European Journal of Pharmaceutical Sciences 111 (2018) 482–491

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European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

Rheological analysis of itraconazole-polymer mixtures to determine optimal MARK

melt extrusion temperature for development of amorphous solid dispersion
Nayan Solanki, Simerdeep Singh Gupta1, Abu T.M. Serajuddin⁎
College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The objective of this investigation was to develop a systematic method for the determination of optimal pro-
Amorphous solid dispersion cessing temperatures of drug-polymer mixtures for the development of amorphous solid dispersion (ASD) by
Rheology melt extrusion. Since melt extrusion is performed at high temperature, it is essential that the processing tem-
Melt extrusion perature should be as low as possible to minimize degradation of drug and polymer, and yet the temperature
Polymers
should be high enough that the drug-polymer mixture attains certain viscosity that is extrudable and the drug
Processing temperature
Rheological analysis
dissolves in the molten polymer. By using itraconazole (ITZ) and polyvinyl caprolactam-polyvinyl acetate-
Plasticization polyethylene glycol graft co-polymer (Soluplus®, BASF) as, respectively, the model drug and the polymeric
Melt viscosity carrier, melt viscosities of drug-polymer mixtures with 5, 10, 20 and 30% ITZ were studied as functions of
temperature and angular frequency. All these concentrations were below the miscibility limit as it was shown
separately by film casting that ITZ was miscible with the polymer up to 40%. Since the angular frequency of a
rheometer may not be high enough to simulate the shear rate within an extruder, torque analysis as a function of
temperature during melt extrusion of selected drug-polymer mixtures was also conducted. The presence of
dissolved ITZ had a plasticizing effect on the polymer used, and an intersection point around 150–155 °C was
observed, above which viscosities of drug-polymer mixtures were lower than that of polymer itself. Drug-
polymer mixtures with 5 to 30% ITZ were extrudable at 150 °C, and torque analysis showed that the mixture
with 20% ITZ can be extruded even at 145 °C. These temperatures were 17 to 22 °C below the melting point of
ITZ (167 °C). ITZ dissolved due to the drug-polymer miscibility, the viscosity attained, and the shear rate gen-
erated. It was confirmed by PXRD and DSC that the extrudates were amorphous. Viscosity and miscibility of
drug-polymer mixtures during melt extrusion were identified as critical factors in determining optimal proces-
sing temperature.

1. Introduction
Amorphous solid dispersion (ASD) has been investigated extensively
to increase dissolution rate and bioavailability of poorly water-soluble
drugs (Leuner and Dressman 2000; Tong et al. 2008). Depending on the
nature of drugs and carriers used and their relative concentrations,
drugs may be molecularly dispersed in ASD as follows: (a) solid solu-
tion, where the solute (drug) replaces solvent (carrier) molecule, (b)
interstitial solid solution by the distribution of solute in the interstices,
and (c) random distribution of solute in the amorphous carrier, which is
sometimes referred to as amorphous solid solution (Baghel et al. 2016).
How the drug is dispersed in the carrier may influence the miscibility
between them. However, for the successful development of ASD as the
pharmaceutical product, it is essential that both drug and carrier are
miscible in such a way that there is no crystallization of drug during
shelf life of the formulation. As defined by Baghel et al. (2016), the
drug-polymer miscibility is the ability of the drug to remain dissolved in
the polymeric carrier by molecular distribution, interstitial distribution
or random distribution. Water-soluble amorphous polymers are com-
monly used in the ASD of poorly water-soluble drugs. Once the poly-
meric carrier is dissolved in aqueous media in the gastrointestinal tract
after oral administration of such a formulation, the drug is released in
the form of an aqueous solution or in the finely divided state having
high surface area that redissolves rapidly (Tong et al. 2008).
Despite many potential advantages of ASD, its use in drug products
was hampered for a long time because of various issues related to its
preparation and processing into dosage forms (Serajuddin 1999). For
example, the solvent evaporation was for a long time the most common
method of preparing an ASD, where large amount of organic solvent
was necessary to dissolve a water-insoluble drug and the water-soluble

⁎
Corresponding author.
E-mail address: serajuda@stjohns.edu (A.T.M. Serajuddin).
1
Current affiliation: Teva Pharmaceuticals USA Inc., 577 Chipeta Way, Salt Lake City, UT 84108.

http://dx.doi.org/10.1016/j.ejps.2017.10.034
Received 13 April 2017; Received in revised form 29 September 2017; Accepted 24 October 2017
0928-0987/ © 2017 Elsevier B.V. All rights reserved.
N. Solanki et al.
carrier in a common medium, and the solvent handling during sub-
sequent drying created formulation and manufacturing difficulties
(Serajuddin 1999; Tong et al. 2008). The situation has improved greatly
during the past 10 to 15 years because of the introduction of hot melt
extrusion (HME) for the preparation of ASD, and, indeed, HME has now
emerged as the most promising technique for this purpose. Using HME,
the drug is dissolved in the amorphous polymer at an elevated tem-
perature (Breitenbach 2002; Crowley et al. 2007; Patil et al. 2016) to
produce ASD. However, there are only very limited reports in the lit-
erature on the identification of optimal temperature for melt extrusion
of drug-polymer mixtures. The chemical stability of drug could be a
major issue with HME, especially at or near the melting point of drug
(Lakshman et al. 2008; Verreck et al. 2006). There is also the potential
for the degradation of polymer at a high temperature (Sarode et al.
2014). It is, therefore, essential that the drug-polymer mixture should
be processed in a melt extruder at as low temperature as possible. Even
when there is no thermal degradation, the temperature should not be so
high that the extrudates are very soft and do not form filaments that can
be further processed into dosage forms. At the same time, the tem-
perature should also not be so low that the drug does not dissolve in the
polymer or the material is not extrudable. It is essential to select an
operating temperature such that the drug dissolves in the polymer
during extrusion, the drug-polymer mixture is extrudable and there is
no chemical degradation.
For melt extrusion, the drug-polymer mixture has to be heated to a
temperature where the melt viscosity of drug-polymer mixture inside
the barrel is within the extrudable range (Aho et al. 2016; Gupta et al.
