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Journal of Pharmacy
Research Paper
And Pharmacology

Using Flory–Huggins phase diagrams as a pre-formulation

tool for the production of amorphous solid dispersions:
a comparison between hot-melt extrusion and spray drying
Yiwei Tiana, Vincent Caronb, David S. Jonesa, Anne-Marie Healyb and Gavin P. Andrewsa
a
The Drug Delivery and Biomaterials Group, School of Pharmacy, Medical Biology Centre, Queen’s University, Belfast, UK and bSchool of Pharmacy
and Pharmaceutical Sciences, Main Department, Trinity College Dublin, Dublin, Ireland

Keywords
amorphous solid dispersion; Flory–Huggins
phase diagram; hot-melt extrusion; physical
stability; spray drying
Correspondence
Gavin P. Andrews, The Drug Delivery and
Biomaterials Group, School of Pharmacy,
Medical Biology Centre, Queen’s University,
97 Lisburn Road, Belfast BT9 7BL, Northern
Ireland, UK.
E-mail: g.andrews@qub.ac.uk
Received May 24, 2013
Accepted August 6, 2013
doi: 10.1111/jphp.12141
Abstract
Objectives Amorphous drug forms provide a useful method of enhancing the dis-
solution performance of poorly water-soluble drugs; however, they are inherently
unstable. In this article, we have used Flory–Huggins theory to predict drug solubil-
ity and miscibility in polymer candidates, and used this information to compare
spray drying and melt extrusion as processes to manufacture solid dispersions.
Method Solid dispersions were prepared using two different techniques (hot-melt
extrusion and spray drying), and characterised using a combination of thermal
(thermogravimetric analysis and differential scanning calorimetry), spectroscopic
(Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction methods.
Key findings Spray drying permitted generation of amorphous solid dispersions
across a wider drug concentration than melt extrusion. Melt extrusion provided
sufficient energy for more intimate mixing to be achieved between drug and
polymer, which may improve physical stability. It was also confirmed that stronger
drug–polymer interactions might be generated through melt extrusion. Remixing
and dissolution of recrystallised felodipine into the polymeric matrices did occur
during the modulated differential scanning calorimetry analysis, but the comple-
mentary information provided from FTIR confirms that all freshly prepared
spray-dried samples were amorphous with the existence of amorphous drug
domains within high drug-loaded samples.
Conclusion Using temperature–composition phase diagrams to probe the rel-
evance of temperature and drug composition in specific polymer candidates facili-
tates polymer screening for the purpose of formulating solid dispersions.

Introduction
Amorphous drug forms provide a useful method of
enhancing the dissolution performance of poorly water-
soluble drugs; however, they are inherently unstable. One
way to overcome this is to disperse amorphous drug mol-
ecules, at a molecular level, into polymeric matrices,[1,2] that
is, through the development of drug delivery systems
wherein the drug (solute) is completely dissolved into the
polymer (solid solvent).[3,4] In such cases, drug–polymer
miscibility has been shown to be highly important in
understanding the physical stability of these systems.[5–7]
Consequently, the solubility or miscibility of drug within
polymeric matrices has been gaining increasing interest.[8]
Furthermore, consideration of thermodynamic miscibility
is gaining significant relevance in the development of
molecular dispersions that perform consistently (with
regard to physical stability) over pharmaceutical relevant
time scales.
While numerous approaches have been used to study the
thermodynamic mixing of polymer–polymer blends,[9,10]
there are fewer articles available with regard to pharmaceu-
tical drug–polymer systems.[11,12] Although the measure-
ment of drug solubility within a low molecular weight
solvent is reasonably straightforward, it is experimentally
difficult, because of viscosity effects, to measure the
true solubility of crystalline drug in polymeric carriers,
especially across a range of pharmaceutical relevant

