Mixer torque rheometry (MTR) was evaluated for its ability to predict optimal liquid-to-solid ratios (L/S) for producing pharmaceutical pellets via extrusion-spheronization. Various active pharmaceutical ingredients (APIs) were formulated at low and high loadings and tested using MTR to determine the L/S that produced maximum torque during wet mixing (L/SmaxT). Pellets were then extruded-spheronized at L/SmaxT and other L/S ratios and evaluated. L/SmaxT was generally 0.8 for low solubility APIs and decreased to 0.6 for more soluble APIs. Pellets produced at L/S

1. Predicting optimal wet granulation parameters for
extrusion-spheronisation of pharmaceutical pellets using a mixer
torque rheometer
Manuel Kuhs, John Moore, Gayathri Kollamaram, Gavin Walker, Denise Croker*
Bernal Institute, University of Limerick, Ireland
A R T I C L E I N F O
Article history:
Received 27 July 2016
Received in revised form 25 November 2016
Accepted 26 November 2016
Available online 30 November 2016
Keywords:
Pre-formulation
Mixer torque rheometry
Extrusionspheronisation
Wet granulation
Liquid-solid ratio
A B S T R A C T
Mixer torque rheometry (MTR) was evaluated as a pre-production (pre-formulation and optimization)
tool for predicting ideal liquid-to-solid ratios (L/S) for extrusion-spheronisation of a wide range of APIs
using 10 g formulations. APIs of low, medium and high solubility were formulated at low and high
loadings (15 and 40% w/w, respectively) with PVP as binder (5%) and MCC as the major excipient. L/S
corresponding to the maximum torque produced during wet massing in the MTR, L/S(maxT), was 0.8 for
the low solubility APIs, which decreased to 0.6 for some of the more soluble APIs, especially at high
loadings. Formulations extruded-spheronised at L/SmaxT) produced pellets of acceptable size (between
900 and 1400 um) for all formulations, but mostly of unacceptable shape (dumb-bells of aspect ratio 1.2).
Increasing L/S by 25% successfully produced spherical or near-spherical (aspect ratio 1.1) pellets for all
formulations except one of the highly soluble APIs (piracetam) at high loading. Overall, MTR was
demonstrated to be a useful pre-formulation and optimization tool in extrusion-spheronisation.
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
Extrusion-spheronisation is one of the most popular techniques
for producing pharmaceutical pellets. In this process, the
formulation is first agglomerated by mixing with a liquid (usually
water), following which the wet mass is extruded and then
spheronised. This first step, wet granulation, is critical in
influencing many of the characteristics of the final pellets such
as sphericity, porosity, dissolution and disintegration. A mixer-
torque rheometer (MTR), first investigated by Rowe and col-
leagues, (Rowe and Sadeghnejad,1987) can be used to characterise
the rheological properties of the wet mass, and is gaining
popularity (Sakr et al., 2012; Zhang and Lamberto, 2014) in
determining the “end point” of wet granulation, defined as the
maximum torque required to mix the mass. The torque describes
the mass resistance to mixing, and the maximum is assumed to
correspond to the strongest particle–particle binding (capillary
state). The influence of mixing parameters on the measured torque
has been studied in detail by Rowe et al. (Hancock et al.,1991) MTR
and its application was reviewed several years ago (Sakr et al.,
2012).
In terms of applications, several companies have begun using
MTR to reduce pre-formulation work for agitated filter dryers by
successfully predicting the maximum wet massing possible
without causing agglomeration in the subsequent drying step
(am Ende et al., 2013; Birch and Marziano, 2013; Zhang and
Lamberto, 2014). The ability of MTR to predict ideal wet
granulation conditions for achieving optimum quality of pellets
produced by extrusion-spheronisation of the wet mass has
received probably the most attention. Several studies examined
the impact of different grades of microcrystalline cellulose (MCC)
on the final extruded-spheronised pellets (Alvarez et al., 2002; Soh
et al., 2006). In the latest of these studies, the authors found the
torque values measured during wet massing of eleven grades of
MCC strongly correlated with final pellet properties such as
friability, flow and density, concluding that MTR can be used to
reduce preformulation work related to changes in MCC grades (Soh
et al., 2006). Alternatively, a texture analyser has recently been
demonstrated to predict pellet qualities of a range of 120
pharmaceutical formulations from the wet mass characteristics
* Corresponding author.