2014). Such a processing temperature has to be above the glass tran-
sition temperature (Tg) of polymer used. However, if the drug has a
melting point higher than the Tg of polymer, it is not necessary that the
drug-polymer mixture has to be heated above the melting point of drug.
The mixture may be extruded to form ASD at a temperature much lower
than the melting point of the drug, provided (a) the drug dissolves in
the molten polymer and (b) the viscosity of the polymer is within the
extrudable range.
Although it may be possible to decrease melt viscosity and thus
lower processing temperature for hot melt extrusion by incorporating a
plasticizer, the added plasticizer may not be miscible with the polymer
and its presence may cause crystallization of drug from the system
(Gumaste et al. 2016). Gupta et al. (2015) demonstrated that it may not
be necessary to add a separate plasticizer during melt extrusion as the
dissolved drug may itself serve as the plasticizer. They were successfully
able to prepare ASD by extruding mixtures of carbamazepine (CBZ) and
Soluplus® (Tg = 72 °C) at a temperature almost 60 °C below the CBZ
melting point of 191 °C as the drug had major impact in lowering
viscosity of the polymer. For the drug to be able to act as a plasticizer, it
has to be miscible with the polymer, where the degree of plasticizing
effect depends on drug concentration and processing temperature.
There are also several other reports on the effect of drug on the
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European Journal of Pharmaceutical Sciences 111 (2018) 482–491
Fig. 1. Chemical structures of (a) itraconazole and (b) Soluplus®.
rheology of drug-polymer mixtures, such as acetaminophen-poly-
ethylene oxide (Suwardie et al. 2011; Yang et al. 2011), ibuprofen-ethyl
cellulose (De Brabander et al. 2002), indomethacin-HPMCAS MF
(Sarode et al. 2013), indomethacin-polyethylene oxide (Aho et al.
2016) and indomethacin-Eudragit EPO (Liu et al. 2012). Aho et al.
(2016) asserted that the rheological measurement should be a standard
part of material characterization for hot melt extrusion. However, no
systematic study to take advantage of the plasticizing effect of drug in
identifying processing conditions has been reported in the literature.
As mentioned above, the Soluplus®-CBZ mixture was considered to
be a miscible system where the drug dissolved in molten polymer at
temperatures almost 60 °C below its melting point of 191 °C (Gupta
et al. 2015). This may not be a model system for all drugs as there may
be drug-polymer combinations that may not be as freely miscible and,
even when they are miscible, they may not adequately reduce the
viscosity of the system for melt extrusion. In order to investigate such a
possible scenario, we chose itraconazole (ITZ) as a model drug in the
present study. ITZ (Fig. 1) with molecular weight of 706 g/mol is a
much bulkier molecule than CBZ (236 g/mol). Parikh et al. (2015) re-
ported that ITZ is miscible with Soluplus® up to 40% w/w. Given that
ITZ is miscible with Soluplus® and it has a lower melting point (166 °C)
than that of CBZ (191 °C), one could hypothesize that melt extrusion of
Soluplus®-ITZ mixture could be performed at lower temperatures than
Soluplus®-CBZ systems. Because of the much lower melting point of ITZ
than CBZ, one could also consider the viscosity of Soluplus®-ITZ system
at different drug concentrations and various processing temperatures
could be lower than that of the Soluplus®-CBZ system. In the present
investigation, we put this hypothesis to test.
Earlier, Six et al. (2004) performed melt extrusion of ITZ with
Kollidon® VA 64 (vinylpyrrolidone-vinyl acetate copolymer) at a barrel
temperature above the melting point of the drug without considering
the possibility of performing the experiment below the drug melting
point. Zhang et al. (2013) reported the preparation Soluplus®-ITZ melt
extrudates at a lower temperature of 160 °C; however, there was no
justification given for the selection of this specific extrusion tempera-
ture. Yang et al. (2016) demonstrated that nifedipine-copovidone
amorphous solid dispersion can be prepared by extrusion at 13 °C below
the melting point of nifedipine (173 °C), which they referred to as the
critical temperature. The processing temperature had to be at or above
the critical temperature for optimal melt extrusion and molecular level
mixing of drug and polymer. However, the authors used only 50:50-
mixture of nifedipine and copovidone in their study and there was no
mention of whether the critical temperature would vary depending on
drug to polymer ratios. In the present study, we conducted rheological
analysis of Soluplus®-ITZ mixtures at different ratios to identify pro-
cessing conditions for the preparation of ASD by melt extrusion. The
results obtained from rheological analysis were confirmed by preparing
extrudates, which were then analyzed by modulated differential scan-
ning calorimetric (mDSC) analysis and powder X-ray diffraction (PXRD)
N. Solanki et al.
analysis.
2. Materials and methods
2.1. Materials
Itraconazole was donated by a major manufacturer of generic
pharmaceuticals located in the US. Soluplus®, which is chemically
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-
polymer, was donated by BASF Corporation (Tarrytown, New York).
Because of its relatively low Tg (~ 72 °C), Soluplus® has extensively
been investigated for melt extrusion. Structures of both itraconazole
and Soluplus® are given in Fig. 1.
2.2. Rheology
The rheological analysis was carried out to determine effects of
angular frequencies, temperature and drug concentrations on the
complex viscosity of drug-polymer physical mixture(s). The experi-
ments were performed using Discovery Hybrid Rheometer-2 equipped
with an oven heating assembly using 25 mm parallel plate geometry
(TA Instruments, Newcastle, DE). The samples were prepared by com-
pressing uniform ITZ-polymer mixtures by Carver Press into slugs of
25 mm diameter and 2 mm thickness as described earlier (Gupta et al.
2016; Meena et al. 2014; Parikh et al. 2014). The rheometer was cali-
brated for zero gap prior to the analysis at starting temperature of the
experiment.
Two different types of rheological tests were performed to evaluate
samples:
i) Oscillation temperature sweep was performed to determine the
effect of temperatures on complex viscosity at angular frequency of
0.1 rad/s, oscillation strain of 0.5% and ramp rate of 5 °C/min. In this
test, samples were heated from low to high as well as from high to low
temperatures. Prior to analysis, each sample was equilibrated at the
starting temperature for 120 s. For the low to high temperature test, the
samples were heated from 135 to 180 °C, and for the high to low
temperature test, different starting temperatures of 170, 160, 150 and
140 °C were used and then the samples were cooled down to ~110 °C at
5 °C/min.
ii) Oscillation frequency test was performed to determine the effect
of angular frequency on complex viscosity. For this test, the complex
viscosity was studied at different temperatures in the range of 140 to
170 °C at the interval of 10 °C by varying the oscillation frequency
gradually from 0.1 to 100 rad/s at the oscillation strain of 0.5%.
