduction phase: large-volume
processing and small volume processing (each explained in
detail below). The large-volume processing technique was
used to process suspensions on the order of 1 L in total
volume, which allowed sampling the suspension multiple
times during the size reduction process, and additionally,
retention of enough material at the conclusion of the
experiment ensures adequate shelf life. Alternatively, the
small-volume processing technique was developed for this
work to reduce processing times by cycling small amounts
of suspension continuously. The large-volume technique
was used in the design of experiments, while the smallvolume technique was used to isolate the effect of polymer
concentration with all other process variables held constant.
The effects of solid loading, polymer concentration, and
operating pressure on the final mean particle size after 20
full homogenization cycles were quantified using a 3 3

Fig. 1 Particle size distribution of griseofulvin following re-crystallization

in acetone; distribution was obtained using laser diffraction

Fig. 2 Images of griseofulvin crystals produced by re-crystallization in

acetone using optical microscopy at 40 and 100, respectively, displaying
the relative size and habit of the crystals prior to homogenization

Latin squares design with two repetitions; the experimental

design is shown in Table 1. Re-crystallized griseofulvin (1,
4, and 7 wt.%) and HPMC (1, 3, and 5 wt.%) were both
weighed and added to a glass beaker. Near boiling (95C)
deionized water was added by mass to bring the entire

Fig. 3 Diagram of particle breakup inside a piston gap high-pressure

homogenizer

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Table 1 Latin squares design of
experiments for operating pressure, solid loadings, and polymer concentration in a highpressure homogenizer

J Pharm Innov (2011) 6:97106

HPMC (wt.%)

1% wt. Drug (psi)

4% wt. Drug (psi)

7% wt. Drug (psi)

16,000
28,000
22,000

22,000
16,000
28,000

28,000
22,000
16,000

1
3
5

solution mass to 750 g. The resulting slurry was then

immediately mixed using a magnetic stir bar and cooled to
40C, forming a homogeneous HPMC gel. The resulting
suspensions were transferred to a Chemglass doublewalled sealed vessel prior to operation. The jacketed mixing
vessels were each agitated using a Chemglass Ruston
impeller and a bottom scraper (CG-2091-07 and CG-2081A-04, respectively) at a constant 180 rpm. Two pre-cycles
were conducted at 7,250 psi to minimize any jamming.
After two such pre-milling cycles, the dispersion was
exposed to high-pressure homogenization at 16,000,
22,000, or 28,000 psi using either a large- or smallvolume production technique. Particle size distributions
were analyzed prior to homogenization and incrementally
every five cycles during operation.
The homogenizer pressure range used was based on
literature data and on the operating envelope of the machine
[2, 1214]. The drug weight was based on reasonable upper
and lower contents for a possible product formulation. It
was determined experimentally that HPMC concentrations
above 5% were too viscous to be transported into the
machine by the suction of the positive displacement pump
alone (specific to the Methocel F50 brand of HPMC);
therefore, 5 wt.% was used as the upper limit.
Large-Volume Suspension Production
Large-volume suspensions were homogenized in series.
The setup incorporated the alternation of the suspension
between two 1-L jacketed agitated vessels (Chemglass
CG-1929-14) during each homogenization cycle; a
schematic is shown in Fig. 4. Each cycle involved
feeding from a suspension-filled jacketed vessel (referred
to in Fig. 4 as tank A) into an initially empty jacketed

Fig. 4 Schematic of the high-pressure homogenization large-volume

experimental method

vessel (tank B). When the tank was close to empty, the
cleaning solution of deionized water and acetone was
added to the tank and the outlet of the homogenizer was
redirected to a waste container; care was taken to ensure
that the concentration of the suspension was retained
throughout the experiments. After cleaning, the process
was repeated using tank B as the feed tank and tank A as
the receiving tank. The first 20 mL of the restarted
suspension was also discarded to establish pressure and
minimize any water dilution. It should also be noted that
the cleaning and discarding of material in this case was
done for analytical purposes and would not be necessary
from a processing standpoint.
Small-Volume Suspension Production Technique
The small-volume process developed for this work involved a
short-circuiting of the flow to cut the product reservoir out
of the loop. By minimizing the volume of the system, a small
sample could be cycled through the homogenizer several
times per minute, as opposed to several times per hour in the
large-volume experiments. Since the homogenizer is a
positive displacement pump and the fluid is incompressible,
it was necessary to allow the volume of the flow system to
vary with the changing volume of the pump displacement. In
order to accomplish this task while minimizing mixing, a 10cm-long piece of 0.25-in. ID Latex tubing was used to connect
the exit of the HPH to the entrance, as shown in Fig. 5. The
suspension was continuously fed into the homogenizer from
the same reactor setup used in the large-volume cycles until
the desired pressure was reached. The closed system was
then implemented by closing the four-port and the two-way
inlet and outlet valves shown in Fig. 5. The total volume of

