Article

pubs.acs.org/molecularpharmaceutics

Construction of DrugPolymer Thermodynamic Phase Diagrams

Using FloryHuggins Interaction Theory: Identifying the Relevance
of Temperature and Drug Weight Fraction to Phase Separation
within Solid Dispersions
Yiwei Tian, Jonathan Booth, Elizabeth Meehan, David S. Jones, Shu Li, and 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, United Kingdom

Pharmaceutical Development, AstraZeneca, Silk Rd Business Park, Maccleseld, SK10 2NA

ABSTRACT: Amorphous drugpolymer solid dispersions have the potential to
enhance the dissolution performance and thus bioavailability of BCS class II drug
compounds. The principle drawback of this approach is the limited physical
stability of amorphous drug within the dispersion. Accurate determination of the
solubility and miscibility of drug in the polymer matrix is the key to the successful
design and development of such systems. In this paper, we propose a novel
method, based on FloryHuggins theory, to predict and compare the solubility
and miscibility of drug in polymeric systems. The systems chosen for this study
are (1) hydroxypropyl methylcellulose acetate succinate HF grade (HPMCASHF)felodipine (FD) and (2) Soluplus (a graft copolymer of polyvinyl
caprolactampolyvinyl acetatepolyethylene glycol)FD. Samples containing
dierent drug compositions were mixed, ball milled, and then analyzed by
dierential scanning calorimetry (DSC). The value of the drugpolymer
interaction parameter was calculated from the crystalline drug melting
depression data and extrapolated to lower temperatures. The interaction parameter was also calculated at 25 C for both
systems using the van Krevelen solubility parameter method. The rank order of interaction parameters of the two systems
obtained at this temperature was comparable. Diagrams of drugpolymer temperaturecomposition and free energy of mixing
(Gmix) were constructed for both systems. The maximum crystalline drug solubility and amorphous drug miscibility may be
predicted based on the phase diagrams. Hyper-DSC was used to assess the validity of constructed phase diagrams by annealing
solid dispersions at specic drug loadings. Three dierent samples for each polymer were selected to represent dierent regions
within the phase diagram.
KEYWORDS: drugpolymer thermodynamic phase diagrams, FloryHuggins interaction theory, HPMCAS-HFfelodipine,
Soluplusfelodipine, high-speed dierential scanning calorimetry

INTRODUCTION
Over the past decade, formulations containing amorphous
drugs have become extremely attractive due to the signicant
enhancement in solubility and dissolution rate that may be
achieved.13 The apparent aqueous solubility of the drug once
incorporated into a dispersed system can be signicantly higher
than its crystalline counterpart.46 However, drugs in an
amorphous state are inherently unstable and tend to crystallize
during storage and/or dissolution.7 A common strategy for
increasing the solubility and stability of an amorphous drug is
to disperse it in a polymeric matrix, thus forming an amorphous
solid dispersion. Melt extrusion, spray drying, and other
relevant techniques may be used to obtain an intricate blend
of drug and polymer. To make full use of a solid dispersion
strategy, knowledge of the drug solubility and drugpolymer
miscibility in the matrix of choice is necessary. The conventional approach to selecting a suitable polymeric carrier to form
an amorphous drug solid dispersion may involve several steps,
2012 American Chemical Society

including investigation of a range of drug loadings for each

polymer candidate, identication of the most suitable
preparation method, and selection of appropriate processing
conditions.8,9 In doing so, one aims to achieve the most suitable
processing conditions and drug/polymer ratio to promote
mixing between drug and polymer and thus improve stability.
One important point to consider is that attainment of a onephase system requires the two components to be thermodynamically miscible during processing. Furthermore, because
solid dispersion preparation may take place at nonambient
temperatures and/or in the presence of solvent (e.g., melt
extrusion and spray drying), perturbation of the system during
processing can lead to dynamic system that re-equilibrates
Received:
Revised:
Accepted:
Published:
236

July 16, 2012

October 17, 2012
October 30, 2012
October 30, 2012
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postprocessing.10 Consequently, a more logical and rationale

approach would be to better understand the degree of drug
over/undersaturation in the polymeric matrix as a function of
temperature and how this can be linked to the molecular
structure and physical properties of both components. In
particular, it would be useful to identify drugpolymer
combinations that form strong adhesive interactions using
simple experimental methods and to use this information to
guide the selection of appropriate drug loadings and processing
conditions, to maximize stability of the amorphous solid
dispersion.
Previously, we reported a method based upon small-scale
dierential scanning calorimetry (DSC) measurements wherein
the FloryHuggins (FH) interaction parameter could be
determined from physically mixed drug/polymer mixtures.11
The Gibb's free energy of mixing (Gmix) was not favorable
when was positive, indicating immiscibility. Conversely, when
took a negative value, the Gmix was negative, suggesting
miscibility between drug and polymer. In this current article, we
wanted to extend our understanding of FH interaction theory
relative to drugpolymer miscibility and to determine whether
this approach could be used in a more overarching manner to
understand the thermodynamics of drugpolymer mixing
during processing and better inform our choice of polymeric
carrier in future melt extrusion studies. More specically, we
wanted to build upon our previous work and construct phase
diagrams that provide information through which we can
understand the relationship between drug composition,
temperature, and phase separation. We aimed to oer
information on the solubility and miscibility of the drug within
the polymeric matrix. Development of appropriate phase
diagrams that oer signicant correlation between experimental
measurements and end product performance (physical
stability) would undoubtedly expedite early stage formulation
development.
To date, there have been limited articles describing the use of
theoretical calculations to determine the solubility/miscibility
of the drug within polymer matrices and hence dene phase
stability.12 Equally, there is a clear decit of articles describing
the use of experimental methods to predict the drugpolymer
phase boundaries. What has been published is largely restricted
to solubility determination in low molecular weight liquid
monomers and/or oligomers.10,13,14 In so doing, the apparent
solubility of the drug in the short chain system (monomer/
oligomer) may be predicted by using the drug activity
coecient , which acts as a bridge connecting the interaction
parameter and drug solubility. One signicant drawback of
this approach is the assumption that the molecular environment
of the drug within the short chain system adequately represents
that in the solid polymeric matrix. Furthermore, aside from
polyvinypyrrolidone and related polymers (vinyl acetate
copolymers), obtaining small chain oligomeric equivalents for
pharmaceutical polymers is dicult without custom synthesis.
There are a number of interesting articles that have reported
using the endset melting point depression to obtain a constant
drugpolymer interaction parameter that may be used to
construct the binary phase diagrams.1517 Interestingly, the
interaction parameter, , is considered temperature independent. More recently, has been shown to be not only
concentration dependent but also temperature dependent.18,19
In light of this information, within this article, we have
developed this theory to construct phase diagrams that are
relevant to both temperature and drug composition and thus