2.3. Establishment of linear viscoelastic region
To compare viscoelastic properties of different materials and for-
mulations, it is essential that the rheological analysis is conducted in
the linear viscoelastic region (LVE). In this region, the complex visc-
osity and modulus (storage and/or loss) remain constant. Therefore, to
determine linear viscoelastic range (LVE), the oscillation amplitude test
was performed for Soluplus® and a Soluplus®-ITZ mixture (30% ITZ) at
160 °C by keeping the angular frequency constant at 0.1 rad/s, while
the strain or stress was varied by increasing the oscillation amplitude.
As shown in Fig. 2, the complex viscosity, the storage modulus (G’) and
the loss modulus (G”) of Soluplus® remain fairly constant up to 100%
strain. In case of the ITZ-Soluplus mixture, although some decrease in
the storage modulus (G’) was observed, complex viscosity and loss
modulus remained practically unchanged. In the present study, we
conducted all oscillatory tests only at 0.5% oscillation strain, which is
well within the linear viscoelastic range of Soluplus® and other test
samples. In the present study, the maximum drug concentration used
was 30% w/w. Therefore, these results indicate that the determination
of complex viscosity would be reproducible irrespective of the change
in drug concentration and conditions.
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2.4. Validation of Cox-Merz rule
As mentioned above, oscillatory rheological test rather than the
rotational (flow) rheology was performed in the present investigation.
This is because it is difficult to determine the steady shear viscosity of
polymeric melts using rotational rheology as the sample tends to frac-
ture at the edge and flow out of the plate geometry (Tanner and
Keentok 1983). This is especially true when the analysis is performed at
high shear rates. Thus, the results of the viscosity measurements could
be misleading and might not be representative of processes involving
higher shear rates like melt extrusion and injection molding. On the
other hand, oscillatory rheological tests can be performed to measure
complex viscosity over a wide angular frequency (rad/s) range keeping
the strain low on the sample. Tests were conducted to ensure that the
rheological testing in the present investigation follows the empirical
Cox-Merz rule, which essentially states that steady state viscosity as a
function of shear rate can be estimated from the complex viscosity as a
function of angular frequency if the two curves generated by such de-
terminations coincide with or overlay on each other (Cox and Merz
1958 and 1959). Thus, the Cox-Merz transformation can be applied to
determine steady shear rate viscosity from oscillatory (dynamic) fre-
quency sweep, and if Cox-Merz rule is validated, the results obtained
from this oscillatory test can be used to predict viscosity for processes
involving high shear rates, such as HME (Kulicke and Porter 1980). To
test the Cox-Merz rule, Fig. 3 gives the overlay of flow sweep and os-
cillation frequency sweep (dynamic frequency sweep) for Soluplus®,
where the flow sweep was performed at lower shear rates of 0.01 to 0.5
1/s) and the oscillation frequency test was performed at higher angular
frequencies of 0.1 to 100 rad/s. The Cox-Merz transformation was ap-
plied using TRIOS software by TA instruments on oscillation frequency
results to obtain shear rate data. It can be seen in Fig. 3 that the two
curves overlap in the shear rate range of 0.1 to 0.5 1/s, thus validating
Cox-Merz rule. Therefore, the results of oscillatory rheological tests for
Soluplus® can be used to infer processing conditions involving higher
shear rate, such as HME.
2.5. Torque analysis by hot melt extrusion
The torque analysis of the neat polymer and the drug-polymer
mixtures (10, 20 and 30% w/w drug) was performed using Process 11
Parallel Twin-Screw Extruder (Thermo Scientific Inc., Bridgewater, NJ,
USA). Physical blends of drug and polymer were prepared using a
Turbula mixture, and the mixtures were then fed into the extruder at
the rate of 1 g/min using Thermo 11 mm single screw volumetric
feeder, while maintaining the screw speed of 100 RPM and the barrel
temperature of 150°C. Screw configuration of three kneading zones
containing forward kneading elements and series of conveying elements
was used to conduct extrusion of Soluplus®-ITZ mixtures. The screw
configuration is given in Fig. 1 of the Supplementary Material. In the
first kneading zone, near the feeding area, 7 kneading elements with
offset angle of 30° followed by 7 kneading elements of 60° were used. In
the second kneading zone, 6 kneading elements with offset angle of 60°
were used. In third kneading zone, 4 kneading elements of 60°, followed
by 7 kneading elements of 90° were used. The extrudates were obtained
on a conveyer belt, where they cooled down at room temperature. The
torque generated during melt extrusion was recorded as a mean torque
value of six observations and plotted against the drug concentration to
determine the effect of drug concentration on the torque. To study the
effect of temperature on torque, a constant drug concentration of 20%
w/w was used for extrusion at different temperatures.
2.6. Differential scanning calorimetry (DSC)
The thermal analysis of physical mixtures and milled melt-extruded
samples was performed using a modulated DSC (DSC Q200, TA
Instruments, Newcastle, DE). Briefly, about 5 mg of sample was placed
N. Solanki et al.
Fig. 2. Plots of viscoelastic properties of Soluplus® and Soluplus®-ITZ mixture (70:30 w/w) at 160 °C and angular frequency of 0.1 rad/s as a function of oscillation strain: (A) complex
viscosity vs oscillation strain, and (B) storage and loss modulus vs oscillation strain. All oscillatory tests in the present study were conducted at 0.5% oscillatory strain, which is within the
linear viscoelastic range (LVE) of polymer and drug-polymer mixtures.
Fig. 3. Overlay of flow sweep and Cox-Merz transformed oscillatory frequency sweep to
validate Cox-Merz relationship for Soluplus at 160 °C. When the two curves overlap, the
Cox-Merz rule is validated.
in an aluminum pan, which was then crimped with a lid on. The pan
was equilibrated at 50 °C for 5 min followed by heating at 10 °C per
minute to 225 °C using the modulation cycle of 1.59 °C every minute.