Fig. 5 Schematic of the high-pressure homogenization small-volume

experimental method

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101

the system was divided by the measured flow rate at a

desired operating pressure. The total volume of the system
was found by collecting the fluid exiting the system after the
inlet was closed off. The processing time was tuned
according to the measured flow rate and capacity to simulate
the desired number of cycles at the operating pressure and
corresponding flow rate. After processing, the valves were
reopened and 5 mL of suspension was discarded prior to
sampling.

Rheology

Analysis

Results and Discussion

Light Scattering Size Analysis

A 3 3 Latin squares experimental design with two

repetitions was used to determine the effect of solids
concentration, polymer concentration, and operating pressure on the achievable particle size reduction at a 95%
confidence level. The design of experiments is shown in
Table 1. The Latin squares design of experiments was
conducted using the aforementioned large-volume homogenization method described in Materials and Methods;
large-volume experiments were designed to mimic the
effects that would be seen at the industrial scale. The
resulting mean, median, D10, D90, and polydispersity index
(PI) are shown in Table 2. All data were determined using
laser diffraction; each reported mean is the average of two
experiments, and the error is reported as the standard
deviation of the mean. The polydispersity index was
defined as the difference between the D90 and D10, divided
by the median, where higher values indicate more polydispersity. An analysis of variance (ANOVA) was performed
on the mean values from the resulting suspensions from the
Latin squares design of experiments. The ANOVA was
specifically designed to identify the statistically significant
factors affecting particle breakdown at the 95% confidence
level; the results are shown in Table 3. Interactions were not
analyzed due to the limitations of the Latin squares
methodology. The individual and collective impact of each
variable are further discussed below.

All particle suspensions were analyzed using a BeckmanCoulter LS-13 320 laser diffraction apparatus. Samples
were run for combined obscuration and polarization
intensity differential scattering analysis. A refractive index
of 1.672 was used for griseofulvin [15]. The unit was
thoroughly rinsed between samples; acetone or isopropyl
alcohol was used if cleaning was required. Samples were
held in glass vials.
Microscopy
Optical microscope images were taken using a confocal
laser scanning microscope from Carl Zeiss, Inc. (model
Zeiss Axiovert 100). Scanning electron microscope (SEM)
images were taken using a Gemini Leo-1530-VP SEM.
Samples were prepared using aluminum sample stubs
coated with a circular carbon tape; a 57-mm silicon wafer
was placed in the center of the tape. Next, vials of
suspension were centrifuged for 30 min at 20,000 rpm.
The particles were harvested using a laboratory spoon and
spread throughout the top of the silicon waver with care to
remove any excess liquid. Samples were vacuumdesiccated and sputter-coated with carbon using a BalTech MED-020 coating system prior to imaging.

Rheology data were obtained using a stress-controlled

Malvern Gemini rheometer. The samples were loaded in a
40-mm parallel acrylic plate geometry with acrylic outer shell
to reduce any water loss. The bottom plate temperature was
kept constant at 40C to closely mimic experimental
conditions; the gap between the plates was set to 100 m.