256 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al.
temperatures. A method of doing so, published by Tao et al.
involved ball milling or cryomilling to maximise the interac-
tion between drug and polymer particles, thus improving the
accuracy in determining the dissolution point of drug within
the polymeric matrix.[13] This method has been further inves-
tigated and utilised to determine important thermodynamic
parameters, such as the Flory–Huggins (F–H) interaction
parameter (χ) and theoretical solubility of the drug in a
polymer at defined temperatures.[14,15] A more recent publica-
tion by our group has reported a thermal method that can be
used in combination with F–H theory to construct the full
temperature–composition phase diagram. Moreover, we have
shown the temperature dependence of the F–H interaction
parameter, χ, and defined the level of drug saturation within
specific polymeric matrices across a wide temperature
range.[16] Knowledge of this information certainly advances
our understanding of the physical stability in respect to ther-
modynamic miscibility as a function of temperature and
drug composition.
The objective of this current article was to extend this
work through construction of temperature–composition
phase diagrams of an amorphous drug in the presence of dif-
ferent polymeric carriers. Once complete, we wanted to use
this information as a pre-formulation tool to rank polymers
in terms of suitability to formulate molecular drug disper-
sions. Moreover, based upon the obtained thermodynamic
information of drug–polymer system through the phase
diagram, we might be starting to understand the effects of
different processing techniques, namely hot-melt extrusion
(HME) and spray drying, in the production of amorphous
solid dispersion. The model drug selected in this study was
felodipine (FD). Three polymeric candidates, namely poly-
vinylpyrrolidone (PVP grade K15 (PVPK15)), polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus,
BASF, Ludwigshafen, Germany) and hydroxypropyl methyl-
cellulose acetate succinate (HPMCAS grade HF (HPMCAS-
HF, Shin-Etsu, Tokyo, Japan)), were used as model carriers.
Materials and Methods
Materials
Felodipine with a purity of 99.9% was a gift from Eli Lilly
(Kinsale, Ireland). HPMCAS-HF was supplied by Shin-Etsu
Chemical Co. (brand name AQOAT). Polyvinyl caprolactam-
polyvinyl acetate-polyethylene glycol graft copolymer (brand
name Soluplus) was a generous gift from BASF Chemical Co.
Methods
Preparation of amorphous solid dispersion
systems via hot-melt extrusion
Amorphous solid dispersions of FD with polymeric carriers
(PVPK15, Soluplus or HPMCAS) were manufactured via
© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Spray-dried and HME solid dispersions
HME using a co-rotating twin-screw extruder (HAAKE
Minilab, Thermo Fisher Scientific, Loughborough, UK).
Three different drug loadings were prepared (20%, 50% and
80% w/w, respectively). To achieve an accurate drug to
polymer ratio through the extrusion, a ball mill mixer
(Retsch, model MM200, Haan, Germany) was used to break
down the particle size of the polymer granules, followed by
dry mixing with drug using a mortar and pestle. The pre-
pared mixtures were then extruded at a temperature of
140°C and a screw speed of 100 rpm. Melt extrudates were
milled and passed through a 250–180 μm sieve, and stored
in a desiccator over silica gel at a temperature of 20°C. A
suitable quantity of the physical mixtures was kept for
analysis to compare with corresponding extrudates.
Preparation of amorphous solid dispersion
systems via spray drying
Amorphous FD solid dispersion samples were manufac-
tured by spray drying (Büchi Laboratoriums-Technik AG,
Flawil, Switzerland) using HPMCAS, Soluplus and PVPK15.
Three different drug loadings were prepared (20%, 50% and
80% w/w, respectively). In a typical procedure, a total of 1 g
of drug and polymer were dissolved in 250 ml of solvent
water solution (acetone 95% v/v, water 5% v/v for
HPMCAS system and ethanol 95% v/v, water 5% v/v for
Soluplus and PVPK15 systems). The spray drying param-
eters were set as follows: airflow of 670 Nl/h per pump
setting of 30% (9 ml/min), aspirator setting of 100% (−50
to −60 mbar), inlet temperature 85°C, outlet temperature
between 56 and 59°C. The inlet temperature was selected to
be slightly above the boiling point of the solvent and ensure
the quick drying of the droplets. Before spray drying, the
dissolved solutions were sonicated for a suitable length of
time to ensure a complete dissolution of FD into the poly-
meric solution. The solubility of FD in the solvent mixture
was checked by measuring 50 mg of FD into amber
ampoules containing 10 ml of the solvent mixture. The
drug was freely soluble indicating solubility was above
5 mg/ml, which was sufficient for spray drying.
Sample preparation for construction of binary
phase diagram
The method of preparing a ball-milled physical mixture of
drug and polymer was adapted from a previous publication
described by our group.[16] Drug and polymer mixtures with
different compositions were firstly mixed using a mortar
and pestle, followed by a ball mill mixer (Retsch, model
MM200). In a typical procedure, drug and polymer powder
(sample total 1 g) was milled with one stainless steel ball at
20 Hz. A predefined milling time of 2 min was chosen,
which was subsequently followed by a 2-min interval. This
257
Spray-dried and HME solid dispersions
procedure was repeated to a maximum of ten mill-stop
cycles (max 20-min mill time) to maximise the drug–
polymer interaction.
Thermal analysis
A modulated differential scanning calorimetry (MDSC,
Q100, TA Instrument, Elstree, UK) was used throughout.
Indium and zinc were used to standardise the cell tempera-
ture, and dry nitrogen was used as the purge gas. A 5–10 mg
powder sample was packed into an aluminium pan with a
lid. A pinhole was made in the lid to allow the moisture to
escape. Before conducting the experiments, all ball-milled
samples were dried in a vacuum oven for at least 24 h prior
and after the milling. Melting depression experiments were
conducted at heating rate of 1°C/min, 20–200°C. The end-
point of the melting endothermic peak was calculated from
the intercept point of the endothermic trace and the post-
melting baseline.
A heat–cool–heat cycle was also used to characterise the
solid-state properties of freshly prepared amorphous solid
dispersions. The parameters used for these experiments
were as follows: heating range, 0–170°C; heating rate, 5°C/
min; period of modulation, 60 s; and amplitude of modula-
tion, 0.8°C. The temperature of the glass transition was
measured at the midpoint of the reversing heat flow signal,
and the temperature of recrystallisation or melting event
was measured from the total heat flow signal. The non-
reversing heat flow signal was also used to confirm several
thermal events, such as recrystallisation and enthalpic
recovery.
Thermogravimetric analysis (TGA) was used to examine
the thermal stability of pharmaceutical ingredients. Experi-
ments were conducted using a Thermal Advantage Model
Q500 TGA (TA Instruments). Samples were heated at a rate
of 10°C/min, 20–400°C, and the % mass remaining was
plotted as a function of temperature. Isothermal studies
were also conducted for FD and polymeric ingredients by
heating samples up to a particular temperature of interest
(150–160°C in this study), and holding at this temperature
for at least 1 h. In all TGA experiments, nitrogen gas was
used as the purge gas (flow rate 60 ml/min) in the furnace
chamber.
Powder X-ray diffraction
Powder X-ray diffraction (PXRD) measurements were per-
formed on individual ingredients, drug–polymer physical
mixtures and solid dispersions prepared by spray drying or
HME. The powders were packed onto a standard glass
sample holder using a Rigaku Miniflex II desktop X-ray
diffractometer (Rigaku, Woodlands, TX, USA) with Bragg–
Brentano geometry. The PXRD patterns were recorded
3–40° on the 2θ scale, using a step width of 0.01° 2θ and
258 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al.
scan rate of 1° 2θ/min. Details of machine calibration and
data processing were described in a previous publication.[16]
Fourier transform infrared spectroscopy
Infrared spectra were recorded on a Jasco-400 FT-IR spec-
trometer (Jasco, Easton, MD, USA) incorporating version 2
of the Jasco Spectra Manager software. Powdered samples
with a particle size ranging 90–180 μm were compressed
into 0.2-g potassium bromide discs at a weight ratio of 1%.
Discs were prepared by compression under 8–10 tons for
2 min. Physical mixtures at the same drug–polymer compo-
sitions were also examined to differentiate drug–polymer
interactions. All experiments were recorded in absorbance
mode of 350–5000/cm using a resolution of 2/cm and accu-
mulation of data across 64 scans.
Statistical analysis
For MDSC analysis, the effect of drug loading on the Tg
values of the system was statistically analysed using one-way
analysis of variance. Individual differences in each treat-
ment group were identified using Tukey’s post-hoc test,
wherein P < 0.05 denoted significance.
Results and Discussion
Characterisation of raw polymers
and physical mixture of
felodipine–polymer systems
The unprocessed raw polymer Soluplus, PVPK15 and
HPMCAS-HF were characterised by MDSC (Figure S1). All
three polymers were amorphous with distinctive glass tran-
sitions evident at approximately 85 ± 1.5°C for Soluplus,
120 ± 0.5°C for PVPK15 and 122 ± 1.2°C for HPMCAS-HF.
Quench-cooled FD was characterised using the same
MDSC procedure, and the glass transition temperature was
recorded at 46 ± 1°C. Physical mixtures of three different
polymers with crystalline drug FD were also characterised
by PXRD (Figures S2–S4) The diffractogram of unpro-
cessed FD exhibits well-defined Bragg peaks, characteristic
of crystalline form I,[17] which is the most stable polymorph
at room temperature and atmospheric pressure. The PXRD
pattern of crystalline drug–polymer physical mixtures was
characterised by a halo contribution underneath the Bragg
peaks, which is from amorphous polymer contained within
the mixture; the amorphous polymer and its area increase
as the crystalline drug composition decreases. Fourier trans-
form infrared spectroscopy (FTIR) was also used as a com-
plementary technique to identify the physical and chemical
nature of crystalline FD, amorphous FD, Soluplus, PVPK15
and HPMCAS-HF (Figures S5 and S6).
Potential molecular interactions within crystalline form
I of FD are shown in Figure 1. The 3D structures were
Yiwei Tian et al.
Figure 1 Molecular interactions within felodipine form I, a coopera-
tion of two methyl ester and two ethyl ester groups connected via
amine groups, the hydrogen atom being shared between methyl ester
and ethyl ester groups.
constructed and optimised using ACDLabs 12.0 software
(Toronto, Canada). Crystal packing in form I of crystalline
FD may result in hydrogen bonding among secondary
amine group, methyl carbonyl group and ethyl carbonyl
group. Using FTIR (Figures S5–S6), the hydrogen bonded
N-H group in crystalline form I gives a stretching band at
3370/cm, which is a red-shifted relative to the
non-hydrogen bonded N-H group at 3420/cm.[18] In the
1600–1800 region of FTIR spectra, this hydrogen bonding
also causes a red shift of the C=O stretching band. The dis-
tinctive absorbance peak for C=O stretching in crystalline
form I was recorded at 1695/cm. Relative to crystalline FD,
the red-shifted N-H and C=O groups within amorphous
FD were observed at 3339/cm and 1684/cm, respectively.
There were also absorbance peaks recorded at 3420/cm and
1698/cm attributable to the non-hydrogen bonded amine
group in the dihydropyridine ring and carbonyl group in
the ethyl ester, respectively. The occurrence of larger red-
shifted bands in the amorphous form of FD relative to crys-
talline form I is indicative of enhancement of hydrogen
bonding between the nitrogen in the dihydropyridine ring
and the oxygen in the carbonyl group of FD. The shared
hydrogen bonding between N-H and C=O in form I is
replaced with single hydrogen bonding between N-H of the
dihydropyridine ring and C=O of the methyl ester, whereas
the C=O of ethyl ester group is free of hydrogen bonding in
the amorphous FD (1698/cm) because of stronger shielding
relative to methyl ester. For polymer spectra, in 4000–
2500/cm region, Soluplus and HPMCAS-HF both show a
broad absorbance peak at 3700–3400/cm associated with
the O–H stretching. There is no hydrogen donor in PVP.
In the 2000–1500/cm region, a single, sharp carbonyl peak
© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Spray-dried and HME solid dispersions
was observed at 1744/cm for HPMCAS and 1667/cm for
PVPK15, respectively, while for Soluplus peaks at 1739/cm
and 1638/cm are associated with the carbonyl groups in the
vinyl acetate and caprolactam segments.[19] These specified
groups could potentially interact with drug molecules
within the solid dispersion and significantly influence the
performance of the final product.
Construction of the phase diagram of
felodipine in different polymeric matrices
Crystalline FD exists in two polymorphs: form I with a
melting temperature of 140–145°C and enthalpy of fusion
of 31.5 kJ/mol; and form II with melting temperature of
130–135°C and enthalpy of fusion of 26.7 kJ/mol.[17] FD
was supplied as form I (verified from differential scanning
calorimetry (DSC) and PXRD analyses), and there was no
detectable polymorphism conversion in any of the pro-
cesses, neither in the ball mill/mixing nor during slow
heating in the DSC. It was noted that the ball-milled
sample presented less intense Bragg peaks which, when
compared with the unprocessed crystalline FD, were
broadened. The relationship of Tend and composition of
FD in the mixture is presented in Table 1. The Tend is
defined as the endset melting point of FD. Determination
of the melting endset temperature of FD in PVPK15 or
Soluplus was not possible at wt% FD < 0.7. Below this
level, the drug dissolved into the polymer during slow
heating and the dissolution event were very broad, result-
ing in an inaccurate determination. With the same
assumption that the upper critical solution temperature
exists in the system of FD–PVPK15, the linear relationship
of interaction parameter χ vs 1/T was applied (Figure 2a).
At increased temperature, there is a significant deviation
from linearity; however, given that the χ value is less than
would be predicted by the linear relationship, the resultant
phase diagrams would in many cases be an underestima-
tion of miscibility.[16] The plots of free energy of mixing
(ΔGmix/RT) and temperature–composition phase diagram
of FD–PVPK15 were also constructed (Figure 2b and 2c).
The phase diagrams of systems FD–HPMCAS and
FD–Soluplus constructed from previous publication were
also used in this work (Figure 3a and 3b; permission
required to use this figure).[16] It is clear that the level of
miscibility between FD and PVPK15 is much higher than
FD–HPMCAS and FD–Soluplus. For example, at a tem-
perature of 25°C, 0.1 w/w of FD may be fully dissolved
into the PVPK15 based on this constructed phase diagram,
which is very close to the result reported previously.[20]
Additionally, for the metastable region of this system, a
value of up to 0.25 w/w of FD may be locally stabilised
within the polymer PVPK15 (spinodal curve) at 25°C. This
information, when coupled with the maximum solubility
259
Spray-dried and HME solid dispersions Yiwei Tian et al.