E-mail address: denise.croker@ul.ie (D. Croker).
http://dx.doi.org/10.1016/j.ijpharm.2016.11.057
0378-5173/© 2016 Elsevier B.V. All rights reserved.
International Journal of Pharmaceutics 517 (2017) 19–24
Contents lists available at ScienceDirect
International Journal of Pharmaceutics
journal homepage: www.elsevier.com/locate/ijpharm

2. (Gao et al., 2013). The only studies involving APIs relating MTR to
extrusion-spheronisation performance have been focussed on
demonstrating correlation of MTR values with dissolution rates of
sustained release pellets (Ibrahim, 2013; Mahrous et al., 2010).
There is to date no published study investigating the ability of MTR
to predict the effect of different APIs at different liquid-to-solid (L/
S) ratios on the subsequent extrusion-spheronisation performance.
We examine here the ability of MTR to predict ideal wet
granulation parameters for producing optimum pellets of a wide
range of active pharmaceutical ingredients (APIs). Each API was
formulated at a low and high loading (15 and 40%), respectively,
with polyvinylpyrrolidone (PVP, 5%, a popular binder) and MCC (80
and 55%, respectively; one of the most common excipients in
extrusion-spheronisation). For each formulation, MTR was used to
measure the relationship between torque and L/S. Pellets were
extruded-spheronised corresponding to the maximum torque
conditions, as well as several other conditions for comparison. The
sphericity and particle size distribution of the resultant pellets
were measured, and correlated to the rheological behaviour of the
wet mass as measured by MTR.
2. Materials and methods
2.1. Formulations
2.1.1. Mixer torque rheometer
Using a Mixer Torque Rheometer (Mixer Torque Rheometer 3,
Caleva, UK), the relationship between torque of wet massing and
liquid-solid ratio (L/S) was measured for each formulation using a
multiple addition method at 50 rpm. For each of the following
periods the torque was measured for 20s, and the mean line torque
relative to the first measurement reported for that period: in the
first period, the torque of the empty bowl was measured and set as
the baseline (i.e. 0 torque); in the second period,10 g of formulation
were added and mixed for 40s, following which the torque was
measured for the dry powder in the third. Then water was added by
a computer-controlled syringe pump in 2 mL (i.e. L/S of 0.2) steps
(except for the blank, which had 4 mL steps), mixing for 40 s after
each addition before measuring the torque and then adding the
next 2 mL. This was repeated until at least 12 mL were added.
The L/S corresponding to the maximum torque measured, was
subsequently wet massed in the MTR using a variable mix time
method at 50 rpm, with the torque for each section again
calculated as the mean torque measured over 20s. First, the
torque baseline was measured with an empty mixing bowl,
followed by addition of 10 g formulation which was mixed for 50 s
before measuring the torque. Then the total amount (as deter-
mined by L/S) of liquid binder was added in a single 20 s step and
the torque measured again. This was followed by three more
mixing sessions of 20s, for each of which the torque was again
measured. Thus the total mixing time is 5 1
/2 min. In comparison,
the torque values measured for L/S of 0.8 (the most common L/S(max
T)) in the multiple addition method is for 5 min of mixing, which is
almost equivalent.
As most formulations did not yield spherical pellets at L/S(maxT),
these formulations were wet granulated again, usually at 1.2 Â L/
S(maxT), using the same method as described in the previous
paragraph.