Table 2 Resulting mean, median, D10, D90, and polydispersity index for each of the suspensions created in the Latin squares design of
experiments
Exp. ID
1
2
3
4
5
6
7
8
9

% Drug

% HPMC

Pressure (psi)

Mean size (m)

Median size (m)

D10 (m)

D90 (m)

PI (m)

1
4
7
1
4
7
1
4
7

1
1
1
3
3
3
5
5
5

16,000
28,000
22,000
22,000
16,000
28,000
28,000
22,000
16,000

4.410.71
3.300.28
4.650.04
4.200.47
4.540.51
3.490.36
4.680.80
4.840.53
7.150.68

4.090.63
2.900.32
4.390.01
3.810.51
4.030.58
3.070.41
4.270.73
4.360.38
6.410.48

1.390.07
1.230.02
1.880.03
1.320.04
1.340.04
1.230.01
1.330.09
1.300.01
1.540.02

7.951.48
6.030.49
7.810.01
7.690.81
8.580.87
6.470.68
8.711.58
9.191.32
13.81.50

1.60
1.66
1.35
1.67
1.80
1.71
1.73
1.80
1.91

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Table 3 ANOVA table analysis for operating pressure, solid concentrations, and polymer concentration resulting from the Latin squares
design of experiments
Source

df

SS

MS

Solids concentration
HPMC concentration
Operating pressure
Repetitions
Error
Total

2
2
2
1
10
17

2.478
8.488
7.135
0.744
3.057
21.901

1.239
4.244
3.567
0.744
0.306

4.052
13.881
11.668
2.432

p value
0.051
0.001
0.002
0.150

Operating Pressure
The operating pressure of the high-pressure homogenizer is
defined as the dynamic pressure measured within the piston
gap of the apparatus, and it is generally regarded as an
important factor affecting the breakup of particles, cells, or
emulsion droplets [2, 12]. Not surprisingly, the operating
pressure was a significant factor in the breakup of the
griseofulvin suspension at a 95% confidence level (p=
0.002). This result indicates that a homogenizer operating at
a higher dynamic pressure would be more effective in
reducing particle size, both in the rate of breakup and in the
final mean particle size. It should be noted that the
relationship between the operating pressure and the resulting particle size distribution has been shown to be effective
only up to 28,000 psi and, additionally, that dynamic
pressures as high as 58,000 psi have been shown to have no
significant effect on particle size reduction in comparison to
28,000 psi [1]. Thus, this study was limited to only
28,000 psi. Furthermore, this study was limited to 20
high-pressure cycles as it has been shown that very little
breakup occurs after 20 cycles [1, 14]. Evidence of this is
shown in Fig. 6 for a 1% (w/w) griseofulvin suspension
with a 1% (w/w) polymer (HPMC) concentration that was
processed at 28,000 bar. In Fig. 6, it is clear that neither the
mean particle size nor the median particle size changes
significantly after 510 cycles. Therefore, after 20 cycles, it
can be assumed that very little particle breakup will be
observed. It should be noted that the smallest griseofulvin
suspension size in the design of experiments was observed
at the 28,000-psi pressure (4% solids, 1% polymer,
28,000 psi), with a mean particle size of 3.30 m and a
median of 2.90 m, further illustrating the impact of the
operating pressure.
Solid Loadings
While the effect of operating pressure on the homogenization of particles has been well studied, the effect of solid

Fig. 6 Effect of the number of cycles on the mean and median

griseofulvin particle diameter over 20 high-pressure cycles

concentrations has not been established. The Latin squares

design of experiments contained three values for solid
concentrations, 1%, 4% and 7%, all of which could be
physically processed by the piston gap homogenizer. The
results of the Latin squares design (shown in Table 3)
indicate, somewhat counterintuitively, that the concentration of drug was statistically significant near the 95%
confidence level (p=0.051), showing that the concentration
of particles in the suspension has a negative effect on the
particle breakup. While current understanding suggests that
high-pressure homogenization is governed largely by shear
and cavitation forces [16], and not as much by particle
particle grinding, it was nonetheless hypothesized that
elevated concentrations of particles would increase the
particle breakup due to milling and grinding between
particles. As a result, these data support the hypothesis that
the total quantity of energy used for particle breakup in the
form of shear, cavitation, and particle grinding is significantly less effective when distributed over a larger
population of particles, ultimately resulting in a net
decrease in the ability to reduce particle size in cases when
a viscosity-modifying polymer is present. It should also be
noted that these concentrations would translate well into an
adequate drug concentration in a polymer-based drug
delivery system where it has been shown that 530% (w/w)
active pharmaceutical ingredients (API, post-drying) can
be incorporated into a polymer-based oral strip film or
coating containing 220% (w/w) HPMC. Current marketed products include films and coatings containing
cough suppressants, vitamins, and nicotine; however, the
market is expected to continue to incorporate additional
drugs ranging from local anesthetics to poorly watersoluble drugs at dosages containing several milligrams of
API per square centimeter of film [1719].