provide information relevant to practical manufacture of solid

amorphous drug dispersions.
In this study, we provide a practical approach that is based
upon melting point depression data and FH theory to
construct drugpolymer binary phase diagrams. Using melting
point depression data, the temperature dependence of
interaction parameter may be calculated for drug and
amorphous polymer mixtures.20,21 These parameters may be
used to establish miscibility between drug and polymer as a
function of temperature and composition. Given the increasing
importance being attached to drugpolymer miscibility within
the pharmaceutical arena and the potential correlation to
physical stability, it is imperative that such phase diagrams are
better understood. Moreover, the increasing trend to
manufacture solid dispersions using nonambient technologies
such as melt extrusion make it even more important to dene a
drugpolymertemperature framework in which miscibility
and solubility of drug within the respective polymer be dened.
In this paper, we present, for the rst time, a constructive and
critical evaluation of an experimental method that may be used
for the construction of drugpolymer phase diagrams and
provide a relevant discussion on how these phase boundaries
can be used to evaluate polymeric materials during the
preparation of solid dispersions. The model drug selected in
this study was felodipine (FD). Two polymeric carriers
commonly used in the production of melt extrudates were
selected, namely, hydroxypropyl methylcellulose acetate
succinate HF grade (HPMCAS-HF) and a graft copolymer of
polyvinyl caprolactampolyvinyl acetatepolyethylene glycol
(Soluplus).
Theoretical Considerations. According to FH theory,
the Gibb's free energy change that accompanies mixing of a
drugpolymer binary system may be expressed as:
Gmix = Hmix T Smix

(1)

Subsequently, the Gibb's free energy may be expressed as a

function of the FH interaction parameter, :
drug

poly
Gmix = RT
ln drug +
ln poly + drug poly drug poly
N
N
A

(2)

where is the volume fraction, N is the molecular volume of

the drug or polymer, is the FH interaction parameter, R is
the molar gas constant, and T is the temperature. In a drug
polymer mixture, we may dene NA as the molecular size of the
drug, in which case NB = mNA, where m is the ratio of the
volume of a polymer chain to drug molecular volume (eq 3):
M w(poly)

m=

poly
M w(drug)
drug

(3)

where the Mw(poly) and Mw(drug) are the molecular weight of

polymer and drug, respectively, and the poly and drug are the
density of polymer and drug, respectively. The free energy of
mixing for a drugpolymer binary system may therefore be
written alternatively as:

poly
Gmix = RT drug ln drug +
ln poly + drug poly drug poly
m

(4)

The free energy of mixing (Gmix) may therefore be

calculated at a specied temperature with respect to the
corresponding interaction parameter. Furthermore, melting
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Figure 1. Chemical structure of (a) FD, (b) Soluplus, and (c) HPMCAS. m, n, and I represent the number of repeat units within each
respective polymer. In HPMCAS, n = 75; in Soluplus, n = 13, m = 30, and I = 57.

binary systems, then Gmix versus composition and temperature may be constructed simply by combining eqs 4 and 5 with
eq 7. Furthermore, the maximum drugpolymer miscibility
boundary (spinodal curve) may be calculated by determining
the second derivative of the free energy (eq 4) and setting equal
to zero as shown in eq 8:

point depression data collected from DSC may be used to

predict the drugpolymer interaction parameter using the
following equation:14,17

1
1
R
1

=
ln drug + 1 poly

H
Tm
Tm0
m

+ drug poly poly 2

1
1
+
2drug poly = 0
drug
mpoly poly

(5)

where is the volume fraction of the drug, Tm and Tm0 are the
melting points of the drug crystal in the drug/polymer mixture
and the pure drug, respectively, R is the gas constant, and H is
the heat of fusion of the drug.
It should be noted that the interaction parameter is not
constant but temperature and composition dependent.2225 To
develop a phase diagram to accommodate variation in
temperature, we dene the temperature dependence of the
drugpolymer interaction parameter as shown in eq 6:
drug poly = A +

B
+ C1 + C22
T

where the interaction parameter can be substituted from eq 7.