2.1.2. Extrusion-spheronisation
The wet mass was then extruded in a Mini Single Screw
Extruder (Caleva, UK) running at 100 rpm with a circular die
diameter 0.8 mm and depth 4 mm (prior to extrusion large clumps
were broken up using a mortar and pestle to prevent clogging of
the extruder feed port). The entire batch of extrudate was then
spheronised in a Mini Bowl Spheroniser (Caleva, UK) of diameter
12 cm and height 6.5 cm for 15 min at 2000 rpm and the resultant
pellets left to dry overnight at ambient conditions prior to analysis.
2.1.3. Characterisation
A particle image analyser (Eyecon, Innopharma Labs, Ireland,
software v. 0.6.3) was used to measure the sphericity and size
distribution of the pellets. Its mechanism of operation is outlined
elsewhere (Silva et al., 2013); in short, it fits an ellipse to the
measured outline of each detected particle and records the
maximum and minimum diameter of each fitted ellipse, the ratio
of which is taken as the aspect ratio. The averages of the 3
parameters are then calculated for each sample, along with the
coefficient of variation (CV) of the aspect ratio. Compared to other
particle sizing methods, the Eyecon generally gives comparable
results in its nominal range of 50–3000 um, though it tends to
overestimate the presence of over-sized particles especially when
care to separate particles during analysis is not taken (Hagrasy
et al., 2013; Kumar et al., 2015; McAuliffe et al., 2014; Silva et al.,
2013).
In our case, the Eyecon was used in batch mode, in which a
subsample of pellets is analysed by the Eyecon. As the Eyecon
analyses only a small portion of the sample presented to it at a
time, the position of the sample relative to the Eyecon is varied to
capture most of the subsample. Depending on the pellet size,
around 20–50 pellets are visible to the Eyecon in a single snapshot.
For every subsample, 15–20 snapshots were measured by the
Eyecon to give an average, representative result. Care was taken to
ensure that pellets formed a monolayer.
3. Results & discussion
3.1. Torque measurements
The general trend of the torque profiles for L/S produced by MTR
(see example in Fig. 1) always followed the expected pattern
corresponding to the different wetting phases. With increasing L/S,
an initial increase in torque is observed (usually interpreted as
corresponding to pendular and funicular wetting phases) reaching
a maximum (capillary phase), followed by a relatively steep decline
(droplet phase) (Sakr et al., 2012). The peak represents the L/S with
the strongest resistance to mixing (L/S(maxT)) as evidenced by the
highest measured torque value. This is usually considered to be a
Fig. 1. Rheological profile of wet massing of theophylline 15% formulation as
measured by MTR, repeated three times. There are two points at L/S = 0; the first is
the torque measured before powder addition, i.e. for the empty mixing bowl, which
is taken as the baseline; the second is after powder addition but before liquid
addition. The somewhat low reproducibility is discussed below. Points are actual
data; curves are guides for the eyes only.
20 M. Kuhs et al. / International Journal of Pharmaceutics 517 (2017) 19–24

3. good approximation for the optimal L/S for wet granulation, which
is the hypothesis tested here.
As expected, the blank formulation, which contains more MCC
than any other tested formulation, required the greatest amount of
liquid to reach maximum torque (L/S(maxT) = 1.2, see Table 3).
L/S(maxT) for low solubility APIs was 0.8 at both low and high
loadings, while the more soluble APIs tended towards 0.6 at high
loading, with only the most soluble API, ranitidine hydrochloride,
having 0.6 at both high and low loading. L/S(maxT) of 0.6 occuring
only for the more water-soluble APIs, i.e. theophylline, piracetam
and ranitidine hydrochloride, is likely due to the API partially
dissolving in the water and thus reducing the amount of solids
needing to be granulated. It thus appears that for wet massing with
MCC as the main excipient and 5% PVP as binder, the solubility of
the API may be sufficient to explain the variation in the end point of
granulation as defined by L/S(maxT). Though it would be desirable to
measure the relationship between L/S and torque at an L/S
resolution greater than 0.2, it is doubtful whether this would be
feasible, as the large standard deviations between repeat experi-
ments discussed later would likely mask any differences.