Table 1 Dissolution temperature endpoint measured by DSC for felodipine with PVPK15, Soluplus and HPMCAS systems; n = 3, represents as
average ± standard deviation

w/w felodipine Tend (°C) with PVPK15 Tend (°C) with Soluplus Tend (°C) with HPMCAS

0.95 141.47 ± 0.0 141.55 ± 0.05 141.1 ± 0.1

0.9 140.50 ± 0.12 140.92 ± 0.2 140.7 ± 0.05
0.85 139.25 ± 0.15 140.11 ± 0.5 140.0 ± 0.02
0.8 137.29 ± 0.21 138.43 ± 0.2 139.62 ± 0.3
0.75 134.93 ± 0.05 136.38 ± 0.0 139.01 ± 0.1
0.7 131.99 ± 0.2 135.05 ± 0.2 138.65 ± 0.5
0.65 a a
138.04 ± 0.8
0.6 a a
137.49 ± 1.1
0.55 a a
137.05 ± 0.5

DSC, differential scanning calorimetry; HPMCAS, hydroxypropyl methylcellulose acetate succinate; PVPK15, PVP grade K15. aDetermination is not
possible because of the weakness of the thermal event.

and metastability values for HPMCAS (0.001 and 0.6,
respectively) and FD–Soluplus (0.02 and 3.69, respec-
tively), provides a means of ranking polymers against mis-
cibility and solubility at different temperatures.
Hot-melt extrusion and spray drying
Undoubtedly, the most important factor when manufactur-
ing drug delivery platforms through an HME process is
ensuring thermal stability of the active pharmaceutical
ingredient and excipients. TGA provides general informa-
tion relating to the thermal stability of pharmaceutical
ingredients in this regard. In this study, the thermal degra-
dation temperatures were measured for each individual
ingredient, and they were 200°C for FD, 250°C for Soluplus,
380–390°C for PVP and 200°C for HPMCAS.
The principle of this study is to examine the use of
temperature–composition phase diagram to evaluate the
ability of preparing fully amorphous solid dispersions;
therefore, the effect of process parameters is not included in
our considerations. For HME, the temperature was chosen
based on the lowest temperature where the mixture could
be extruded (140°C) without a significant torque output
(20–80 N.cm). This would reduce the effects of shearing
stress, and thus reduce the possibility of mechanical degra-
dation.[21] A regular rod-shaped melt extrudate with smooth
surface was obtained in all cases. From visual inspection,
the 20% w/w and 50% w/w FD-loaded extrudates were
transparent, while, 80% w/w drug-loaded melt extrudates
were opaque.
To compare HME and spray drying, the same drug–
polymer combinations were also prepared by spray drying
at the same drug compositions. TGA studies show that the
moisture/solvent contents in spray-dried samples were
approximately 3–5%, while no moisture content was
detected in melt-extruded samples. PXRD, FTIR and MDSC
were used to characterise HME and spray-dried solid dis-
persions immediately after preparation.
Powder X-ray diffraction of amorphous
solid dispersions
Figure 4a–4c shows the PXRD patterns of drug–polymer
solid dispersions prepared via the two different techniques.
The absence of Bragg peaks in the PXRD profiles indicates
that almost all the samples were X-ray amorphous except
melt-extruded 80% FD–HPMCAS, which features a small
Bragg peak recorded at 21.56°2θ, a peak characteristic of
crystalline FD form I suggesting the existence of crystalline
content within high drug-loaded melt extrudates. In con-
trast, samples prepared by spray drying were all XRD amor-
phous. As expected, these results correlate with earlier work
wherein we described FD–HPMCAS combination as having
the weakest interaction (positive χ value) indicative of
unfavourable mixing. However, the results obtained from
PXRD cannot be used in isolation to define the physical
nature of these solids, since an X-ray amorphous state
(nanocrystalline) is achievable through grinding, and it is
often observed as a broad halo peak in PXRD.[22] In such
systems, it is recommended that further characterisation be
conducted using complementary techniques (c).
Modulated differential scanning calorimetry
analysis on amorphous solid dispersions
MDSC was used to further study the nature of solid disper-
sions prepared via HME and spray drying. The MDSC
results for FD–polymer systems are summarised in Table 2
(standard deviations can be found in Table S1), as well as
the theoretical glass transition temperature for each binary
mixture Tg,mix, calculated using the Couchman–Karasz (CK)
model, as shown in Equation 1 and 2:
w1Tg 1 + Kw2Tg 2
Tg ,mix = (1)
w1 + Kw2
where, w1,2 and Tg,1,2 are the weight fraction and glass transi-
tion temperature of component one and two as binary

260 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al. Spray-dried and HME solid dispersions

(a) –0.5

–1

–1.5
x

y = 3679.2x – 10.383
–2 R2 = 0.9084

–2.5

–3
0.0024 0.00241 0.00242 0.00243 0.00244 0.00245 0.00246 0.00247 0.00248
1/T per K
(b) 0.6 0°C
25°C
50°C
0.4 80°C
100°C
120°C
0.2

0
ΔGmix/RT

–0.2

–0.4

–0.6

–0.8
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Volume fraction (φ)
(c) 145

125

105
Temperature (°C)

Solubility FD in PVPK15
Spinodal FD in PVPK15
85 System Tg
UCST

65

45

25
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Weight fraction of drug

Figure 2 (a) Variation of the interaction parameter χ as a function of temperature. The solid line represents the line of best fit to experimental
data, (b) ΔGmix/RT as function of drug volume fraction for felodipine and PVPK15, and (c) binary temperature–composition phase diagram for
felodipine and PVPK15. UCST, upper critical solution temperature.