Thereby, the maximum drugpolymer miscibility curve may be
obtained.18

MATERIALS AND METHODS

Materials. FD with a purity of 99.9% was a gift from
AstraZeneca (Maccleseld, United Kingdom). HPMCAS-HF
was supplied by Shin-Etsu Chemical Co. (brand name
AQOAT). Polyvinyl caprolactampolyvinyl acetatepolyethylene glycol graft copolymer (brand name Soluplus) was a
generous gift from BASF Chemical Co. (Ludwigshafen,
Germany). The chemical structures of these ingredients are
shown in Figure 1.
Methods. Sample Preparation. Drug and polymer
mixtures with dierent compositions were rst mixed using a
mortar and pestle followed by a ball mill mixer (Retsch, model
MM200, Germany). In a typical procedure, drug and polymer
powder sample totaling 1 g was milled inside the container with
one stainless steel ball at 20 Hz. A predened milling time of 2
min was chosen, which was subsequently followed by a 2 min
interval. This procedure was repeated to a maximum of up to
10 mill-stop cycles (max 20 min mill time) to determine
optimum milling conditions.
Thermal Analysis. Power compensation DSC (DSC8000,
Perkin-Elmer, United Kingdom) was used throughout this
study. Nitrogen was used as the purge gas for low speed
scanning; helium gas was used for high speed scanning. A 510
mg powder sample was packed into an aluminum 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. Melting
depression experiments were conducted at heating rate of 1
C/min from 20 to 200 C. The end point of the melting
endothermic peak was calculated from the intercept point of
the endothermic trace and the postmelting baseline. Given that

(6)

where A is the value of the temperature-independent term

(entropic contribution), B is the value of the temperaturedependent term (enthalpic contribution), and C1 and C2 are
tting constants of with respect to volume fraction. This
relationship subsequently has been simplied (eq 7) and has
proven to be sucient in many polymerpolymer systems
exhibiting an upper critical solution temperature (UCST):
drug poly = A +

B
T

(8)

(7)

wherein the dependence of on volume fraction (composition)

is negligible relative to temperature.18 This rst order
relationship between and temperature is an additional
assumption of FH polymer solution theory, which summarizes the nontrivial dependencies of on polymer composition,
chain length, and temperature. More recently, the variation of
the relationship between and temperature has been previously
reported,26,27 and the rst order relationship between and 1/
T has been used to extrapolate the value of for drugpolymer
binary systems outside experimental temperatures.19,28 In this
study, we have employed eq 7 that relates to temperature and
used this to identify FH constants A and B.
If the relationship between and T within a given
temperature range can be determined for certain drugpolymer
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Table 1. Physical Properties of FD, HPMCAS, and Soluplus

molecular volume (cm3/mol)
FD
HPMCAS
Soluplus

300.19
14007.78b
116161.62b

MW (g/mol)

density (g/cm3)

384.25
18000
115000

1.28
1.28
0.99

solubility parameterc (MPa)1/2

Hfusion (kJ/mol)

24.39
32.10
31.22

26.03

Data reported in the literature.10 bValues calculated by dividing molecular weight by true density. cSolubility parameters were calculated using the
group contribution method.

parameters is provided by Barton.29 In this study, the van

Krevelen group contribution method has been used to calculate
the solubility parameter, which may be expressed as:

the drugpolymer particle surface interaction is a critical

requirement for melting point depression experiments, dierent
milling cycles were tested to achieve the optimal depression
results. From initial experiments, it was shown that increasing
the milling time up to four cycles (8 min of milling time)
resulted in an increased melting depression. Thereafter, no
further melting depression was observed during increased cycle
load (data not shown). Therefore, 8 min of milling time was
selected for all samples.
Annealing experiments were used to corroborate drug
polymer phase diagrams. Drugpolymer solid dispersions were
rst prepared via a solvent evaporation method. Clear drug
polymer solutions at specied compositions were prepared, and
the solvent was removed using a rotary evaporator (Buchi,
Germany). Following rotary evaporation, the resulting
amorphous solid dispersion samples were then left in a vacuum
oven at room temperature to allow any residual solvent to
escape. The prepared solid dispersion was then annealed for 24
h in the DSC at predened temperatures (guided by drug
polymer phase diagrams). Once annealed, the sample was fast
cooled at a rate of 200 C/min to 60 C and then heated at
200 C/min to 200 C to determine the phase composition of
the system. The thermal stability of drugpolymer mixtures
during annealing was determined using thermogravimetric
analysis (TGA) (TA Instruments, United Kingdom). Approximately 10 mg of sample was weighed and heated at 20 C/min
to a temperature 5 C higher than the highest annealing
temperature and held at this temperature for 24 h. Weight
losses of only 0.2 wt % (approximate) were recorded after
annealing.
To characterize the Tg of a freshly prepared drugpolymer
solid dispersion, ball-milled drugpolymer mixtures of varying
composition were held for 5 min in the DSC furnace at a
temperature above that of the melting temperature of pure
drug. Subsequently, samples were fast cooled to 60 C to
form an amorphous solid dispersion and immediately heated, at
a rate of 200 C/min, up to 200 C. This coolheat cycle was
performed at least twice until a constant Tg value was obtained;
this value was used to represent the Tg of freshly prepared
amorphous solid dispersions.
Powder X-ray Diraction. The solid-state properties of ballmilled samples were determined using a MiniFlex II powder Xray diractometer (Rigaku, United States). Radiation was
generated from a copper source operating at a voltage of 40 kV
and a current of 40 mA. The test samples were packed into a
glass sample holder and scanned from 0 to 40 2, using a step
width of 0.01 2 and a scan rate of 1 2 per minute;
continuous mode was used.
Prediction of Solubility/Miscibility Using Drug and
Polymer Solubility Parameters. Solubility parameters are
often used when predicting the miscibility or compatibility of
a mixture, and this technique is well established in polymer
solvent/polymerpolymer solution studies. A comprehensive
discussion of solubility parameters and other cohesion

total =

d 2 + p2 + h 2

(9)

where and d, p, and h are the components of disperse forces,

polar group forces, and hydrogen bond energy, respectively.
These may be calculated as follows:
d =

Fdi
;
V

p = a

Fp2
V

h =

E hi
V

(10)