The scans were analyzed for the presence of Tg and melting endotherm
to determine whether the drug had converted completely to the
amorphous form after extrusion. The Tg was obtained by deconvolution
of total heat flow into reversible and nonreversible phenomena using
Universal Analysis software (TA instruments, DE, USA).
2.7. Powder X-ray diffraction (PXRD)
PXRD patterns of the milled melt extrudates and physical mixtures
were obtained using a Shimadzu 6000 powder X-ray diffractometer
(Shimadzu, Tokyo, Japan). For such analysis, monochromatic CuKα
radiation source was operated at 40 kV and 30 mA, with the scanning
rate 2°θ/min over the range of 10–60° (2θ). Results were analyzed for
the presence of characteristic crystalline peaks in the final products.
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European Journal of Pharmaceutical Sciences 111 (2018) 482–491
3. Results
3.1. Effect of temperature on rheological properties of Soluplus®-
itraconazole mixtures at angular frequency of 0.1 rad/s
In a previous study using Soluplus® and carbamazepine (Gupta et al.
2015), we observed that the drug-polymer mixtures could be extruded
much below the melting temperature of drug as the drug dissolved in
the polymer and reduced the viscosity of polymer by serving as a
plasticizer. Therefore, in the present study, we first investigated the
effect of temperature on the complex viscosity of Soluplus® itself as well
as different Soluplus®-ITZ mixtures. The results at three different
starting temperatures of 140, 150 and 160 °C are given in Fig. 4 (A, B
and C, respectively). In a separate study (Parikh et al. 2015), it was
demonstrated by the film casting technique that ITZ was miscible with
Soluplus® up to 40% concentration, and, therefore, drug concentrations
5, 10, 20 and 30% w/w selected in the present study were within the
level of miscibility.
Fig. 4A gives the effect of temperature at 140 °C and lower on the
complex viscosity of Soluplus® and Soluplus®-ITZ mixtures at different
drug concentrations. The complex viscosity vs. temperature profiles of
Soluplus®-ITZ mixtures in the temperature range studied were higher
than that of the Soluplus® itself, indicating the lack of or limited plas-
ticizing effects of ITZ. The complex viscosity profiles of 5 and 10% ITZ
were somewhat closer to that of the neat Soluplus®, while that of 20%
ITZ was considerably higher. The viscosity of 30% ITZ as a function of
temperature was much higher than that of all other mixtures. It was
shown earlier by Gupta et al. (2015) that the viscosity of the material
should ideally be between 10,000 and 1000 Pa.s for optimal extrusion.
However, the viscosity of 30% Soluplus®-ITZ mixture was
~1000,000 Pa.s at 140 °C, and the viscosities of other mixtures were in
the vicinity of 30,000 Pa.s. For the determination of viscosity, the drug-
polymer mixtures were equilibrated at 140 °C for 120 s, and then the
viscosity was recorded as a function of temperature by gradually re-
ducing the temperature. The higher viscosity of Soluplus®-ITZ mixtures
than that of Soluplus® itself indicated that ITZ did not mix with the
polymer under conditions of the viscosity determination and, therefore,
did not have plasticizing effect. The increase in viscosity as a function of
drug concentration may be attributed to undissolved ITZ, which act as a
solid filler and reduced interaction between drug and polymer (Hornsby
et al., 1994).
For samples equilibrated at 150 °C (Fig. 4B), the viscosity profiles
were different than those at 140 °C. The viscosities of mixtures with 5
N. Solanki et al.
Fig. 4. Effects of itraconazole concentrations on complex viscosities of Soluplus®.
Viscosity was determined at 0.1 rad/s angular frequency with starting temperatures of (A)
140 °C, (B) 150 °C, and (C) 160 °C and then cooling to ~ 110 °C at the cooling rate of 5 °C/
min. The increase in viscosity with the decrease in temperature was recorded. The legends
for B and C are the same as that of A. Each value represents the average of two de-
terminations, and the values between the two determinations were highly reproducible.
Complex viscosity between 1 × 104 to 1 × 103 Pa.s at angular frequency of 0.1 rad/s is
optimal for extrusion.
and 10% ITZ were essentially the same but somewhat lower than that of
Soluplus® itself. The viscosity decreased further when the drug con-
centration in the mixture was increased to 20% w/w. Such plasticizing
effects of ITZ could be due to higher concentrations of dissolved drug in
Soluplus® at 150 °C under the experimental conditions of viscosity de-
termination. However, when the ITZ concentration in the drug-polymer
mixture was increased to 30% w/w, the viscosity was much higher than
those of all other mixtures and even higher than that of Soluplus® itself,
indicating that ITZ present did not dissolve completely in the polymer
during the determination of viscosity.
As shown in Fig. 4C, when complex viscosities of ITZ-Soluplus®
mixtures were recorded with the starting temperature of 160 °C and
then reducing the temperature, the viscosity vs. temperature profiles of
all Soluplus®-ITZ mixtures were below that of neat Soluplus®, and the
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European Journal of Pharmaceutical Sciences 111 (2018) 482–491
viscosity decreased continually with the increase in ITZ content. These
results indicate the plasticizing effects of ITZ on Soluplus®. It was evi-
dent that up to 30% w/w ITZ dissolved in Soluplus®, and viscosities in
the temperature range of 160 to 150 °C were within the extrudable
range of 10,000 to 1000 Pa.s.
The above results on the rheological analysis of Soluplus®-ITZ
mixtures at the very low angular frequency of 0.1 rad/s suggest that the
mixtures may be extruded at 150 °C for the ITZ content up to 20% and
at 160 °C for up to 30% ITZ contents. Although separate miscibility
testing by the film casting technique (Parikh et al. 2015) indicated that
as high as 40% ITZ is miscible with Soluplus®, high temperature was
necessary during rheological analysis to enable dissolution of ITZ in the
polymer. The high temperature also reduces viscosity to enable extru-
sion.