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274 261
Spray-dried and HME solid dispersions Yiwei Tian et al.

(a) 145

125

Temperature (°C)
105 Solubility FD in HPMCAS
Spinodal FD in HPMCAS
85 System Tg
UCST
65

45

25
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Weight fraction of drug

(b) 145

125
Temperature (°C)

105

Solubility FD in Soluplus
85 Spinodal FD in Soluplus
System Tg
65 UCST

45

25
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Weight fraction of drug

Figure 3 Binary temperature–composition phase diagram for (a) felodipine and hydroxypropyl methylcellulose acetate succinate, and (b) felodipine
and Soluplus, adapted from previous publication[16] (permission required). UCST, upper critical solution temperature.

system. The constant K in this equation may be calculated
from the corresponding heat capacity change of the pure
components at the glass transition:
ΔCp1
K=
ΔCp2
The heat capacity change (ΔCp) for pure amorphous FD
at the Tg was 0.39 J/g°C, and for Soluplus, PVPK15 and
HPMCAS-HF equal to 0.21 J/g°C, 0.35 J/g°C and 0.32 J/
g°C, respectively. As previously described in the Methods
section, the glass transition temperature was measured
twice through continued heat–cool–heat cycles; therefore, a
more homogeneous mixture was expected after the first
heating. For systems containing 20% FD, the solid disper-
sions exhibited amorphous features with only one inter-
mediate glass transition within the temperature range
between the two pure components, irrespective to the type
(2)
of process technique used for manufacture (Figure 5).
There was almost no variation around this Tg as a function
of heating cycle, suggesting that the optimum mixing
(molecular level) between 20% drug and polymer was
achieved during spray dry or melt extrusion.[23] Further-
more, comparing the Tg values of 20% FD spray-dried solid
dispersion with the values predicted by CK model, only
FD–PVPK15 prepared by spray drying was higher than that

262 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al. Spray-dried and HME solid dispersions

(a) predicted by the CK model, while the values of the other

spray-dried samples were lower than CK predictions
Intensity (CPS)

(∼10°C). It suggests that the drug–polymer interactions

within the 20% FD–PVPK15 spray-dried sample may be
stronger than that achievable through ideal mixing, thus
20% FD + PVPK15 S P resulting in a positive experimental deviation.[18] In con-
50% FD + PVPK15 S P
80% FD + PVPK15 S P trast, Tg measured for 20% FD melt-extruded samples was
5 10 15 20 25 30 35 40 in reasonable agreement with the values predicted by the
CK model.
MDSC thermograms for 50% FD–polymer solid disper-
Intensity (CPS)

sions prepared by melt extrusion and spray drying are

shown in Figures 6 and 7. It is clearly shown that samples
containing PVPK15 and Soluplus possess one Tg after melt
20% FD + PVPK15 HME extrusion, while for the 50% FD–HPMCAS melt extrudate,
50% FD + PVPK15 HME
80% FD + PVPK15 HME a main glass transition (70°C) was observed together with
5 10 15 20 25 30 35 40 a subtle endothermic step at 112°C. Considering the Tg of
2θ
50%FD–HPMCAS occurred at 75°C (second heating) or
(b)
87°C (CK model), it is very likely that this second endo-
Intensity (CPS)

thermic step belongs to the glass transition of a polymer-

rich phase.[24] This second Tg was absent on the second
heating with the presence of one Tg (75°C). These results
20% FD + HF S P
50% FD + HF S P
suggest that 50% FD–HPMCAS sample prepared by melt
80% FD + HF S P extrusion is at least partially phase-separated, indicated by
5 10 15 20 25 30 35 40 the presence of more than one glass transition event
during the first heating. In contrast, melt extrudates of
Intensity (CPS)

50% FD–PVPK15 and 50% FD–Soluplus exhibited one

Tg.
For 50% FD–polymer spray-dried samples (Figure 7),
20% FD + HF HME several thermal events were observed on the first heating,
50% FD + HF HME
80% FD + HF HME but all of them appear to have a glass transition-like event
5 10 15 20 25 30 35 40 around temperature 50–90°C, which is higher than the
2θ
value of pure amorphous FD (45°C). This is indicative of
(c)
an intermixed amorphous drug–polymer solid disper-
Intensity (CPS)

sion (intermediate Tg). However, when the temperature

increases, a broad exothermic plateau-like trace was
observed in all three 50% FD–polymer spray-dried samples,
20% FD + Solu S P
with no distinctive sign of melting events at higher tem-
50% FD + Solu S P
80% FD + Solu S P
peratures (140–145°C). The reverse heat capacity (Cp) in
5 10 15 20 25 30 35 40 the same region was plotted to help understand the nature
of the exothermic event. Relative to the first heat cycle, the
reversing Cp values in the second heating are higher, espe-
Intensity (CPS)

cially in the temperature range where the exothermic

plateau-like traces were observed (Tg–Tm). The reversing Cp
20% FD + Solu HME
of a pure amorphous mixture usually exhibits a significant
50% FD + Solu HME increase as it goes through the glass transition because of
80% FD + Solu HME
the dramatic increase of its enthalpy and entropy in the
5 10 15 20 25 30 35 40 super-cooled liquid state,[25] while for the crystalline form,
2θ
the reversing Cp remains constant until the melting tem-
Figure 4 Normalised powder X-ray diffraction patterns of felodipine perature.[26] Therefore, in this case, the lower Cp in the first
solid dispersions containing (a) PVPK15, (b) hydroxypropyl methyl- heating, following the glass transition and the gradual
cellulose acetate succinate grade HF and (c) Soluplus prepared by hot- decrease of the Cp in the temperature range 70–120°C (for
melt extrusion and spray drying; arrow identifies a characteristic Bragg FD–Soluplus and FD–HPMCAS, respectively), suggests that
peak associated with form I of crystalline felodipine. the crystalline FD content within the spray-dried mixture

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274 263
Spray-dried and HME solid dispersions Yiwei Tian et al.

Table 2 Glass transition temperatures (midpoint) for felodipine–polymer solid dispersions prepared by spray drying and hot-melt extrusion; values
presented are the average of triplicates (n = 3)

Measured Measured Tg,mix predicted by Measured Tm on

wt% FD Tg cycle1 (°C) Tg cycle2 (°C) CK model (°C) cycle1 (°C)

Spray-dried
Soluplus 20 71.7 70.2 80.2 —
50 53.9 58.9 70.9 —
80 53.9/85.79 48.8 57.6 138.4 (ΔH = 0.1 J/g)
PVPK15 20 109.1 107.8 106.2 —
50 50.5/90.6 81.5 84.4 —
80 43.35/103.9 56.77 61.3 —
HPMCAS-HF 20 90.6 87.5 108.8 —
50 57.9 58.5/121.7 87.1 —
80 49.68 49.07 62.9 139.5 (ΔH = 1.7 J/g)
Melt extruded
Soluplus 20 77.6 80 80.2 —
50 58.6 62.8 70.9 —
80 46.5/74.2 47.6 57.6 135.7 (ΔH = 1.9 J/g)
PVPK15 20 100.5 103.9 106.2 —
50 87.35 89 84.4 —
80 51.5/79.5/99.3 52.5 61.3 134.79 (ΔH = 1.1 J/g)
HPMCAS-HF 20 106.5 107.7 108.8 —
50 70/112.2 75.9 87 —
80 47.71/124.43 50 62.9 136.8 (ΔH = 9.6 J/g)

CK, Couchman–Karasz; FD, felodipine; HPMCAS, hydroxypropyl methylcellulose acetate succinate; PVPK15, PVP grade K15. If two glass transition
events were recorded, both values are presented in the table as Tg1/Tg2; ‘—’ refers to non-detectable.