The reproducibility of L/S(maxT) measured by the MTR is
somewhat low, with an average coefficient of variation (CV, as
median/standard deviation) of 14%, which is somewhat higher
than the <10% reported elsewhere (Soh et al., 2006). It is well-
known that wet granulation can exhibit significant reproducibility
issues, which is often linked to irreproducibility in the liquid
addition step (Bardin et al., 2004). The first step in wet granulation
is nucleation, where the liquid impacts and penetrates the powder
bed, and subsequently forms the first granule or “nucleus”. This
first step is determinative of any subsequent steps, and variation
therein will drastically influence all subsequent steps and the final
outcome. In our MTR setup the liquid is added using a computer-
controlled syringe pump. The liquid is injected in small steps
(usually 2 mL) which from visual observation is only a few droplets,
such that sometimes the liquid addition in a single addition step
may not go to completion as the last droplet may hang off the
injection needle until the next liquid addition step begins.
Our result of 1.2 for L/S(maxT) of the blank (MCC PH101 with 5%
PVP) agrees generally with Mahrous et al. (2010) who report 1.35
for the same formulation. Furthermore, both Alvarez et al. (2002)
and Soh et al. (2006) report 1.2 and 1.29, respectively, for PH101
alone without PVP.
3.2. Repeatability
RA15 was extruded-spheronised at L/S(maxT) (0.6, see Table 3)
three times, and each spheronised sample was subsequently
analysed five times by the Eyecon, where each Eyecon analysis
involves around 20 frames of images (see Table 4). Except for the
distribution of aspect ratios reported by the Eyecon (the CV of the
average aspect ratio), all other measurements have acceptable CVs
(<5%) for both the Eyecon technique (intra-sample) and the
extrusion-spheronisation process (inter-sample).
3.3. Pellet characteristics
All formulations were extruded-spheronised at L/S(maxT) as well
as some other L/S values, and the Eyecon used to analyse the size
and sphericity of the resultant pellets.
The sphericity is approximated in this work from the aspect
ratio (calculated by the Eyecon software as the ratio between the
longest and shortest dimension measured (Hagrasy et al., 2013)) by
assuming a generally spherical shape, such that an aspect ratio of 1
is a perfect sphere. The current Eyecon software reports the
average aspect ratio of the pellets to only a single decimal point,
which in our work was sufficient to classify the pellets as either
spherical or near-spherical (aspect ratio 1.1) or non-spherical (1.2
or greater, as verified by visual classification, see Figs. 2 and 3). Due
to the binary nature of the measured aspect ratios (1.1 or 1.2), the
visual classification was necessary to establish confidence in the
aspect ratio’s ability to distinguish spherical from non-spherical
Table 1
Grades and suppliers of materials used.
Material Grade Supplier Aqueous solubility at ambient temperature
MCC Avicel PH101, Ph. Eur. FMC Biopolymer, Cork, Ireland
PVP Kollidon 30, Ph. Eur. BASF, Ludwigshafen, Germany
Indomethacin >99% Sigma-Aldrich <1 mg/mL (MedChem Express, n.d.) (low)
Felodipine >98% Xi’an Lyphar Biotech Co., Ltd <1 mg/mL (MedChem Express,” n.d.) (low)
Theophylline Anhydrous, >99% Sigma-Aldrich 7.3 g/L (Yalkowsky et al., 2010) (medium)
Acetaminophen 102.0% Sigma-Aldrich 12.78 g/L (Granberg and Rasmuson, 1999) (medium)
Piracetam Ph. Eur. CAS 7491–74-9 Axo Industry 72 g/L(n.d.) (high)(Biotech and Piracetam, 2016)
Ranitidine hydrochloride GlaxoSmithKline, 660 g/L(Woods and Otago, 1993) (very high)
Six APIs (grade, purity and suppliers in Table 1) were used at low and high loadings for a total of twelve formulations (see Table 2 for composition), covering drugs in three
solubility ranges (low, medium, high).