3.2. Effect of angular frequency on rheological properties of Soluplus®-
itraconazole mixtures at different temperatures
During melt extrusion, the two components undergo vigorous
mixing under high pressure and shear rate, which accelerates dissolu-
tion of one component into the other. It was, therefore, of interest to
determine what effect the angular frequency would have on the visc-
osity of mixtures at a particular temperature. The effects of angular
frequency on complex viscosities of Soluplus®-ITZ mixtures at (A)
140 °C, (B) 150 °C, and (C) 160 °C are shown in Fig. 5. The viscosity was
first determined at the given temperature at the angular frequency of
0.1 rad/s, which was then increased gradually up to 100 rad/s.
Complex viscosities of the neat polymer and the Soluplus®-ITZ
mixtures with 5, 10, 20 and 30% w/w ITZ concentrations at 140 °C as
the function of angular frequency are shown in Fig. 5A. In all cases,
there was a decrease in viscosity with an increase in angular frequency.
For Soluplus® itself and for 5, 10 and 20% ITZ, viscosities decreased in
almost parallel manner, while for the 30% ITZ concentration, there was
a much sharper decrease in viscosity with the increase in angular fre-
quency. The profound drop in viscosity for 30% drug concentration
may be attributed to the larger amount of undissolved drug initially
present in the mixture, which dissolved gradually when the angular
frequency was increased. The higher viscosities of Soluplus®-ITZ mix-
tures indicate that the drug was not fully dissolved in the polymer
under the test conditions. The excess drug remained as solid particles
that acted as filler and increased the viscosity of drug-polymer mixture.
Similar decrease in viscosity with the increase in angular frequency
was also observed when the rheological study was conducted at 150 °C
(Fig. 4B). However, unlike the results at 140 °C, the viscosity profiles of
the mixtures with 5, 10 and 20% ITZ were either similar or lower than
that of Soluplus® itself. These results indicate plasticization of the
polymer by ITZ. Only at 30% drug load, the viscosity was higher than
that of Soluplus® itself. This is apparently due to the presence of un-
dissolved ITZ. Van Renterghem et al. (2017) recently reported that
when a drug substance is dissolved in the polymer, it reduces the
viscosity of the drug-polymer mixture as compared to that of the
polymer itself. However, when the drug substance is not dissolved in
the polymer and remains as crystalline material in the polymer matrix,
it acts as a filler and increases the viscosity of drug-polymer mixture.
Similar observations were also made previously by Suwardie et al.
(2011) and Yang et al. (2011). While 20% of ITZ in the present study
dissolved in the polymer matrix as observed by the continued decrease
in viscosity with the increase in drug concentration, it is possible that
all 30% of ITZ present did not dissolve and partially remained crys-
talline, thus being responsible for the increased viscosity. There was,
however, a sharp decrease in viscosity of the 30% drug-polymer mix-
ture with the increase in the angular frequency as more ITZ dissolved at
higher frequency. It may also be observed in Fig. 5B that viscosities of
Soluplus®-ITZ mixtures at 5, 10 and 20% drug concentrations were
within the range of 10,000 to 1000 Pa.s, which indicated that these
mixtures may be extruded at 150 °C.
N. Solanki et al.
Fig. 5. Effects of change in angular frequency on complex viscosities of Soluplus® and
different Soluplus®-itraconazole (ITZ) mixtures at (A) 140 °C, (B) 150 °C and (C) 160 °C.
The decrease in viscosity with an increase in angular frequency was recorded for all
temperatures. Each data point represents the average of two determinations. The legends
for B and C are the same as that of A.
When the starting temperature for the determination of viscosity
was increased to 160 °C (Fig. 5C), the rheological profiles at all drug
concentrations were either the same or lower than that of Soluplus®
itself, and there was a progressive decrease in viscosity when the con-
centration was increased to 20% and then to 30%. These results de-
monstrate that all drug concentrations used dissolved in Soluplus® and
exerted plasticizing effect at 160 °C. Similar results were also obtained
at 170 °C, although the viscosities were much lower (viscosity profiles
not shown).
3.3. Combined effects of drug concentration and temperature on rheological
properties of Soluplus®-itraconazole mixtures at different temperatures and
angular frequency of 0.1 rad/s
To summarize the effects of drug concentrations on the viscosity of
polymer, the normalized viscosity values of ITZ at different tempera-
tures as a function of drug concentration are plotted in Fig. 6 according
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European Journal of Pharmaceutical Sciences 111 (2018) 482–491
Fig. 6. Normalized complex viscosity (η) curve of Soluplus®-itraconazole (ITZ) mixtures
at different temperatures as a function of itraconazole concentration and at angular fre-
quency of 0.1 rad/s. The y-axis is a logarithmic ratio of complex viscosity of Soluplus®-ITZ
mixture to complex viscosity of Soluplus® itself. If the viscosity of Soluplus®-ITZ mixture
and neat Soluplus® is the same, logarithmic ratio of their complex viscosities is zero.
When the logarithmic ratio is lower than zero (below dash line), the viscosity of
Soluplus®-ITZ mixture is less than that of Soluplus®, which indicates the plasticization of
Soluplus® due to dissolved ITZ.
to the method reported earlier by Aho et al. (2016). The Y-axis in the
figure is the logarithmic value of the ratio of viscosity of the mixtures to
that of neat Soluplus® at angular frequency of 0.1 rad/s. The ratio of
greater than zero indicates the anti-plasticization effect of drug on the
polymer at the particular temperature, while the ratio of less than zero
shows the plasticization effect of drug on polymer. Thus, values above
the dashed line in the figure may be interpreted as anti-plasticization
effect and below the dashed line as the plasticization effect. The anti-
plasticizing effects at 140 °C indicate that ITZ did not completely dis-
solved in Soluplus® during the viscosity test and certain fractions re-
mained undissolved at this temperature at any of the drug concentra-
tions used, while it did not dissolve completely in the polymer at 150 °C
only at 30% drug concentration. The plasticization effects observed at
160 and 170 °C at all drug concentrations indicate dissolution of ITZ in
Soluplus® up to 30% drug concentration. Based on such normalized
viscosity vs. drug concentration profiles at different temperatures,
processing temperatures for different drug concentrations may be
identified.
The effect of increasing temperature on viscosities for different
drug-polymer ratios are shown in Fig. 7. At 140 °C, all drug-polymer
mixtures exhibited higher viscosities than that of the neat polymer.