20% FD + Soluplus_HME.003
20% FD + PVPK15_HME.001
20% FD + HPMCAS_HME.001
20% FD + Soluplus_SP.txt
20% FD + PVPK15_SP.txt
20% FD + HPMCAS_SP.txt

Exo Up
Rev heat flow (W/g)

20 70 120
Temperature (°C) Universal V4.3A
TA Instruments

Figure 5 Modulated differential scanning calorimetry thermograms of melt-extruded (top three) and spray-dried (bottom three) samples contain-
ing 20 w/w% felodipine with hydroxypropyl methylcellulose acetate succinate grade HF (dash dot line), PVPK15 (dash line) and Soluplus (solid line);
arrow identifies the glass transition of each sample, and the trace of second heating ramp sits below the first heating for each sample.

increases as the temperature increases. This phenomenon sample varies depending upon the polymeric carrier used.
may suggest that although an obvious glass transition was Therefore, if certain temperatures are reached (Tg), the
observed on all 50% FD–polymer spray-dried samples, the reorganisation of amorphous FD into small crystals may
level of drug disorder or distribution in the amorphous occur. And the potential of disordered amorphous FD to

264 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al. Spray-dried and HME solid dispersions

50% FD + Soluplus_HME.001
50% FD + PVPK15_HME.001
50% FD + HPMCAS_HME.004

Exo Up
Rev heat flow (W/g)

100 105 110 115 120 125

20 40 60 80 100 120 140 160

Temperature (°C) Universal V4.3A
TA Instruments

Figure 6 Modulated differential scanning calorimetry thermograms of melt-extruded samples containing 50% w/w felodipine with hydroxypropyl
methylcellulose acetate succinate grade HF (dash dot line), PVPK15 (dash line) and Soluplus (solid line); the trace of second heating sits below the
first heating for each sample; arrow indicates the expansion of second Tg on the first heating of 50 % w/w felodipine–hydroxypropyl methylcellulose
acetate succinate melt extrudate.

recrystallise during heating may be highly polymer depend-
ent. In particular, the slow heating within the MDSC would
provide sufficient time and energy for drug molecular
rearrangement or recrystallisation in spray-dried sample
FD–HPMCAS and FD–Soluplus systems, characterised by
the presence of exothermic events above the glass transition
temperature.
It is also very interesting to note the absence of melting fol-
lowing recrystallisation and the gradual increase in the
reversing Cp, which may suggest dissolution of recrystallised
FD into the polymeric matrix at increased temperature (110–
140°C). The dissolution of crystalline drug into polymeric
matrices below their melting point is in a good agreement
with our theoretical predictions provided by drug–
temperature phase diagrams of these materials (Figures 2 and
3). More specifically, the dissolution temperatures of 1 : 1
(50% w/w) FD : polymeric matrix varied depending upon
polymer type, but were approximately 90°C for PVPK15,
120°C for Soluplus and 125°C for HPMCAS, which is in
good agreement with the temperature at which the reversing
Cp starts to increase (Figure 7). It is also noted that a slight
variation in the temperature of dissolution was predicted by
theoretical calculations relative to the results from MDSC.
This may be attributed to the heating rate used in the DSC.[9]
A rate of 1°C/min was used for solubility calculations and
5°C/min for MDSC experiments.
MDSC results are shown in Figure 8 for 80%
FD–polymer melt extrudates. All samples exhibit a glass
transition at a temperature 45–50°C and a melting peak in
the range 134–136°C, with varying values of enthalpy of
fusion (shown in Table 2). The values for enthalpy of fusion
collected on the first heating were in the following order:
FD–PVPK15 < FD–Soluplus < FD–HPMCAS. Additionally,
several thermal events were observed in samples 80%
FD–PVPK15 and 80% FD–Soluplus between the Tg of pure
amorphous FD (45°C) and polymeric carrier (120°C for
PVPK15 and 85°C for Soluplus). This suggests that, beside a
small level of residual crystalline material, the amorphous
drug distribution within the extrudates is also not molecu-
larly homogeneous. This uneven distribution may result in
a poor physical stability as drug-rich domains would easily
reorganise into nuclei and trigger the spontaneous growth
of crystalline drug.
For 80% FD spray-dried solid dispersions containing
Soluplus and HPMCAS (Figure 9a), a distinctive glass tran-
sition in the range 40–50°C and a melting event in the range
135–140°C were observed. The heat of fusion for the com-
bination of FD–Soluplus (0.06 ± 0.05 J/g) is smaller than
FD–HPMCAS (1.7 J/g). However, most notable from the
MDSC data is that the spray-dried sample containing 80%
FD–PVPK15 exhibited a glass transition, an exothermic
recrystallisation and a broad melting event in the first
MDSC scan (Figure 9b). The behaviour of this particular
spray-dried sample during heating was very similar to the
spray-dried sample containing 50% FD, wherein similar
recrystallisation and broad melting were observed
(Figure 7). As described previously, such an exothermic,
following the glass transition, could be attributed to a less

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274 265
Spray-dried and HME solid dispersions Yiwei Tian et al.

50% FD + HPMCAS
50felo50HPMCAS_SP_first.txt
1.8 50felo50HPMCAS_SP_first.txt
50felo50HPMCAS_SP_second.txt 50felo50HPMCAS_SP_second.txt

1.6
ΔCp first and second heating

Exo Up 1.4

Rev Cp (J/(g·°C))
Rev heat flow (W/g)

1.2

1.0

0.8

0.6
10 30 50 70 90 110 130 150 10 30 50 70 90 110 130 150
Temperature (°C) Universal V4.7A TA Temperature (°C) Universal V4.7A TA

50% FD + PVPK15
50% FD + PVP_SP_first.txt 2.0 50% FD + PVP_SP_first.txt
50% FD + PVP_SP_second.txt 50% FD + PVP_SP_second.txt

1.5
Exo Up
Rev Cp (J/(g·°C))

ΔCp first and second heating

Rev heat flow (W/g)

1.0

0.5

0.0
10 30 50 70 90 110 130 150 10 30 50 70 90 110 130 150
Temperature (°C) Universal V4.7A TA Temperature (°C) Universal V4.7A TA

50% FD + Soluplus
50% FD + Soluplus_SP_first.txt
2.0 50% FD + Soluplus_SP_first.txt
50% FD + Soluplus_SP_second.txt 50% FD + Soluplus_SP_second.txt

ΔCp first and second heating

Rev Cp (J/(g·°C))

Exo Up 1.5
Rev heat flow (W/g)

1.0

0.5
10 30 50 70 90 110 130 150 10 30 50 70 90 110 130 150
Temperature (°C) Universal V4.7A TA Temperature (°C) Universal V4.7A TA

Figure 7 The reversing heat flow (left side) and reversing heat capacity (right side) signals of spray-dried samples containing 50% w/w felodipine.
The first heating ramp is represented as a dashed line, and the second heating ramp is represented as a solid line.