Fdi is the group contribution to the disperse forces, Ehi is the

group contribution to hydrogen bonding energy and Fpi is the
plane symmetry factor of polar groups.29 V is the group
contributions to molar volume. The drugpolymer interaction
parameter therefore may be calculated as follows:18
=

V0
(drug poly )2
RT

(11)

where V0 is the volume of the lattice site. The molar volumes of

a single polymer unit calculated from the group contributions
were used for the HPMCASFD and SoluplusFD systems,
respectively. As shown in eq 11, refers to the square of the
dierence in solubility parameters that were calculated from the
values of group contributions at 25 C. The drugpolymer
interaction parameters for these two systems as calculated from
solubility parameters were used for comparison with results
obtained from melting point depression experiments.
The solubility parameters of Soluplus, HPMCAS-HF, and
FD have been calculated using a group contribution method.
The values of Fdi, Fpi, and Ehi of each group at 25 C used in
this work were chosen from van Krevelen's solubility
parameters.30 The hygroscopicity of the components were
ranked as Soluplus > HPMCAS > FD. Therefore, the plane
symmetry factors of polar group contributions in Soluplus,
HPMCAS-HF, and FD were selected at 0.5x, 0.25x, and 0x,
respectively. The physical properties and solubility parameters
of the materials used in this study are summarized in Table 1.

RESULTS AND DISCUSSION

DrugPolymer Miscibility Using Solubility Parameters. Solubility parameters were estimated using the Hoftyzer
and Van Krevelen method and are provided in Table 1. The
values obtained for Soluplus and HPMCAS were very similar,
31.22 and 32.10 MPa1/2, respectively, whereas FD had a
solubility parameter that was signicantly lower (24.39
MPa1/2). The use of solubility parameters to guide drug
polymer miscibility, in the context of hot melt extrusion, has
been previously reported.31 It is well-known that compounds
with similar solubility parameters (7 MPa1/2) are more likely
to be miscible, whereas compounds with solubility parameters
diering by more than 10 MPa1/2 are most probably
immiscible. In our case, the dierence between the solubility
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Figure 2. DSC thermograms of ball-milled mixtures measured at a heating rate of 1 C/min containing (a) HPMC-AS and FD from top to bottom:
100, 95, 90, 85, 80, 75, 70, 60, and 55% w/w FD, respectively. (b) Soluplus and FD from top to bottom: 100, 95, 90, 85, 80, and 75% w/w FD,
respectively.

melting.28 In a similar fashion, should polymer and drug

interact during processing, the chemical potential and thus the
melting point of the drug would be reduced. Consequently,
DSC may be employed to investigate the miscibility between
drug and polymer to better understand and predict the
performance of amorphous solid dispersions. Previously, it has
been reported that the solubility of a drug within a polymeric
matrix can be determined by measuring dissolution temperatures (endset points) of known drugpolymer compositions.15,16 It is extremely important to recognize that two
processes are occurring simultaneously, amorphous drug
induction and drugpolymer interaction. In this study, we
have used the melting endset point to measure the temperature
of the dissolution end point of the drug in each respective
polymer.17 At this point, the depression in melting endset as a

parameter of FD and both polymers was small (7 MPa1/2).

For FD and HPMCAS, the dierence was 7.71 MPa1/2, and for
FD and Soluplus, the dierence was 6.83 MPa1/2. This would
suggest that FD and Soluplus have a higher miscibility than the
FD and HPMCAS, and further thermal analysis should be
conducted to examine the possibility of forming a glass
solution.31 In this study, thermal analysis was used to construct
a drug composition versus temperature diagram that would be
benecial in oering further understanding of drugpolymer
miscibility and physical stability.
FH Interaction Parameter and Gibb's Free Energy of
Mixing. During solid state processing, for example, ball milling,
the amorphous-to-crystalline drug ratio may be altered. In this
case, milling may increase the amorphous content of the drug,
lower its chemical potential, and hence depress the drug
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result of adding polymer, relative to milled FD (1/Tm 1/

Tmo), may be used along with eq 5 to calculate .19 Because the
endset point of melting may be depressed at increased milling
frequency and duration, it is necessary to determine the
optimum milling conditions to maximize the potential
interaction between two components. The correct use of ball
milling within a suitable time scale will potentially increase the
particle surface interaction and deliver more accurate melting
point depression data. The optimum milling time was
determined to be 16 min, comprising four cycles of 2 min of
milling and 2 min interval. At processing times exceeding 16
min, no further melting point depression was observed.
Figure 2 shows the DSC thermograms obtained for the ballmilled samples containing dierent weight fractions of drug.
Clearly, there is signicant evidence of melting point
depression, suggesting a substantial degree of mixing at the
melting temperature. The endset of melting for FD decreased
with an increasing fraction of HPMCAS or Soluplus. The
eects were greater for Soluplus than HPMCAS. To further
understand drugpolymer miscibility, we estimated the FH
interaction parameter by rearranging eq 5. A plot of (1/Tmmix
1/Tmpure) (Hfus/R) ln(drug) (11/m)polymer versus
polymer2, as shown in Figure 3a, yielded a linear relationship.
For HPMCASFD, an interaction parameter with a value of