Viscosities of drug-polymer mixtures decreased with an increase in
temperature, and, at 0.5% oscillation strain and 0.1 rad/s angular fre-
quency, an intersection point in the approximate temperature range of
150 to 155 °C was observed, above which viscosities of all drug-
polymer mixtures were below that of the polymer itself. Lower viscos-
ities after the intersection point can be attributed to facilitated solubi-
lization and increased dissolution of itraconazole in Soluplus® at ele-
vated temperatures. Viscosities of drug-polymer mixtures were higher
than that of polymer below the intersection temperature due to un-
dissolved drug. When extrusion is performed below the intersection
temperature, drug might remain undissolved in the extrudates. Thus,
the temperature above the intersection point may be considered as an
optimum temperature to conduct melt extrusion and prepare homo-
genous solid dispersion for the particular drug-polymer ratio. It should,
however, be mentioned here that the intersection point observed at 150
to 155 °C obtained at the angular frequency of 0.1 rad/s only. This gives
preliminary guidance with respect to the processing temperature of
drug-polymer mixtures during melt extrusion. The intersection point
could be lower if the angular frequency is increased. It has been shown
later in this paper that the ITZ-Soluplus® mixtures may indeed be
N. Solanki et al. European Journal of Pharmaceutical Sciences 111 (2018) 482–491

150 °C was ~7.5 Nm, and it decreased to 6.5, 5.8 and 4.7 Nm at, re-
spectively, 10, 20 and 30% w/w ITZ concentrations in the mixtures. A
straight-line correlation for decrease in torque with an increase in drug
concentration with R2 value of 0.9951 and a slope of − 0.089 was
observed. It is interesting to note that the torque generated by 30% ITZ
was lower than that of Soluplus® and all other drug-polymer mixtures.
This is unlike the complex viscosity of 30% ITZ at 150 °C observed in
Fig. 5B, where viscosities at all angular frequencies were higher. The
torque analysis, therefore, indicates the possibility of 30% ITZ being
dissolved in the polymer under the experimental conditions of high
pressure and high shear rate during melt extrusion.

3.5. Thermal and powder XRD analyses of melt extrudates

Plots of complex viscosity versus drug concentration in Fig. 6 shows

that viscosities of Soluplus®-ITZ mixtures up to 20% drug concentra-
tions at 150 °C are lower than that of Soluplus® itself, indicating drug-
polymer miscibility. Although the viscosity of the mixture containing
30% ITZ was higher, the torque analysis in Fig. 8 indicates that even
Fig. 7. Effect of increasing temperature from 135 to 180 °C at 5 °C/min on complex
30% ITZ could be dissolved in Soluplus® at 150 °C during melt extru-
viscosity of Soluplus® and Soluplus®-itraconazole (ITZ) mixtures at 0.5% of shear strain
and angular frequency of 0.1 rad/s. An intersection point, where the viscosity of
sion due to high shear rate. To confirm whether ITZ is indeed dissolved
Soluplus®-ITZ mixture intersects with that of Soluplus®, was observed. At temperatures in the polymer in melt extrudates produced at 150 °C, melt extrusion
above the intersection point, itraconazole dissolves in Soluplus®. studies at this temperature were conducted with 10, 20 and 30% drug
concentration and the products were analyzed by differential scanning
calorimetry (DSC) and powder X-ray diffraction (PXRD) analysis. The
processed during melt extrusion at temperature several degrees below
DSC scans presented in Fig. 9 indicate that all concentrations of drug
the intersection point.
were dissolved in Soluplus® during melt extrusion at 150 °C as there
were no endotherms corresponding to the melting of any crystalline
3.4. Effect of drug concentration on torque generated during hot melt drug. It may be noted that the melt extrudate with 20% ITZ produced at
extrusion 145 °C also did not provide any drug endotherm. On the other hand,
there were endotherms in the physical mixtures as well as in the melt
As shown in Fig. 5, there was a decrease in complex viscosity of extrudate produced at 140 °C due to the melting of crystalline ITZ. Si-
Soluplus® and Soluplus®-ITZ mixtures with the increase in angular milarly, the peaks present in the PXRD (Fig. 10) scans of physical
frequency. The effect was most prominent when the undissolved ITZ mixtures disappeared when the drug-polymer mixtures were melt ex-
was present in the mixture; the viscosity decreased sharply when more truded at 150 °C. These results are in agreement with the results of
and more ITZ dissolved with the increase in angular frequency. How- viscosity and torque analysis.
ever, there is a limit how much increase in angular frequency can be
achieved in a rheometer. It is not possible to simulate in a rheometer
the high pressure and friction generated during melt extrusion. For this
reason, Soluplus®-ITZ mixtures were also extruded through the melt
extruder, and the impact of increasing concentration of ITZ on torque
generated was determined. This is somewhat analogous to the de-
termination of viscosity by a torque rheometer (Lu et al. 2016).
In this method, the polymer and the drug-polymer mixtures were
fed into co-rotating twin screws at a constant rate and the torque
generated by the molten mass during extrusion at 150 °C was recorded.
Fig. 8 shows that the torque exerted on twin screws by neat polymer at

Fig. 8. Effects of itraconazole (ITZ) concentration in Soluplus®-ITZ mixtures on torque

generated during melt extrusion at 150 °C. Each data point represents the average Fig. 9. Differential scanning calorimetry (DSC) scans of Soluplus®-ITZ physical mixtures
( ± s.d.) of six determinations. (PM) and extrudates.

488
N. Solanki et al.
3.6. Effect of temperature on melt extrudability
As mentioned above, Soluplus® itself and all its mixtures with ITZ
ranging from 5 to 30% drug could be extruded at 150 °C, which is 17 °C
below the melting point of ITZ. Since the shear rate during rheological
analysis is much lower than that in a melt extruder, it was of interest to
determine whether Soluplus®-ITZ mixtures could also be extruded at
temperatures lower than 150 °C. Therefore, attempts were made to
extrude the neat polymer and the mixtures at 140 °C. However, it was
not possible to extrude the neat Soluplus® and its mixtures with 5, 10
and 30% ITZ at this temperature, and only the mixture with 20% ITZ
could be extruded. The 20% ITZ mixture was also extruded at 145 °C.