266 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al.
Exo Up
Rev heat flow (W/g)
10 30 50
Figure 8 Modulated differential scanning calorimetry thermograms of melt-extruded samples containing 80% felodipine with hydroxypropyl
methylcellulose acetate succinate grade HF (dash dot line), PVPK15 (dash line) and Soluplus (solid line); the trace of second heating sits below the
first heating for each sample.
disordered amorphous system generated via spray drying,
which could reorganise and recrystallise during heating.
With high drug loadings, the subtle exothermic or endo-
thermic event becomes easier to identify, as shown in the
non-reversing heat flow signals in Figure 9b. In addition, it
also demonstrates that by using spray drying with the same
parameters, a fully amorphous phase of 80% FD–PVPK15
may be generated, even though this type of system is not
capable of remaining stable during heating. In contrast,
for the combinations of 80% FD–HPMCAS and 80%
FD–Soluplus, fully amorphous materials were not achieved
using spray dry using the same process parameters. The
MDSC results for 20%, 50% and 80% FD–polymer systems
prepared by both melt extrusion and spray drying demon-
strate that the behaviour of different polymers and drug
loading in the preparation of amorphous FD solid disper-
sions is varied, irrespective of the preparation technique. In
this study, PVPK 15 has shown the greatest potential in
forming amorphous solid dispersions followed by Soluplus
and HPMCAS-HF. This ranking is in a close agreement
with the results predicted using the F–H model in that those
polymers with a more negative drug–polymer interaction
parameter (χ) and high miscibility value should be more
favourable to form the amorphous polymer/drug disper-
sion even at supersaturated drug concentrations.
Fourier transform infrared spectroscopy
It was anticipated that the physical state of drug within the
polymeric amorphous solid dispersions would vary with
© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Spray-dried and HME solid dispersions
80% FD + Soluplus_HME.003
80% FD + PVPK15_HME.001
80% FD + HPMCAS_HME.001
Tg2
70 90 110 130 150
Temperature (°C) Universal V4.3A
TA Instruments
the polymer type, drug–polymer composition, temperature
and processing technique.[27] The polymer, due to its highly
viscous nature, may retard amorphous relaxation, and thus
increase the kinetic barrier for amorphous to crystallisation
conversion. In addition, polymeric materials have been
shown to be efficient crystallisation inhibitors (miscible
binary system).[28] Several studies have provided clear evi-
dence for intermolecular interactions between drug and
polymer in solid dispersions, confirming that the existence
of such bonding is necessary to obtain a completely mis-
cible system at the molecular level. FTIR was used to
examine the intermolecular interactions between FD and
respective polymers in the solid dispersions. Previous
studies on the raw components of the dispersions had
shown that the N-H stretching position is very sensitive to
the type and strength of hydrogen bonding. In particular,
comparison of amorphous and crystalline FD confirmed
weaker hydrogen bonding in crystalline FD. Thereby, to
understand how the polymers interact with FD in the solid
dispersion, it is necessary to compare the differences in the
spectra of pure amorphous FD and FD embedded in
polymer solid dispersions. Figure 10a–10c shows IR spectra
in the N-H region of the solid dispersions FD–PVPK15,
FD–Soluplus and FD–HPMCAS, respectively (see Figure S7
for C=O region). The N-H stretching peak of amorphous
FD was observed at 3339/cm, and the C=O stretching peak
had split into two peaks at 1702 and 1684/cm. For FD
embedded in PVPK15, irrespective of the preparation tech-
nique, the N-H stretching vibration (Figure 10a) exhibited a
sharp peak at 3339/cm at an 80% drug loading, which was
267
Spray-dried and HME solid dispersions Yiwei Tian et al.

(a) 80% FD + HPMCAS_SP_first.txt

80% FD + HPMCAS_SP_second.txt
80% FD + Soluplus_SP_first.txt
80% FD + Soluplus_SP_second.txt

Exo Up

Rev heat flow (W/g)

138.38°C
0.06430J/g

10 30 50 70 90 110 130 150

Temperature (°C) Universal V4.7A

(b) 0.00 0.00

–0.02 recrystallisation

–0.05

Non-rev heat flow (W/g)

–0.04
Rev heat flow (W/g)

Melting
–0.06
–0.10
–0.08

–0.10
–0.15
Second
–0.12
first

–0.14 –0.20
0 20 40 60 80 100 120 140 160 180
Exo Up Temperature (°C) Universal V4.3A
TA Instruments

Figure 9 (a) Modulated differential scanning calorimetry thermograms of spray-dried samples containing 80% felodipine with hydroxypropyl
methylcellulose acetate succinate grade HF (dash line) and Soluplus (solid line); the trace of second heating sits below the first heating for each
sample; arrow points to the expansion of melting on the first heating of 80% felodipine–Soluplus. (b) Modulated differential scanning calorimetry
thermograms of spray-dried samples containing 80% felodipine with PVPK15, the recrystallisation and melting were clearly shown on the non-
reversing heating flow signal during first heating.

similar to the N-H stretching in amorphous FD (amor-
phous drug–drug interaction). This peak was shifted to
3290/cm as drug loading decreased to 50 and 20%. This
downward shift in the position of N-H stretching peak indi-
cates that, at lower drug loadings, a stronger drug–polymer
interaction may be formed instead of amorphous drug–
drug interactions. However, it should also be noted that for
the 50% FD–PVPK15 spray-dried sample, a peak at
3339/cm was observed, which may be attributed to the
existence of amorphous drug–drug interactions within this
particular sample, suggesting phase separation and uneven
distribution of drug in to drug–drug phases, while the
population of drug–polymer interaction (3290/cm) was
completely overlapped by the absorption peak at 3339/cm
(drug–drug interactions) when the drug loading increased
to 80%, irrespective of the process technique used.
A similar result was observed in FD–Soluplus solid dis-
persion (Figure 10b); the number of N-H stretching peaks
in solid dispersion varies as the drug concentration
increases. One clear peak at 3294/cm was observed, attribut-
able to the N-H stretching peak of FD at a concentration
of 20% w/w. This again suggests the existence of strong

268 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al. Spray-dried and HME solid dispersions

(a)
FD–PVPK15

80% FD SP
80% FD HME

50% FD SP

50% FD HME

20% FD SP
20% FD HME
3750 3550 3350 3150 2950 2750 2550
Wave numbers/cm

(b)
FD–Soluplus

80% FD SP
80% FD HME

50% FD SP

50% FD HME

20% FD SP
20% FD HME

3750 3550 3350 3150 2950 2750 2550

Wave numbers/cm

(c)
FD–HPMCAS

80% FD SP

80% FD HME

50% FD SP
50% FD HME

20% FD SP
20% FD HME

3800 3600 3400 3200 3000 2800 2600

Wave numbers/cm

Figure 10 Infrared spectra of solid dispersions showing the N-H stretching region: (a) felodipine–PVPK15 (b) felodipine–Soluplus and (c)
felodipine–HPMCAS; % represent the weight fraction of felodipine in the solid dispersion.