+0.37 (r2 = 0.99) was obtained, whereas for the SoluplusFD

system, an interaction parameter with a value of 0.37 (r2 =
0.99) was obtained. In the case of HPMCAS, the positive value
of is indicative of the weak interactions between drug and
polymer. This is characterized by the limited melting point
depression data observed and athermal mixing (Figure 3a). For
SoluplusFD, the negative value is representative of a
miscible system and an exothermic heat of mixing. Conversely,
large positive interaction values are typically observed for
immiscible systems.13 It should be noted that the values
obtained for the interaction parameter are both very close to
zero. Soluplus is slightly negative and suggests that this polymer
may exhibit more favorable mixing than HPMCAS at
temperatures close to the melting point of FD. The values of
the interaction parameter () for these systems are less
informative with respect to phase separation of drug from the
polymer as a function of temperature and drug composition.
To extend this discussion, we used eq 4 and the values of the
FH interaction parameter to examine the change in Gibb's
free energy as a function of drug fraction (Figure 3b). The
Gibb's free energy for both systems was negative and was
dependent upon drug volume fraction. Interestingly, the Gibb's
free energy plots suggest that both polymers would be miscible
with FD, with Soluplus, as expected, displaying a lower Gibb's
free energy value. The negative Gibb's free energy is not
entirely surprising given that this plot provides an overall
indication of mixing between the drug and the polymer at
temperatures close to the melting point of the drug.
Consequently, we can infer that during a nonambient
processing method such as melt extrusion, we would be likely
to produce a miscible drug and polymer system. However, from
this information, we have no indication of the likelihood of
mixing at temperatures lower than the drug melting point. For
example, using the above information, it would be hard to
determine the level of drugpolymer miscibility to be expected
at room temperature and hence whether phase separation is
likely. One should note that at room temperature, the system
would most likely be below the Tg of the system and may be
kinetically hindered from recrystallization. However, with the
appropriate phase diagram, we should, at least from a
thermodynamic standpoint, be able to determine if recrystallization would be favorable. Moreover, given that the dierence
in solubility parameters of FD and both polymers was close to 7
MPa1/2, we would argue that both systems are miscible but
expect concentration- and temperature-dependent miscibility.31
In this case, within the following sections, we provide a useful
extension of this theory to provide a temperature/composition
phase diagram.
Construction of TemperatureComposition Phase
Diagrams. Melting depression data collected from DSC
experiments was tted to eq 5 to determine the interaction
parameter as a function of temperature. At drug compositions
less than, 0.70 for SoluplusFD, and 0.55 for HPMCASFD,
no melting event was observed. Assuming drugpolymer
binary systems exhibit an UCST, the temperature dependence
of the interaction parameter may be described as rst order as
shown by eq 7. A plot of interaction parameter versus 1/T is
shown in Figure 4. For the SoluplusFD system, a linear
relationship between 1/T and was observed across the
experimental composition range from 0.85 to 0.70. In this case,
the correlation coecient, r2, was determined to be 0.99. The
HPMCASFD system displayed a linear relationship at drug
compositions from 0.70 to 0.55. The r2 value was determined to

Figure 3. (a) FH interaction plot used to determine the FH

interaction parameter close to the melting point of the drug. (b) A plot
of Gmix/RT as a function of drug volume fraction. The lled symbols
represent data calculated using the interaction parameter derived from
panel a, whereas the open symbols represent data using the interaction
parameter derived from eq 7 at a temperature close to the melting
point of pure drug (140 C).
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polymer miscibility predicted by the solubility parameter

method and melt point depression method resulted with
for SoluplusFD being less than HPMCASFD (Table 2).
The values obtained for FH interaction parameter
constants A and B were subsequently used in eq 7, so
that we could obtain values of at dierent temperatures. As
previously reported by our group, the value of the interaction
parameter signicantly aects the Gibb's free energy of
mixing.11 In this article, we have clearly shown that at 25 C
the interaction parameter for these drug polymer systems is
positive (immiscible), whereas at higher temperature, miscibility is promoted. Substituting the interaction values
calculated at dierent temperatures into eq 4, we can begin
to understand the variation in Gibb's free energy of mixing
(Gmix) as a function of drug composition and temperature.
This information is useful in understanding whether specic
drugpolymer compositions will spontaneously phase separate.
Plotting the free energy of mixing for the HPMCASFD and
SoluplusFD binary systems (Figure 5a,b), it is apparent that

Figure 4. Variation of the interaction parameter X as a function of

temperature. The solid line represents the line of best t of eq 7 to
experimental data.

be 0.88. At drug concentrations higher than 0.7 for HPMCAS

and 0.85 for Soluplus, a nonlinear relationship was observed.
Nonlinearity between 1/T and has been previously reported
at high drug loadings in the indomethacin/PVP-VA system.28
This suggests that within specic polymerdrug blends, the
interaction parameter may be dependent upon higher order
concentration terms (e.g., shown in eq 6).18,19 One important
point to consider is that nonlinearity occurs at high drug
loadings, at small values of 1/T, and hence high temperature.
Consequently, at temperatures of interest with respect to
pharmaceutical stability (2060 C), the relationship between
temperature and may be assumed to follow a rst order
relationship. Moreover, at high temperature because the value
obtained by experiments is lower than that used from FH
theory, we know that the phase boundaries (drug solubility and
drug miscibility) determined from this relationship would be
underestimations with respect to drug concentration. Given this
assumption, we were able to obtain values for FH constants A
and B, as described within eq 7 (Table 2). Using this method,
Table 2. FH Interaction Constants A and B Determined
Using Linear Regression Analysis of Experimental DSC Data
and Interaction Parameter, , Calculated at 25C Using
Melting Depression and Solubility Parameter Methods
A
B
a
b

FD + HF system

FD + Soluplus system

18.767
7830.4
7.509
4.122

14.419
5744.7
4.856
2.725

Determined through extrapolation of melting point depression data

to 25 C. bCalculated using van Krevelen solubility parameter method
at 25 C.