Fig. 11 shows that torque values generated during melt extrusion of
20% ITZ at 150, 145 and 140 °C were, respectively, 5.8, 6.8 and 8 Nm,
which are below the maximum torque of the melt extruder used. In case
of the neat polymer and the mixtures with ITZ concentrations of 5, 10
and 30%, the torque generated at 140 °C was > 12 Nm, which stopped
the rotation of screw shafts.
Fig. 11. Effect of change of barrel temperature on torque generated by 20% w/w drug-
polymer mixture during melt extrusion. Below 140 °C, the maximum limit of torque was
reached. Each data point represents the average ( ± SD) of six determinations.
489
European Journal of Pharmaceutical Sciences 111 (2018) 482–491
Fig. 10. Powder X-ray diffraction (PXRD) patterns of
Soluplus®-ITZ physical mixtures (PM) and extrudates.
The effect of drug concentration on the extrudability of Soluplus®-
ITZ mixtures at 140 °C may be explained by the results of the rheolo-
gical analysis. As shown in Fig. 4, complex viscosities of Soluplus® and
Soluplus®-ITZ mixtures with 5 and 10% ITZ were similar when the
rheological analysis was conducted with starting temperatures of 140
and 150 °C, and it may be observed in Fig. 5 that their viscosities were
also very close to each other when the angular frequency at 150 °C was
increased. It is, therefore, expected that the extrudability of these ma-
terials could also be similar or very close to each other. As may be
observed in Fig. 8, torque values generated by Soluplus® itself and 10%
ITZ in the mixture at 150 °C were, respectively, 7.5 and 6.5 Nm. These
values increased beyond the extrusion limit when the temperature was
decreased to 140 °C.
The situation was somewhat different in case of 20% ITZ con-
centration. The viscosity of the mixture with 20% ITZ was much lower
than that of Soluplus® and Soluplus®-ITZ mixtures when both compo-
nents were miscible with each other. Although the viscosity analysis in
Fig. 4 shows that 20% ITZ dissolved in Soluplus® at 150 °C and not at
140 °C, it is possible that the high shear rate within the extruder could
dissolve a higher amount of drug in the molten polymer. This would
decrease viscosity and thus increase melt extrudability. However, DSC
analysis of the extrudate at 140 °C with 20% ITZ exhibited an en-
dotherm at 161 °C for ITZ (Fig. 9). It is possible that although a higher
concentration of ITZ might have dissolved in the polymer at 140 °C
during melt extrusion, the dissolution of ITZ in the polymer was not
complete, i.e., a small fraction ITZ might not have dissolved in the
polymer. In contrast to the DSC analysis, PXRD (Fig. 10) did not show
any characteristic peak for ITZ, indicating that the ITZ might have
converted to the amorphous form. This contradiction of DSC and PXRD
for 20% ITZ mixture processed at 140 °C could be related to the con-
centration of ITZ that remained undissolved; it was possibly below the
detection limit of PXRD (Saleki-Gerhardt et al. 1994).
In case of 30% ITZ concentration, there was excessive amount ITZ
present that did not dissolve in Soluplus® and, as a consequence, the
viscosity remained high and the mixture was not extrudable at 140 °C.
N. Solanki et al.
4. Discussion
Since high temperature is used for melt extrusion, one of the ob-
jectives of the development of processing conditions is to select as low a
temperature as possible where the drug-polymer mixtures can be ex-
truded. Although there are numerous reports on various processing
conditions, such as screw configurations, screw speeds, etc., for melt
extrusion (Thiele 2003), studies on the identification of appropriate
temperatures for melt extrusion of drug-polymer mixtures have been
limited. The present study demonstrates that the rheological analysis
can serve as a useful tool for the identification of melt extrusion tem-
perature.
In this study, complex viscosities of Soluplus® and its mixtures with
ITZ at 5, 10, 20 and 30% as a function of temperature were determined.
It was determined previously by the film casting technique that ITZ was
miscible with Soluplus® up to 40%. Therefore, all drug concentrations
selected should in theory be miscible with Soluplus®. However, for
successful melt extrusion to obtain amorphous solid dispersion, it is
essential that the drug must dissolve in the polymer under the proces-
sing condition of melt extrusion. Therefore, the extrusion temperature
must be selected where the drug would dissolve in the molten polymer
during the short transit time within the extruder. The more ‘fluid’ or
less viscous a polymer is, the higher will be the dissolution rate of the
drug in the polymer. When the viscosity of Soluplus®-ITZ mixtures was
determined at the angular frequency of 0.1 rad/s with the starting
temperature of 140 °C and then lowering the temperature, no plasti-
cizing effects of ITZ on the polymer was observed, indicating that ITZ
was not dissolved in the polymer during rheological analysis at this
temperature. In addition, the complex viscosities of the mixtures at this
temperature were higher than the extrusion range of 10,000 to
1000 Pa.s. at angular frequency of 0.1 rad/s (Gupta et al. 2014). In
contrast, the rheological analysis showed that drug-polymer mixtures
with 5, 10 and 20% ITZ were extrudable at 150 °C and all mixtures,
including 30% ITZ, were extrudable at 160 °C.
The above results gave a preliminary estimate of temperatures that
may be used for the melt extrusion of Soluplus®-ITZ mixtures. However,
it should be recognized that the shear rates of mixtures inside barrels
during melt extrusion is much higher than what can be generated in a
rheometer. The rheological analysis at different temperatures as the
function of angular frequency showed that the viscosity decreases with
the increase in angular frequency and, therefore, the viscosity within
the extruder barrel during melt extrusion would be much lower due to
shear and pressure. This would accelerate the dissolution of drug in the
polymer. The torque analysis of Soluplus®-ITZ mixtures showed that
even 30% ITZ can be extruded at 150 °C. Although the mixture with
20% ITZ could be extruded at a temperature as low as 140 °C, the DSC
analysis indicated that the drug was not completely dissolved.