Table 2
Composition of formulations as% dry mass.
Loading API MCC PVP
blank 0% 95% 5%
low 15% 80% 5%
high 40% 55% 5%
Table 3
L/S (g H2O/g formulation) for each formulation corresponding to the maximum
torque values (max T) recorded by MTR, L/S(max T), along with the corresponding
number of measurements, n.
ID API Loading n L/S(maxT) max T (Nm)
blank – 0% 2 1.2 (0) 0.18 (0.09)
IN15 Indomethacin 15% 1 0.8 0.45
IN40 40% 1 0.8 0.38
FE15 Felodipine 15% 3 0.8 (0.12) 0.23 (0.06)
FE40 40% 3 0.8 (0.23) 0.1 (0.08)
TH15 Theophylline 15% 3 0.8 (0.12) 0.24 (0.04)
TH40 40% 2 0.6 (0) 0.6 (0)
AC15 Acetaminophen 15% 1 0.8 0.51
AC40 40% 2 0.8 (0) 0.8 (0)
PI15 Piracetam 15% 3 0.8 (0.12) 0.25 (0.23)
PI40 40% 4 0.6 (0.25) 0.24 (0.03)
RA15 Ranitidine hydrochloride 15% 3 0.6 (0.06) 0.23 (0.05)
RA40 40% 2 0.6 (0) 0.27 (0.08)
Numbers in parentheses are one standard deviation.
M. Kuhs et al. / International Journal of Pharmaceutics 517 (2017) 19–24 21

4. pellets, while the visual classification alone was deemed insuffi-
cient due to its highly subjective nature.
The average sizes of pellets of all formulations except RA40 at
0.6 L/S were between 900 and 1400 um (Table 5), which is
acceptable for general extrusion-spheronisation purposes. Extru-
sion-spheronisation at L/S(max T) yielded an acceptable aspect ratio
of 1.1 in 4 out of 12 L/S(max T) pellets. As spheronisation generally
progresses in the order extrudated cylinders À> elongated dumb-
bells À> dumb-bells À> spheres, and as this is accompanied by
increasing loss of free liquid available to act as binder, spheronisa-
tion ending with dumb-bells implies too low L/S. Thus, as the 9
formulations that did not yield spherical pellets were all dumb-bell
shaped, 8 of these were subsequently extruded-spheronised by
increasing L/S by 0.2–0.4 (around 25%). This increase in L/S resulted
in spheres for 3 cases, and a mixture of spheres and almost-
spherical pellets (average aspect ratio 1.1 in both cases) for the
remaining 5. Spheronisation for 15 min at 2000 rpm is generally
sufficient to reach the end of spheronisation; to verify this, we
tested spheronising RA15 at L/S(maxT) for 35 min instead of the
normal 15 min, which yielded dumb-bells identical to those
obtained after 15 min, thus verifying that the inability to form
spheres is not due to insufficient spheronisation time. In fact, as L/
S(maxT) corresponds to the end point of granulation, it is expected
that extrusion-spheronisation subsequent to wet granulation will
require some additional moisture to allow especially spheronisa-
tion to occur successfully.
The CV of the aspect ratio of spherical pellets is always <15%,
indicating a satisfactory distribution of aspect ratios, i.e. the
majority of pellets (not just the average) are spherical or near-
spherical where the average aspect ratio is 1.1. Unfortunately it is
currently not possible to obtain a distribution of aspect ratios from
the Eyecon.