Figure 5. (a) Plot of Gmix/RT as a function of drug volume fraction

for FD and HPMCAS at temperatures of 25, 50, 80, 100, 120, and 140
C. (b) Plot of Gmix/RT as a function of drug volume fraction for FD
and Soluplus at temperatures of 25, 50, 80, 100, 120, and 140 C.

we have calculated the interaction parameter, , at 25 C for

both the Soluplus and the HPMCAS system. The interaction
parameters for the two systems at 25 C were also calculated
using solubility parameter method (eq 11, b in Table 2). The
drugpolymer interaction parameter , for each system,
irrespective of the calculation method, was positive. This
suggests limited miscibility existed between FD and HPMCAS
or Soluplus and FD at a temperature of 25 C. As expected, the
value of the interaction parameter decreased at elevated
temperature. Most importantly, a similar rank order of drug

at a temperature of 140 C, the Gmix of both systems is

negative and convex. At this elevated temperature, homogeneous mixtures are generated that are thermodynamically stable
at all drugpolymer compositions. As shown in Figure 5a,b, the
temperature at which the Gibb's free energy became positive
was dependent upon the polymer used and the volume fraction
of the drug.
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For the HPMCASFD system temperatures 120 C

resulted in a Gmix/RT that became positive at high drug
loadings. The drug composition at which the Gibb's free energy
became positive decreased as temperature decreased. For
SoluplusFD, temperatures of 100 C resulted in a negative
Gmix/RT at all drugpolymer ratios. As the temperature
decreased (80 C), the Gibb's free energy of mixing became
positive at drug volume fractions >0.3. The calculated solubility
and amorphousamorphous miscibility results for FD in
HPMCAS and Soluplus are summarized, together with the
predictions from the solubility parameter method, in Table 3.
Table 3. Prediction of the Solubility and Miscibility of FD in
HPMCAS and Soluplus Polymeric Systems at a Temperature
of 25 C
maximum values
solubility of FD (%wt) 25 C
solubility of FD (%wt)b 25 C
miscibility of FD (wt%)
25 C
50 C
80 C
100 C
a

HF system

Soluplus system

0.001
0.60

0.02
3.69

7
10
14
22

12
18
31
58

Determined through calculation of melting point depression data to

25 C. bCalculated using van Krevelen solubility parameter method at
25 C.
Figure 6. (a) Binary phase diagram for FD and HPMCAS, annealed at
113 C, with three dierent drug loadings (wt %): 25, 44, and 64%.
(b) Binary phase diagram for FD and Soluplus, annealed at 103 C,
with three dierent drug loadings (wt %): 36, 55, and 72%.

At positive values of Gmix, the system may spontaneously

phase separate to lower its energy level. As the temperature
increases, the enthalpic contribution term (drugpolydrugpoly)
in eq 4 decreases due to a reducing positive value of for the
HPMCAS and Soluplus systems investigated in this study.
Additionally, at 25 C, the drug composition at which Gmix =
0 denes the miscibility limit between drug and polymer under
specied conditions.
Understanding how Gmix varies as a function of T for each
system allows drug solubility and miscibility to be plotted as a
function of drug weight fraction and temperature. This
information may be further combined with the glass transition
temperature to obtain phase diagrams as shown in Figure 6a,b
for the HPMCASFD and SoluplusFD systems, respectively.
The temperaturecomposition phase diagram based on FH
theory oers a framework from which we can better understand
the performance of the FD within the respective polymeric
matrices. In essence, the phase diagram allows one to predict
the maximum solubility of the drug and, the miscibility of
amorphous drug, in the specied amorphous polymer carrier as
a function of temperature. The glass transition curve used in
Figure 6 has been constructed from data derived from freshly
prepared amorphous solid dispersion samples, below which the
molecular mobility will decrease dramatically. The correlation
between the molecular mobility and the crystallization diusion
coecient of an amorphous solid has been discussed
elsewhere.32 Interestingly, below the Tg, should phase
separation be thermodynamically favored, the characteristics
of the polymeric platform (Tg, G, G, Ea to pass Tg) may oer
signicant kinetic barriers to recrystallization, thus stabilizing
the system over pharmaceutical relevant time scales. The drug
solidliquid phase boundary indicates the fraction of crystalline
FD dissolving into the respective polymeric carrier as a function
of both temperature and composition, while the dashed line,
refers to the spinodal curve. To the right-hand-side of the

spinodal curve the drug is present within the polymer in an

unstable state whereas to the left-hand-side of the spinodal
curve the drug is present in a metastable state. In the metastable
zone, the system will be stable to small uctuations however
large uctuation in drug density will result in drug
recrystallization via a nucleation and growth mechanism.
Within this region, nucleation will be prevented until a
signicant energy barrier is overcome. This is especially true
when the temperature is below the glass transition of the
system. To the right-hand side (higher drug concentration) of
the spinodal curve, from a thermodynamic perspective, phase
separation would be favored.
Relative to HPMCASFD systems, the temperature
composition curves of SoluplusFD shifted toward the high
composition range, indicating the higher solubility and
miscibility of FD in the Soluplus system. Using this method
to predict phase boundaries provides detailed information on
potential processing windows, indicating a maximum metastable region in which to formulate an amorphous solid
dispersion system. Additionally, the phase diagrams also
identify regions in which large energetic barriers (kinetic
hindrance) to recrystallization are apparent, that is, thermodynamically favored and kinetically hindered systems. Given the
increasing interest in nonambient processing (melt extrusion or
spray drying) of solid dispersions, the phase diagrams generated
for both polymers would be of high relevance in dening the
temperature and drug composition at which the mixture is
locally stable and/or phase separates. In being able to dene
such, we can use phase diagrams to provide conditions for
maximum interaction between the two components. Additionally, once the system returns to room temperature, we can
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The rst validation point involved the selection of two