However, the extrusion of drug-polymer mixture containing 20% w/w
drug was still possible at 140 °C because of the drop-in viscosity by the
fraction of the drug dissolved. A complete solubilization with 20% ITZ
was, however, observed at 150 °C. To summarize, Soluplus®-ITZ mix-
tures with 5, 10 and 30% ITZ can be extruded at 150 °C and 20% ITZ
can be extruded at a temperature as low as 145 °C where the drug
dissolved completely in the polymer. The above processing tempera-
tures of 150 °C and 145 °C identified for Soluplus®-ITZ mixtures were,
respectively, 17 and 22 °C below the melting point of ITZ (167 °C). In
contrast, mixtures of another drug, carbamazepine, with Soluplus®
could be extruded at 140 °C with 10% w/w drug load, 135 °C with 20%
w/w drug and 125 °C with 30% w/w drug, which were, respectively,
50, 55 and 65 °C below the melting point of 191 °C for carbamazepine
(Gupta et al. 2015). Thus, it is apparent from the two studies that dif-
ferent drugs would have different plasticizing effect on a polymer and,
as a result, their processing temperatures would differ. The difference
between carbamazepine and ITZ could possibly be related to their
molecular weights, respectively, which are 236 and 706 g/mol. How-
ever, further studies are necessary to establish whether the lower
490
European Journal of Pharmaceutical Sciences 111 (2018) 482–491
molecular weight will exhibit higher dissolution rate of drug in the
molten polymer and higher plasticizing effect and, therefore, lower
melt extrusion temperature at a particular drug concentration.
The results of the present investigation with Soluplus®-ITZ mixtures
along with that of the previous investigation with Soluplus®-carbama-
zepine mixtures (Gupta et al. 2015) in our laboratory provide a con-
venient method of identifying optimal melt extrusion temperatures for
drug-polymer mixtures in the development of amorphous solid disper-
sions. The following systematic approach may be followed:
1. Determination of drug-polymer miscibility – The maximum con-
centration of drug that will be miscible with the polymer, i.e., the
amount of drug that will dissolve in the polymer matrix to form a single
phase and there will be no drug crystallization during the product shelf-
life, will be determined separately. In the present investigation, the film
casting method developed by Parikh et al. (2015) was applied, which
showed that up to 40% ITZ was miscible with Soluplus®. Gupta et al.
(2015) ascertained by analyzing the extrudates that the carbamazepine
was soluble in the polymer for > 30% w/w. Other methods, such as
Hildebrand-Scott theoretical model (Hildebrand and Scott 1962) and
Florey-Huggins method (Flory 1953), may also be applied to determine
drug-polymer miscibility.
2. Determine complex viscosity as a function of temperature – As shown
in the present investigation, the viscosity can be studied in two different
ways: (a) Determine the viscosity of drug-polymer mixture at a parti-
cular temperature above the Tg of polymer, but below the melting point
of drug. Then, record viscosity by lowering the temperature. This will
show whether the two components will be dissolved at the starting
temperature used under experimental conditions of viscosity determi-
nation and what impacts the lowering of temperature will have on
viscosity. Such determination of viscosity will also show whether the
viscosity at the temperatures studied is within the extrudable range.
The study can be repeated with different drug concentrations and dif-
ferent starting temperatures. (b) Alternatively, the viscosity of the
mixture can be determined by raising the temperature from low to high.
One disadvantage of this method, however, is that, at low temperature,
the two components are solid under conditions of the viscosity de-
termination and there may not be adequate mixing between them to
elicit any plasticization effect by the drug. Nevertheless, a transition
temperature may be observed when different concentrations of drugs
are used, which is a good estimate of melt extrusion temperature,
provided the viscosity is within the extrudable range.
3. Determine viscosity as a function of angular frequency – This will
show the effect of angular frequency on viscosity at a particular tem-
perature. Although the high pressure and high shear rate of a melt
extruder may not be simulated in a rheometer, this study will show a
trend and indicate whether there could be higher dissolution of drug at
higher shear rate during melt extrusion.
4. Conduct torque analysis by passing the mixtures through a melt ex-
truder – As mentioned earlier, there is a limit how much shear rate can
be exerted by a rheometer. The melt extruder can provide much higher
shear rate than a rheometer and thus the torque analysis can further
optimize the extrusion temperature. For example, in the present study,
it was observed that Soluplus®- ITZ mixtures up to 20% drug con-
centration may be extruded at 150 °C and a higher temperature in the
range of 155 to 160°C may be required for 30% ITZ concentration.
However, the torque analysis indicated that even 30% ITZ may be ex-
truded at 150 °C due to dissolution of the drug during extrusion because
of high shear rate and pressure.
5. Conduct melt extrusion – Finally, the melt extrusion temperature
identified by conducting viscosity analysis should be confirmed by
preparing melt extrudates and analyzing them using suitable techni-
ques, such as DSC and PXRD.
In the present study, only drug-polymer mixtures were used for the
determination of melt extrusion temperature. The method can also be
applied when plasticizers, surfactants and additional polymers are
present in the mixtures. Then, the effects of those additional
N. Solanki et al.
components on miscibility and viscosity will need to be considered.
5. Conclusions
The present study provides a systematic method of identifying op-
timal melt extrusion temperature based on the determination of com-
plex viscosity as functions of temperature and angular frequency, fol-
lowed by torque analysis during extrusion. It was observed that ITZ-
Soluplus® mixtures with drug concentrations ranging from 5 to 30%
may be extruded at 150 °C, which is 17 °C below the melting tem-
perature of ITZ. It was further observed based on torque analysis that
the mixture with 20% ITZ can be extruded at a temperature as low as
145 °C. DSC and PXRD showed that amorphous solid dispersions of ITZ
in Soluplus® were formed in all cases. The ability to extrude drug-
polymer mixtures at temperatures below the melting point of drug can
be attributed to the plasticizing of dissolved drug on the polymer and
the rate of dissolution of drug in the molten polymer. Such a plasti-
cizing effect and the rate of dissolution of drug in the polymer, how-
ever, vary from drug to drug. Unlike the results of present study where
ITZ-Soluplus® mixtures could be extruded at 17–22 °C below the
melting point of ITZ, a previous study from our laboratory showed that
the mixtures of Soluplus® with another drug, carbamazepine, could be
extruded at 50–65 °C below the melting point of carbamazepine
(191 °C).
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ejps.2017.10.034.
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