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274 269
Spray-dried and HME solid dispersions
Table 3 Infrared spectroscopy peak assignments for amorphous
felodipine and felodipine–polymer solid dispersion systems
Wave
Sample number/cm Assignment
Amorphous 3339 N-H, H-bonded with other drug molecules
felodipine 1701 C=O, non-H-bonded
1684 C=O, H-bonded
HPMCAS–FD 3470 OH peak, H-bonded with drug molecules
3366 N-H, H-bonded with HPMCAS
1745 ester C=O from HPMCAS
1701 C=O of felodipine, non-H-bonded
1684 C=O, H-bonded with drug molecule
Soluplus–FD 3455 free OH from Soluplus
3339 N-H, H-bonded with other drug molecule
3294 N-H, strong H-bonding with Soluplus
1749 Unbonded C=O from Soluplus
1701 C=O of felodipine, non-H-bonded
PVPK15–FD 3290 N-H, strong H-bonding with PVP
3339 N-H, H-bonded with other drug molecule
FD, felodipine; HPMCAS, hydroxypropyl methylcellulose acetate
succinate; PVP, polyvinylpyrrolidone; PVPK15, PVP grade K15.
drug–polymer interactions formed between drug and
polymer. When the drug concentration increased to 50%,
two separate peaks were recorded at 3294/cm and 3339/cm,
attributed to drug–polymer and drug–drug interactions,
respectively. The intensity of peak at 3339/cm was further
increased as the drug concentration reached 80%, which
confirms that high drug concentrations in the solid disper-
sion leads to drug–drug/polymer–drug phase separation.
It is also noted that the N-H peak at 3339/cm was
also observed in the 50% FD–Soluplus, irrespective of
the preparation technique unlike the combination
FD–PVPK15.
In contrast to FD–PVPK15 and FD–Soluplus solid dis-
persions, there was only a subtle change noted in the N-H
stretching peak of FD–HPMCAS solid dispersion, indicat-
ing that the interaction formed between N-H of FD and the
acceptor groups of HPMCAS was weaker than the interac-
tion formed in other two solid dispersions (Figure 10c).
However, it was also noted that for FD–HPMCAS, the
broad O–H stretching peak shifted downward from
3485/cm to 3470/cm. In this case, we suggest that the O–H
of HPMCAS may also act as an H-bond donor to interact
with the C=O of FD. This may replace the interaction
between N-H of FD and C=O of HPMCAS. Therefore, a
joint interaction between the O–H, C=O of HPMCAS and
C=O, N-H of FD may be formed in the solid dispersion.[29]
A summary of main peak shifts relating to FD within the
three polymer solid dispersions is shown in Table 3.
General Discussion
Although it is well accepted that melt extrusion and spray
drying are widely used to prepare amorphous drug–
270 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al.
polymer solid dispersions, and are associated with ease of
scale-up, the level of disorder of crystalline drug and homo-
geneity of drug distribution within amorphous dispersions
is not well understood.[30,31] Quantitative and qualitative
analysis of the amorphous content, as well as the differen-
tiation of amorphous and nanocrystalline solid dispersions,
is very important as it significantly influences the physical
state and final performance of drug product. Furthermore,
the effect of residual crystalline content within amorphous
solid dispersions is not easily resolved; extensive storage
studies are normally required to understand stability.
Herein, we propose a method that provides the thermody-
namic drug–polymer temperature–composition phase
diagram with the aim of probing solubility and miscibility
of a crystalline drug in a polymeric carrier. Development
of such small-scale screening tool potentially allows us to
compare the level of drug solubility and miscibility in poly-
meric materials, and directly compare how different pro-
cessing techniques affect amorphous solid dispersions.
The relevance of drug–polymer
temperature–composition phase diagrams
to the production of amorphous
solid dispersion
Freshly manufactured drug–polymer solid dispersions at
20%, 50% and 80% w/w drug loadings were characterised
using three different techniques: PXRD, MDSC and FTIR.
Obviously, there are limitations in regard to detection of
residual crystalline material within manufactured solid dis-
persions,[32] but qualitative comparison demonstrates that
using the F–H model to compare the drug–polymer inter-
action is very useful for ranking suitable polymer candi-
dates. In this study, we constructed the maximum solubility
and miscibility curves for FD–PVPK15, FD–Soluplus and
FD–HPMCAS systems. This diagram reveals important
information to aid understanding of the relevance of
temperature and drug fraction in terms of designing ther-
modynamically stable amorphous drug solid dispersion
systems. As shown in Table 4, using this tool, the physical
status of these three drug–polymer systems processed at dif-
ferent temperatures were predicted (80°C for spray drying
and 140°C for HME). Comparing the predictions with
experimental results, we may be able to better understand
both processes and better define an optimum operating
space for manufacture of stable amorphous systems. F–H
theory was also used to reveal drug–polymer interactions
wherein PVPK15 was identified as the polymeric material
capable of providing the strongest interaction with FD, fol-
lowed by Soluplus and then HPMCAS. Following manufac-
ture of solid dispersions, the characterisation results from
PXRD provided the general classification on whether the
system was X-ray amorphous or not. Bragg diffraction
Yiwei Tian et al.
Table 4 The predicted physical status of drug–polymer solid dispersion systems using constructed F–H temperature–composition phase diagrams
FD (w/w%) in PVP
Spray dry at 85°C 20 50 80
Physical status √ √ Meta
HME at 140°C 20 50 80
Physical status √ √ √ √
FD, felodipine, HME, hot-melt extrusion; PVP, polyvinylpyrrolidone. ‘√’, ‘Meta’ and ‘x’ indicates the thermodynamic status of systems as stable, meta-
stable and unstable at conditions of processing based on the phase diagrams, respectively.
peaks were only observed in 80% FD–HPMCAS-melt
extrudates, while the rest of the solid dispersions were clas-
sified as X-ray amorphous, irrespective of the drug compo-
sition and preparation technique. However, it was evident
that crystalline content was present in samples containing
80% w/w FD solid dispersions, which was classified as X-ray
amorphous (Figures 4 and 8). Melting events recorded by
MDSC for all 80% FD-melt extrudates, as well as 80%
FD–Soluplus and 80% FD–HPMCAS spray-dried samples,
confirm the presence of crystalline drug. Because of the
complex nature of amorphous solid dispersion systems,
further characterisation using alternative X-ray equipment
or spectral data treatment (pairwise distribution function)
may be required to identify information regarding molecu-
lar packing and level of disorder.[33] This suggests that F–H
phase diagrams reveal important information relating to
the solubility and miscibility of drug in different polymeric
systems, and also provide a good approximation of the
ability of a polymeric carrier to form amorphous solid
dispersions.
Production of amorphous solid dispersion
by melt extrusion or spray drying
HME is a well-known technique within the food and plastic
industries, with increasing use over the last century.
Recently, it has started to draw attention from the pharma-
ceutical industry as an emerging non-ambient drug delivery
technology capable of providing a viable method to
produce a range of delivery platforms with sustained, modi-
fied or targeted drug release profiles. In particular, over the
last decade, HME has been touted as an attractive method
for producing amorphous solid drug dispersions.
During pharmaceutical HME, the drug is typically pre-
mixed with a polymeric carrier and introduced into a
heated barrel containing rotating twin screws that convey
the mixture through a feed, mixing and melting zone.
Often, during extrusion, the drug dissolves into the polymer
melt and formed using a preselected die or other
downstream-processing equipment. The details of extru-
sion, while important, are beyond the remit of this article.
After cooling, the drug is dispersed at the micro-, nano- or
even molecular level within the formulation, which has
© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Spray-dried and HME solid dispersions
FD (w/w%) in HPMCAS FD (w/w%) in Soluplus
20 50 80 20 50 80
x x x Meta x x
20 50 80 20 50 80
√ √ √ √ √
been verified by several groups.[6,34] Additionally, it has also
been demonstrated that HME provides sufficient energy
for a high-level drug–polymer interaction to occur within
the process, as the glass transition temperatures of melt
extruded formulation were significantly higher than those
calculated using Gordon–Taylor or CK model.[6] Relative to
HME, spray drying is a well-established method for produc-
ing amorphous solid dispersions. This process is inexpen-
sive, fast and easy to scale up in the industry, which is why
it has been used in preparing numerous amorphous solid
dispersions.[35] Typically, the drug and polymer are both dis-
solved into a common solvent or co-solvent, and the
obtained solution is sprayed into tiny droplets, rapidly dried
through hot air and solidified into a solid form. The solvent
selection, the concentration of the drug and polymer in the
solvent solution, and the speed and temperature of the
drying process significantly affect the properties of formed
solid dispersions, such as the stability, dissolution rate and
water uptake.[36]
From this study, it was evident that the final physical
status of the binary mixture after manufacture was not only
affected by thermodynamic properties but also the nature
of preparation technique. For the systems under considera-
tion, spray drying provided the greatest potential to gener-
ate drug–polymer dispersions across a wider concentration
in which the sample should be thermodynamically unsta-
ble, and thus a high tendency to recrystallise (in the case of
FD–HPMCAS and FD–Soluplus; Table 4). The two tech-
niques are very different in nature; spray drying is a solvent
solution and drying process, whereas melt extrusion
involves heating and shear mixing. It is clear that for melt
extrusion, an acceptable level of flowability is essential for
material to be conveyed forward within the extrusion
barrel, yet not completely liquid since the friction between
material and screw is the driving force for this conveyance.
There is a limited window for extrusion in terms of
temperature and drug composition; however, within this
window, the viscosity of the system may prevent intimate
mixing, and hence the inability to generate fully amorphous
systems (50% and 80% high drug-loading systems; Table 4).
For example, as shown in Figures 2 and 3, the dissolution
temperature for FD into polymeric carrier increases as the
drug concentration increases. However, at high drug con-
271
Spray-dried and HME solid dispersions
centration, if the temperature exceeds the requirement for
drug dissolution, the viscosity of the mixture may be too low
to be conveyed forward. Therefore, the need for matrix flow
limits the drug loading that may be manufactured via melt
extrusion. Although the processability, in terms of drug
loading, is less than that achievable via spray drying, melt
extrusion can optimise the drug–polymer interaction as well
as amorphous drug distribution within the mixture. These
two factors may be attributed to the advanced design of twin-
screw extrusion systems. As shown in this study, a clear and
repeatable glass transition was recorded for most melt-
extruded samples at drug loadings up to 50% (Figures 5 and
6). Although multiple amorphous phases may be obtained
for high drug-loaded extrudates, no recrystallisation was
observed in any of these samples during MDSC analysis.
Moreover, no difference was observed in the N-H peak posi-
tion in solid dispersions prepared via melt extrusion;
however, the ratio of drug–drug and drug–polymer interac-
tions appears to be different especially in certain spray-dried
samples (Figure 10). For example, there was only one group
of interactions (drug–polymer at 3290/cm) observed in melt-
extruded 50% FD–PVPK15 solid dispersions compared with
two groups of interaction (3290 and 3339/cm) in the spray-
dried sample.
On the other hand, for spray drying, the reason for better
efficacy in obtaining amorphous solid dispersion maybe
due to the fact that it is a rapid drying process that is by
nature a solution of disordered drug and polymer liquid.
The two excipients are already molecularly dissolved within
the solvent. Therefore, obtaining an amorphous solid dis-
persion mainly involves rapidly drying the solvent without
inducing any nucleation or crystalline material. The selec-
tion of polymeric carrier will affect the level of solvent
retained in the sample as well as the extent of drug–polymer
interaction, which would subsequently influence the physi-
cal stability of the solid dispersion samples.[23] Essentially, if
the interaction between the residual solvent and each of the
two components is different, the solvent may induce immis-
cibility. It has also been reported that the residual moisture
will promote immiscibility and lead to extensive phase sepa-
ration.[37,38] In this study, the residual solvent in the spray-
dried samples immediately following manufacture (∼3–5%)
may potentially reduce the level of drug–polymer interac-
tions, resulting in a less disordered system, for example,
amorphous drug–drug domains distributed within the
polymeric matrix, which could lead to recrystallisation
during temperature fluctuation (Figures 7 and 9). Thus,
two types of interaction were observed in FTIR and
recrystallisation within MDSC for spray-dried samples con-
taining 50% and 80% w/w FD systems. The variation in
drug–polymer/drug–drug interaction probed by FTIR
together with the evidence from MDSC may indicate that a
less uniform drug distribution was obtained through spray
272 © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 256–274
Yiwei Tian et al.
drying, while the amorphous drug within the solid disper-
sion obtained from melt extrusion was more homogene-
ously distributed. As for quantitative analysis on the drug
distribution within the solid dispersion, this may be
achieved by further studies using higher resolution tech-
niques, such as localised thermal analysis or nanoscale IR
spectroscopy.
Importance of drug disorder and
distribution within solid dispersions
First, the principal aim of forming a drug into an amor-
phous form is to achieve a solubility advantage, as proposed
by the method of Parks and coworkers:[39]
⎛ σa ⎞
ΔG ≅ − RTln ⎜ Tc ⎟ (3)
⎝ σT ⎠
where ΔG is the free energy difference between the crystal-
line and amorphous states, σTa σTc is the solubility ratio of
amorphous to crystalline form, R is the gas constant, and T
is the temperature of interest. It can be seen that the overall
free energy difference between amorphous and crystalline
form is the reason for higher solubility. On the other hand,
this energy difference is also the major thermodynamic
driving force for the amorphous to crystalline transforma-
tion. As a formulation strategy, solid dispersions employ a
long-chain viscous polymer alongside amorphous drugs to
maintain the solubility advantage. The overall conforma-
tion of the drug molecules within the mixture will be
increased because of the presence of the polymer; thus, the
entropic barrier for amorphous drug recrystallisation will
also be significantly altered. Second, when a binary system is
formed, the drug distribution within the system becomes an
added factor to consider. To compare to its own status, the
solid dispersion of amorphous drug evenly distributed
within the amorphous polymeric matrix would exhibit a
large entropy that would be expected to show the best
physical stability. The ranking of drug–polymer systems
using F–H theory has shown good agreement to the physi-
cal state of amorphous solid dispersion in this study, result-
ing in different levels of drug disorder or drug distribution
within the polymeric matrices. This disorder and distribu-
tion would be crucial to understanding the physical stability
of amorphous solid dispersion systems.[40]
Clearly, more work is needed to understand the effects of
process parameter in terms of individual preparation tech-
niques at the level of drug disorder and distribution within
the polymeric matrices. In addition, given the complexity of
the physical state and the interactions promoted between
drug and polymer candidates during the processing, more
efforts are required in developing and validating the F–H
theory-based phase diagrams for the purpose of forming a
stable amorphous drug–polymer solid dispersions.
Yiwei Tian et al. Spray-dried and HME solid dispersions