PI40 pellets extruded-spheronised at L/S(maxT) (0.6) were sticky,
likely due to the high loading of a highly soluble API. It was thus
considered unfeasible to increase L/S as was done for other
formulations that did not yield spherical pellets at L/S(maxT); L/S
was instead reduced to 0.5. The resultant pellets were spherical,
although the pellet surface was highly irregular, rendering these
pellets unusable. Most likely this is an artefact of piracetam
dissolved in water precipitating as the water evaporates during
drying.
Interestingly, the formulations that yielded spherical pellets at
L/S(maxT) were the least soluble APIs (indomethacin and felodipine)
and one of the medium-solubility APIs also at high loading
(acetaminophen). It thus seems that L/S(maxT) only gives acceptable
pellets for poorly soluble APIs at high loading. From our work it
seems that formulations which do not yield spherical pellets at L/
S(maxT) should be spheronised at L/S + 25%.
Table 4
Extrusion-spheronisation and Eyecon repeatability measurements.
Extrusion-Spheronisation Run Eyecon Measurement Avg aspect ratio CV aspect ratio Avg min diameter (um) Avg max diameter (um)
1 1 1.2 0.286 925.6 1054.4
2 1.2 0.204 920.9 1059.6
3 1.2 0.265 926 1051.6
4 1.2 0.246 903.6 1030
5 1.2 0.213 921.9 1043.9
mean 1.2 0.243 919.6 1047.9
stdev 0 0.035 9.2 11.5
CV 0.0% 14.2% 1.0% 1.1%
2 1 1.2 0.255 903.4 1026.9
2 1.2 0.176 906.5 1023.1
3 1.2 0.202 901 1021.7
4 1.2 0.309 902.2 1029.8
5 1.2 0.242 896 1024
mean 1.2 0.237 901.8 1025.1
stdev 0 0.051 3.8 3.2
CV 0.0% 21.6% 0.4% 0.3%
3 1 1.2 0.17 942.2
2 1.1 0.137 943.9 1070.3
3 1.1 0.128 950.2 1074.5
4 1.2 0.128 935.7 1076
5 1.2 0.127 923.64 1055.88
mean 1.16 0.138 939.1 1069.2
stdev 0.0548 0.018 10.1 9.2
CV 4.7% 13.3% 1.1% 0.9%
Intra-sample mean 1.187 0.206 920.2 1047.4
stdev 0.0231 0.059 18.7 22.0
CV 1.9% 28.6% 2.0% 2.1%
Fig. 2. Eyecon aspect ratio compared to visual classification of pellets as in Fig. 3.
22 M. Kuhs et al. / International Journal of Pharmaceutics 517 (2017) 19–24

5. Fig. 3. Typical examples of pellets visually categorised as (a) spherical, (b) spheres and near-spherical pellets, (c) dumb-bells, and (d) elongated dumb-bells.
Table 5
Size and shape of pellets as measured by the Eyecon and confirmed by visual inspection (1 = spherical, 2 = spherical and near-spherical, 3 = dumb-bells, 4 = elongated dumb-
bells; see Fig. 3).
API Loading L/S Difference to L/
S(maxT)
Avg min diameter
(um)
Avg max diameter
(um)
Avg aspect
ratio
shape (visual inspection by
human)
CV aspect ratio
blank 0% 1.2 0 1038 1173 1.1 2 11%
Indomethacin 15% 0.8 0 903 1039 1.2 3 14%
15% 1 0.2 1045 1155 1.1 2 11%
40% 0.8 0 1073 1146 1.1 1 9%
Felodipine 15% 0.6 À0.2 903 1065 1.2 4 19%
15% 1 0.2 1057 1150 1.1 1 10%
40% 0.8 0 1056 1125 1.1 1 10%
Theophylline 15% 0.8 0 1150 1331 1.2 3 17%
15% 1 0.2 1031 1146 1.1 2 11%
40% 0.6 0 965 1124 1.2 4 23%
40% 0.8 0.2 1031 1146 1.1 2 11%
Acetaminophen 15% 0.8 0 1024 1153 1.1 2 14%
15% 1 0.2 1007 1059 1.1 1 9%
40% 0.8 0 1265 1334 1.1 1 14%
40% 1 0.2 1046 1097 1.1 1 8%
Piracetam 15% 0.8 0 1153 1299 1.2 3 19%
15% 1 0.2 1021 1168 1.1 2 9%
40% 0.6a
0a
919 1085 1.2 3 23%
40% 0.5 À0.1 1000 1092 1.1 1 with spiky surface (Fig. 4) 20%
Ranitidine
Hydrochl
15% 0.6 0 846 987 1.2 3 13%
15% 1 0.4 988 1079 1.1 2 10%
40% 0.6 0 644 739 1.2 4 22%
a
Produced sticky pellets.