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Polymer Concentration
The third factor that was analyzed using the Latin squares
design of experiments was the polymer concentration.
Three distinct polymer concentrations were used1%,
3%, and 5%of Methocel F50 HPMC. The results of
the Latin squares design (Table 3) indicate that the polymer
concentration was a significant factor in particle breakup at
the 95% confidence level (p=0.001). Therefore, it can be
concluded that suspensions containing a high concentration
of polymer will significantly alter the effect of particle
breakup in a high-pressure homogenizer. It is important to
note that high polymer concentration not only increases the
steric interactions with the small drug particles but also that
the particles are additionally stabilized by the kinetic
stability due to the restricted movement in high-viscosity
and non-Newtonian fluids. Therefore, a virtual trade-off
is evident where the ability to break down the particle
suspension is limited by the ability to stabilize the
suspension.
The importance of the polymer concentration, as well as
solid loadings and operating pressure, is better visualized
using surface plots. Figure 7 displays three separate surface
plots comparing the polymer concentration, solid concentrations, and operating pressure in alternating configurations. In Fig. 7a, drug concentration and polymer
concentration are displayed, where it is clear that there is
a significant reduction in homogenizer performance at
higher levels of both polymer and drug concentrations,
corresponding to a higher resulting particle size. In Fig. 7b,
a comparison of operating pressure with solid concentrations illustrates that lower operating pressures combined
with a high drug concentration also decreases the particle
size reduction capability in the homogenizer and, consequently, also results in significantly larger particles. Finally,
in Fig. 7c, it is quite clear by visualizing the effect of
polymer concentration and operating pressure that the most
optimal configuration for size reduction lies in lower
polymer concentrations and higher operating pressures at
all three solid loadings. In combination, all three surface
plots illustrate the intricate interplay between the three
parameters, and when used in conjunction with statistical
analysis, this demonstrates a viable parameter space for
selecting operating conditions based on minimizing losses
in homogenizer performance.
The presence of agglomerates was evaluated by microscopy. The visual appearance of agglomerates would
indicate that the larger particles observed were actually
agglomerates, not primary particles. Both optical and
scanning electron microscope images of the resulting
HPMC-stabilized griseofulvin suspension are shown in
Fig. 8. Clearly, there are no agglomerates present in the

Fig. 7 Surface plots for mean particle diameter as a function of

polymer concentration versus drug concentration (a), operating
pressure versus drug concentration (b), and polymer concentration
versus operating pressure (c)

system; the resulting particle size distributions represent the

primary particle size. Furthermore, it should be noted that
several of the high polymer concentration suspensions were

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Fig. 9 Griseofulvin suspension mean particle size as a function of

polymer concentration at 22,000- and 28,000-psi operating pressures
and a 1% (w/w) solid concentration

Fig. 8 Optical and scanning electron microscope images of griseofulvin suspensions following high-pressure homogenization

subjected to sonication during particle size analysis to break

any potential agglomerates; however, no change in particle
size distribution was evident. Therefore, it can be concluded
that HPMC adequately dispersed and kinetically stabilized the
primary particles in suspension.
To further explore how the polymer concentration affects
the final achievable particle size in the HPH process,
smaller volume experiments were performed (described in
Materials and Methods) and used to isolate the effect of
the polymer concentration at a single solid concentration of
1% and at two different operating pressures of 22,000 and
28,000 psi. The results of this study are shown in Fig. 9,
where each data point is an average of three experiments
and the error represents one standard deviation of the mean.
These results suggest that there exists a notable minimum
particle size obtained at approximately 2% HPMC by
weight. Therefore, in this case, it was concluded that for an
HPMC (Methocel F50) concentration of 2% (w/w), there
exists enough stabilizer to prevent agglomeration while not
significantly affecting the fluid rheology enough to reduce
homogenizer performance, as shown at higher concentra-