systems within the metastable zone; that is, it was below the
solidliquid curve. In this case, we manufactured a 25% FD/
HPMCAS dispersion and a 36% FD/Soluplus dispersion and
annealed for 24 h at temperature 113 and 103 C for HPMCAS
and Soluplus, respectively. At these conditions, both systems
exist at drug concentrations exceeding thermodynamically
favorable molecular mixing but within a miscibility limit. As
shown in Figure 8, both systems exhibited two glass transitions.
For the SoluplusFD system, glass transitions were observed at
approximately 56 and 88 C. The lower Tg value is very close to
that of amorphous drug, implying a drug-rich phase, whereas
the higher temperature transition could be perceived to contain
a higher proportion of polymer, thus elevating the Tg to 88 C.
Within the HPMCASFD system, two glass transition events
were also observed, at approximately 71 and 88 C. Again, we
expect the lower transition event to represent a phase
containing a greater drug proportion. The identication of
two glass transitions for both HPMCAS and Soluplus systems
in this region suggests that the free energy landscape permits
decomposition of the mixture into two liquid phases rather
than direct transformation to amorphous polymer and
crystalline drug. To further understand the phase boundaries,
a Soluplus dispersion containing 55% FD and a HPMC-AS
dispersion containing 44% FD were manufactured and
annealed under previously described conditions. These drug
loadings were selected as they represented drug volume
fractions slightly beyond the spinodal curve, that is, within
the unstable region for both systems. A glass transition was
observed for both polymeric systems and a small endothermic
transition indicative of low levels of crystalline drug within the
matrix (H = 0.31 J/g for 55% FDSoluplus and H = 0.69 J/
g for 44% FDHPMCAS; the expansion of melting
endotherms is shown within Figure 7). At the highest drug
weight fractions (64% for HPMCAS and 72% for Soluplus), a
glass transition was observed in both cases. This transition was
lower than the Tg of the polymer, suggesting that amorphous
drug was still present, while large endothermic peaks were
observed in addition to the glass transitions (H = 27.1 J/g for
72% FDSoluplus and H = 40.1 J/g for 64% FD
HPMCAS). These results conrm the existence of increased
crystalline drug within the polymeric dispersions in which drug
exists in a supersaturated state that has a high thermodynamic
driving force toward recrystallization. In this high drug-loaded
region, since we are beyond the spinodal decomposition curve,
spontaneous crystallization occurs in the absence of any
signicant energy barrier.

assess whether this brings the system to a state of

thermodynamic instability wherein the drug is oversaturated
within the polymer. In such cases, the development of
formulations possessing high kinetic barriers to recrystallization
could be used as a method of stabilization over pharmaceutical
relevant time scales.
Validation of TemperatureComposition Phase Diagram. Crystallization from the amorphous state is an extremely
complex process and dependent upon thermodynamic factors,
storage conditions (humidity, temperature), and other kinetic
factors.33 In this study, we wanted to evaluate constructed
phase diagrams by examining the thermal stability of selected
drugpolymer ratios at predened temperatures. In all
validation work, HyperDSC was used. Given that molecular
mobility of a drug below the Tg is limited and even further
restricted following dispersion within a high viscosity polymer,
evaluation of constructed phase diagrams was conducted by
annealing samples in the DSC at temperatures exceeding the Tg
for a 24 h period. While we recognize that above the Tg, drugs
are kinetically hindered by other factors such as viscosity and
drugpolymer interactions, the propensity for recrystallization
at T > Tg, where there is global mobility within the platform, is
undoubtedly greater. Three drugpolymer compositions were
chosen for each polymer system, based on the temperature
composition diagrams shown in Figure 6a,b (see Table 4). The
Table 4. DrugPolymer Dispersions Used for Validation of
Phase Diagrams

FDHPMCASa
FDSoluplusb
comments

metastable
zone

unstable
supersaturated zone
drug = x

unstable supersaturated
zone drug = y, y > x

25 wt %

44 wt %

64 wt %

36 wt %

55 wt %

72 wt %

Recrystallization expected within the metastable and unstable

zone but less likely in metastable region.

Drug percentage validated at 113 C. bDrug percentage validated at

data at 103 C.
a

phase diagrams that we have constructed exhibit two critical

curves, a solidliquid phase curve and a maximum drug
polymer miscibility curve (2G/2 = 0), often referred to as
the spinodal decomposition curve. The solidliquid phase
curve has been determined from melting point depression data.
Above this curve, the system is one phase; hence, this
represents the maximum solubility of the drug within the
polymer. Theoretically, the metastable zone, which may be
dened as the region above the drugpolymer miscibility curve
and below the solidliquid curve,27 is likely to produce a drug
polymer system that is metastable and stable to small
uctuations in drug concentration. Clearly, kinetic eects are
greater at temperature < Tg. The DSC was carefully calibrated
at a scanning speed (200 C/min) using the melting
temperatures of indium and zinc as reference standards.
Helium was used as the purge gas to enhance the thermal
conductivity of the sample and DSC cell environment during
heating. The high scanning speed power compensation DSC
provided more accurate data in sample scanning, especially in
identifying the existence of the amorphousamorphous
metastability.34,35 Typical HyperDSC results are shown in
Figures 7 and 8.

GENERAL DISCUSSION
Over the past decade, the interest in using amorphous drug
dispersions to enhance the solubility of poorly soluble drugs has
increased dramatically.36 Amorphous drug forms possess shortrange order and require a lower energy input to achieve
aqueous dissolution. Furthermore, because amorphous drugs
exhibit high levels of supersaturation in aqueous media, a higher
apparent solubility may be realized. In contrast to the crystalline
form, the amorphous form of a drug is thermodynamically
unstable and may recrystallize during storage and/or
dissolution.37 Therefore, one of the foremost challenges in
developing amorphous drug dispersions is to inhibit crystallization, particularly during storage. Moreover, one key aspect is
being able to determine the likelihood for recrystallization and
developing platforms that can inhibit such transformations. In
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Figure 7. HyperDSC thermograms of HPMCAS-FD and Soluplus-FD solid dispersions (annealed for 24 h) containing varying FD weight
percentages: (1) 36% FD-Soluplus, (2) 25% FD-HPMCAS, (3) 55% FD-Soluplus, (4) 44% FD-HPMCAS, (5) 72% FD-Soluplus, (6) 64% FDHPMCAS, and (7) 100% FD.