M. Kuhs et al. / International Journal of Pharmaceutics 517 (2017) 19–24 23

6. 4. Conclusion
The ability of L/S(max T) as measured by MTR to predict the ideal
L/S for wet granulating for subsequent extrusion-spheronisation
was examined for formulations with MCC, PVP and APIs ranging
from insoluble to highly soluble,. The presence, but not the type, of
API had a significant effect on L/S(maxT); whereas MCC alone (with
5% PVP) had an L/S(maxT) of 1.2, this reduced to 0.6–0.8 for
formulations containing a low or high loading (15 or 40%,
respectively) of API, regardless of the type of API. L/S(maxT) was
0.8 for the poorly soluble APIs, which tended to decrease to 0.6 as
the API solubility and loading increased.
Extrusion-spheronisation of all formulations at L/S(max T) had
mixed results; while pellet size was usually acceptable (between
900 and 1400 um), the pellets did not usually achieve sphericity, in
some cases retaining a near-spherical but distinct dumb-bell shape
(average aspect ratio usually 1.2), especially for the more soluble
APIs. In all but one case, increasing L/S by 25% for these
formulations resulted in aspect ratios of 1.1, suggesting that for
more soluble formulations the ideal L/S for extrusion-spheronisa-
tion is slightly higher than L/S(maxT). Unsurprisingly, extrusion-
spheronisation of highly-soluble APIs at high loadings may not be
possible at all, as evidenced by piracetam, where the best pellets,
though spherical, had highly irregular surfaces.
Generally it was found that MTR is able to quickly give an
approximate L/S for extrusion-spheronisation of active formula-
tions to produce spherical or near-spherical (aspect ratio 1.1)
pellets. This should be able to reduce pre-formulation work and
help eliminate trial-and-error approaches and the “hand-squeeze”
tests for determining the end point of wet granulation.
Recently a texture analyser has also been investigated for
predicting extrusion-spheronisation performance, which requires
measuring multiple properties of the wet mass such as hardness,
springiness, chewiness and resilience (Gao et al., 2013). The
present study would indicate that MTR could be a much simpler
and faster method for reducing extrusion-spheronisation work.
In the future it could be beneficial to map the relationship
between different values of L/S and subsequent sphericity of pellets
to elucidate the relationship between torque measured by an MTR
and extrusion-spheronisation in more detail, and in particular to
test the generality of the L/S(maxT) + 25% conclusion. It would also
be interesting to measure L/S(maxT) for formulations containing
only API and PVP, as this may give a clearer indication of the
influence of API on the API/MCC/PVP mixture. Furthermore, main
excipients other than MCC, such as lactose, could also be
investigated.
Acknowledgements
This work was funded by Science Foundation Ireland (SFI)
under the following awards: Synthesis and Solid State Pharma-
ceutical Centre (SSPC) – (12/RC/2275); Pharmaceutical Powder
Extrusion Suite – (12/RI/2345); Model Predictive Control of
Continuous Pharmaceutical Processes – (13/IA/1980).
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Fig. 4. The irregular surface of PI40 L/S 0.5 spherical pellets.
24 M. Kuhs et al. / International Journal of Pharmaceutics 517 (2017) 19–24