tions (note the large increase in size at the 28,000-psi

operating pressure).
To quantify the effect of HPMC on the continuous phase
rheology, constitutive behavior at various concentrations
was analyzed using a rheometer. Interestingly, as shown in
Fig. 10, when solutions of HPMC were exposed to a
constant strain rheology sweep, the solution began to take
on non-Newtonian characteristics above 2% polymer
concentrations. This has also been found by Chen and
Huang in 2008 where HPMC solutions were described to
have Bingham pseudoplastic behavior at high concentrations [20, 21]. The onset of these non-Newtonian characteristics is indicative of the point where the concentration of
the polymer is great enough that polymerpolymer interactions become significant. These data also suggest that the
presence of excess polymer in solution will disrupt the

Fig. 10 Rheological properties of HPMC solution as a function of

concentration

J Pharm Innov (2011) 6:97106

mechanism of breakdown within the fluid, as suggested by

the design of experiments.
In summary, while there exist many different types of
gel-forming biocompatible polymers for suspension stabilization, this study concludes that in order not to affect
particle breakup, polymers should only be used in sufficient
concentrations to stabilize the particles. Any additional
change in rheological properties, through either excessive
viscosity or non-Newtonian behavior, will significantly
impact the particle size reduction and, thus, the overall
homogenizer performance. This result was also found for
alternate top-down particle size reduction techniques.
Specifically, the same trend has been exhibited in recent
literature [22, 23] where it was found that there was also an
optimal value for the use of non-ionic polymer stabilizers
during media milling. It was found that once the milled
particles were adequately coated with stabilizer, the rate of
particle breakage was optimized. The further addition of
stabilizer significantly increased the suspension viscosity
and resulted in an overall negative effect on particle size
reduction. In addition, larger particles found at lower
concentrations of polymer stabilizer were also attributed
to the irreversible formation of agglomerates due to the
presence of van der Waals forces.
This work represents an alternative top-down methodology containing high levels of biocompatible polymers for
the production of micron, submicron, and nanoscale
particles that has been shown to contrast with media
milling by offering an increased production rate, wellestablished scalability, and the elimination of possible
contamination while sacrificing the ability to mill significantly
higher levels of solid concentrations [24]. As a result, it is the
authors belief that high-pressure homogenization is an
excellent technique for the particle size reduction of poorly
water-soluble APIs while simultaneously and successfully
incorporating the gel-forming excipients to not only help
with the particle size reduction and subsequent stabilization
of particles but also to be usefully incorporated into the final
film, capsule, or coating formulation.

Conclusions
In this work, drug suspensions containing relatively high
concentrations of biocompatible polymers were reduced in
size using a piston gap high-pressure homogenizer. A
statistical design of experiments was used to determine the
most influential factors governing the resulting particle size.
It was found that the operating pressure, drug concentration, and polymer concentration were all statistically
significant at a 95% confidence level on the final size of
the drug suspension. It was subsequently found that while
biocompatible polymers are not limited by their cytotox-

105

icity in the resulting product, they will ultimately be limited

by the impact of their rheological properties on particle
breakup. Specifically, it was found that for F50 Methocel
brand HPMC, a concentration of 2% (w/w) could be used to
adequately stabilize the suspension while not significantly
affecting breakup; however, above 2%, the elevated
viscosity (>10 cP) and non-Newtonian behavior resulted
in a decreased homogenizer performance and larger mean
particle size of the suspension. As a consequence, high
concentrations of polymers may be used to adequately
stabilize drug suspensions so long as the polymerpolymer
interactions do not considerably increase the viscosity and/
or allow for non-Newtonian behavior. As a result of this
work, it is clear that there exists a viable parameter space
for the combination of high-pressure homogenization with
high polymer concentrations to produce stabilized drug
suspensions, which may in turn be used to create many
novel drug delivery products including polymer-based
films, coatings, and capsules.

Acknowledgments The authors would like to acknowledge the

work of our undergraduate researchers throughout this project,
including: Daniel Fritz, Fred Acheampong, and Roger Saez. In
addition, the authors would like to acknowledge the support of the
NSF ERC-SOPS center for funding, grant EEC-0540855 (PI F.J.
Muzzio).

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