Conclusions However, the residual solvent could potentially induce or

In this article, F–H theory has been used to predict the drug
solubility and miscibility in polymer candidates, and a
drug–polymer temperature–composition phase diagrams
were constructed for individual drug–polymer combina-
tions. Drug solubility and miscibility at defined tempera-
tures have an impact upon the drug distribution within the
polymeric matrices. Given this information, we evaluated
polymeric materials and made a direct comparison between
two commonly used solid dispersions processing techniques
(spray drying and melt extrusion). Spray drying permitted
generation of amorphous solid dispersions to be produced
across a wider drug concentration than melt extrusion.
promote drug–polymer phase separation, resulting in local
drug domains within the system. Melt extrusion provides
sufficient energy for more intimate mixing to be achieved
between drug and polymer, which may improve physical
stability. It was also confirmed that stronger drug–polymer
interactions might be generated through melt extrusion. In
conclusion, achieving molecular level miscibility and high
levels of drug distribution within the polymer is of critical
importance in the optimisation of the physical stability.
Using temperature–composition phase diagrams is an
important screening tool to probe the relevance of tempera-
ture and drug composition in specific polymer candidates
for the purpose of formulating solid dispersions.

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Supporting Information
Additional Supporting Information may
be found in the online version of this
article at the publisher’s web site:
Table S1 The thermal analysis of amor-
phous solid dispersion samples prepared
by HME and Spray drying methods (data
are shown as average of three samples ±
standard deviation).
Figure S1 Modulated differential scan-
ning calorimetry thermograms of unpro-
cessed polymers Soluplus, PVPK15 and
HPMCAS-HF, and quench-cooled amor-
phous felodipine.
Figure S2 The powder X-ray diffraction
patterns of crystalline felodipine–Soluplus
physical mixtures containing 20%, 50%
and 80% wt% of drug. Crystalline and
amorphous felodipine were also plotted
for comparison.
Figure S3 The powder X-ray diffraction
patterns of crystalline felodipine–PVPK15
physical mixtures containing 20%, 50%
and 80% wt% of drug. Crystalline and
amorphous felodipine were also plotted
for comparison.
Figure S4 The powder X-ray diffraction
patterns of crystalline felodipine–
HPMCAS-HF physical mixtures contain-
ing 20%, 50% and 80% wt% of drug.
Crystalline and amorphous felodipine
were also plotted for comparison.
Figure S5 The Fourier transform infrared
spectroscopy spectra of amorphous
felodipine, crystalline felodipine, polymer
Soluplus, HPMCAS-HF and PVPK15 at
the region of 4000–2500/cm.
Figure S6 The Fourier transform infrared
spectroscopy spectra of amorphous
felodipine, crystalline felodipine, polymer
Soluplus, HPMCAS-HF and PVPK15 at
the region of 2000–500/cm.
Figure S7 Infrared spectra of solid disper-
sion showing the C=O stretching region
(a) felodipine–PVPK15 (b) felodipine–
Soluplus and (c) felodipine–HPMCAS;
percentages represent the weight fraction
of felodipine in the solid dispersion.