Metastability plays a signicant role in polymer phase

transitions, which has been proven theoretically and experimentally.42,45 Similar to polymerpolymer liquid mixtures,
drugpolymer amorphous (liquid) mixtures can also be
supercooled well below the equilibrium temperature (dened
composition) and thus have no crystalline content. In this
system, with consideration of the Gibb's free energy of mixing,
there is the potential for specic drugpolymer compositions
to decompose into coexisting amorphous (liquid) phases rather
than transform directly into lower energy crystal state
(crystallization). Hence, amorphousamorphous (liquid
liquid) phase separation may precede crystallization. In this
metastable region, an appropriately formulated system can
provide a suciently high kinetic barrier and thus prevent
phase separation. At drug compositions within the metastable
zone, drug is supersaturated in the polymeric carrier; however,
supersaturation may be maintained by the apparent miscibility
of the components in the amorphous state, particularly if the
storage temperature is below the Tg of the drugpolymer
system (Figure 9, zone D). Above the Tg, molecular mobility is
high, and the system may achieve equilibrium quite quickly;
below this temperature, the metastable system falls into a
frozen state characterized by low molecular mobility and long
relaxation times, characteristic of glassy structures. Consequently, in this state, the miscibility is an apparent value,27
which suggests that a supersaturated amorphous drugpolymer
solid dispersion mixture (zone D) may remain crystal-free over
pharmaceutically relevant time scales, if engineered appropriately. This is an interesting and particularly useful consideration

light of the above, drug is often embedded in a solid polymeric

matrix as a solid dispersion to produce an amorphous mixture
of drug and the polymer (often observed as a single Tg). These
drugpolymer platforms may therefore oer improved
solubility while also increasing stability. In such systems,
dening drugpolymer miscibility and the maximum drug
solubility within the chosen carrier is of paramount importance
to maintain long-term stability.38,39
In this article, we report a small-scale experimental method
that is very useful in dening the miscibility and solubility of a
model poorly soluble drug (FD) in two model polymeric
carriers, namely, HPMCAS-HF and Soluplus. Applying a
combination of DSC and FH interaction theory, we have
constructed phase diagrams for both systems. Importantly, the
phase diagram clearly identies the phase boundaries of the
system. As shown in Figure 9, above the liquidsolid boundary
(zones A and B), drugpolymer mixtures are expected to
remain stable with respect to innitesimal uctuations within
the system. The predicted equilibrium solubility of drug within
both polymeric carriers is relatively low. This liquidsolid
phase boundary has been determined from melting point
depression experiments, in which the melting point of the
crystalline drug drops to lower temperatures, due to
interactions between drug and amorphous polymer.20,40
Below the liquidsolid phase boundary (lower temperature),
a metastable zone exists (Figure 9, zones C and D),
representing a metastable state.41,42 Phase separation (physical
decomposition) within this zone not only requires activation
energy input but also needs to overcome kinetic eects.
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Figure 8. Expansion of the glass transition region from HyperDSC thermograms shown in Figure 7: (1) 36% FD-Soluplus, (2) 25% FD-HPMCAS,
(3) 55% FD-Soluplus, (4) 44% FD-HPMCAS, (5) 72% FD-Soluplus, and (6) 64% FD-HPMCAS.

composition at which the Gibb's free energy curve cuts the xaxis. By contrast, decomposition in the unstable state (zones E
and F from Figure 9) will be more favorable.10

CONCLUSION

This study has established a small-scale thermal method that

can be used in combination with FH interaction theory to
predict the physical stability of amorphous drug solid
dispersions. The temperature dependence of was successfully
determined for both HPMCASFD and SoluplusFD systems.
Phase diagrams of temperaturecomposition and free energy of
mixing (Gmix) were constructed, and it was noted that the
interaction parameters of HPMCASFD and SoluplusFD
calculated using the melting point depression method were
comparable to those calculated using van Krevelen's solubility
parameter method. The relative rank of the interaction
parameters was consistent, regardless of the method used in
their calculation. The solubility and miscibility of FD in
Soluplus were higher than in HPMCAS. The constructed phase
diagrams were assessed above the glass transition temperature
of the amorphous solid dispersion system. The results clearly
identied a metastable and unstable concentration for each
system. Given the increasing interest over the last 5 years in
using melt extrusion to produce amorphous dispersions, the
construction of drug compositiontemperature phase diagrams
allows one to readily identify a temperature/drug load space in
which it becomes possible to engineer stable solid dispersions.

Figure 9. Phase diagram of a model drugpolymer binary system

based on FH theory.

for formulations containing amorphous drugs.43 Local stability

of binary drugpolymer systems containing drug as a solute
and polymeric carrier as a solvent is possible within a dened
composition and temperature range. As shown in Figure 5a,b,
the drug composition at which the free energy of the system
becomes positive is dependent upon the temperature and the
polymeric matrix being used. Undoubtedly, polymers that are
capable of oering complementary hydrogen-bonding sites to
the drug will provide greater resistance to crystallization.44 An
increased stability would be expected at the point when Gmix
is at a minimum, that is, drug compositions lower than the drug
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AUTHOR INFORMATION

Corresponding Author

*Address: Medical Biology Centre, 97 Lisburn Road, Belfast,

BT9 7BL, United Kingdom. Tel: +44(0)28 9097 2646. Fax:
+44(0)289024 7794. E-mail: g.andrews@qub.ac.uk.
Notes

The authors declare no competing nancial interest.

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