COMMENTARY

Drug–Polymer Solubility and Miscibility: Stability

Consideration and Practical Challenges in Amorphous
Solid Dispersion Development
FENG QIAN, JUN HUANG, MUNIR A. HUSSAIN
Bristol-MyersSquibb Co., Biopharmaceutics R&D, One Squibb Dr., Bldg. 105/Room 2474, New Brunswick, New Jersey 08903

Received 15 September 2009; revised 1 December 2009; accepted 2 December 2009

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22074

ABSTRACT: Drug–polymer solid dispersion has been demonstrated as a feasible approach to

formulate poorly water-soluble drugs in the amorphous form, for the enhancement of dissolution
rate and bioperformance. The solubility (for crystalline drug) and miscibility (for amorphous
drug) in the polymer are directly related to the stabilization of amorphous drug against
crystallization. Therefore, it is important for pharmaceutical scientists to rationally assess
solubility and miscibility in order to select the optimal formulation (e.g., polymer type, drug
loading, etc.) and recommend storage conditions, with respect to maximizing the physical
stability. This commentary attempts to discuss the concepts and implications of the drug–
polymer solubility and miscibility on the stabilization of solid dispersions, review recent
literatures, and propose some practical strategies for the evaluation and development of such
systems utilizing a working diagram. ß 2010 Wiley-Liss, Inc. and the American Pharmacists Associa-
tion J Pharm Sci 99:2941–2947, 2010
Keywords: amorphous solid dispersion; solubility; miscibility; physical stability; glass
transition temperature; drug loading

INTRODUCTION dispersions, wherein an amorphous drug–polymer

Development of amorphous drugs has been an
inspiring topic in pharmaceutical research for both
industrial and academic scientists. With the fact that
many compounds from current discovery programs
are poorly water-soluble, amorphous drugs are
advantageous over their crystalline counterparts
with higher solubility, faster dissolution rate, and
enhanced oral bioavailability.1,2 On the other hand,
amorphous solids are physically unstable relative to
the crystalline state and the stability of amorphous
drugs against crystallization is critical for pharma-
ceutical development because crystallization negates
the advantages of amorphous solids.3,4
Since initially introduced by Sekiguchi et al.,5,6
solid dispersions have been drawing continuous
interests for the enhancement of drug bioavailability.
Among a variety of solid dispersions, amorphous
Correspondence to: Munir A. Hussain (Telephone: 732-227-
3272; Fax: 732-227-3752; E-mail: munir.hussain@bms.com)
Journal of Pharmaceutical Sciences, Vol. 99, 2941–2947 (2010)
ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association
composite is generated by methods such as spray
drying and hot-melt extrusion, has become one of the
most promising and viable amorphous formulation
approaches.7,8 Compared with other noncrystalline
drug delivery approaches such as cosolvency or self-
emulsifying drug delivery systems (SEDDS),9,10
amorphous solid dispersions are more amenable to
be developed into preferred solid dosage forms as the
final drug product, which often leads to highly
desirable advantages over liquid or semisolid for-
mulations including lower manufacturing cost, smal-
ler pill burden, improved physical and chemical
stability, possibility of combination dosage forms,
etc. For clarification, ‘‘solid dispersion’’ discussed in
this commentary refers to the most widely investi-
gated amorphous solid dispersion, wherein a crystal-
lizable, small molecule drug disperses in an
amorphous polymer matrix. Systems containing
semicrystalline polymers like PEG11–13 or Pluro-
nic114 involve other scientific considerations and will
not be included in this discussion.
Due to the lack of adequate understanding of the
nonequilibrium glassy state and other practical

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010 2941

2942 QIAN, HUANG AND HUSSAIN
complexities,15 the mechanisms as to why solid
dispersions can stabilize amorphous drugs are not
yet fully understood besides several commonly
accepted viewpoints. For example, the addition of a
high-Tg (glass transition temperature) polymer ele-
vates the Tg of the amorphous system and therefore
may reduce its molecular mobility required for
crystallization at certain storage temperatures.3
Thermodynamically the drug has a lower chemical
potential when mixed with a polymer, resulting in the
change of crystallization driving force. It is also
generally accepted that drug–polymer intermolecular
interactions are important for the stabilization of
the solid dispersion.16–18 Underneath all the above
considerations there is an important assumption that
the two components (drug and polymer) are mixed
homogeneously at the molecular level. This assump-
tion is directly related to the solubility (for the
crystalline drug) and/or miscibility (for the amor-
phous drug) in the polymer matrix, two terms that
appear straightforward while have sometimes been
used with confusion. This commentary briefly dis-
cusses the drug–polymer solubility and miscibility
with regard to the concepts and their implications to
the stabilization of solid dispersions (e.g., polymer
selection, stability assessment, etc.), within the scope
of industrial formulation strategies. Literature
review of the current progress on the determina-
tion/estimation of the solubility and miscibility will
also be discussed.
DRUG–POLYMER SOLUBILITY AND
MISCIBILITY: CONCEPTS AND IMPLICATIONS
In regular small-molecule solutions, solubility is
defined as an equilibrium thermodynamic parameter,
at which the chemical potential of the solute in the
solid phase is the same as that in the liquid (solution)
phase. This definition can be extended for polymer
solvents assuming equilibrium can always be reached
when the temperature of measurement is well-above
Tg of the system. When the temperature is close to or
below Tg, the system becomes too viscous to maintain
equilibrium and the solubility determined experi-
mentally (if possible) lacks a clear physical meaning
and can only be defined as ‘‘apparent’’ to be dis-
tinguished from the equilibrium solubility. The
equilibrium solubility at low temperatures may be
estimated by extrapolation or model prediction.
Unlike the solubility curves we usually encounter,
a common miscibility curve in the phase diagram of
an A–B binary mixture has the ‘‘inverted U’’ shape as
exemplified by the phenol–water phase diagram.19
Above the upper critical temperature Tc, A and B are
completely miscible with each other; while below the
upper critical temperature, the system becomes
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
partially miscible and the A-rich two-component
phase coexists with the B-rich phase and their
equilibrium compositions are determined by the
two miscibility values on the curve. Under the scope
of this commentary, the compositional miscibility of
drug in polymer is practically more relevant than the
miscibility of the polymer in the drug in the sense that
polymer is more likely to be the dominant phase in
these systems for typical small molecule drug–
polymer solid dispersions developed in pharmaceu-
tical industry. In other words, our discussions will
focus on the temperature/composition range within
which the drug–polymer miscibility may be regarded
as the ‘‘solubility’’ of the amorphous drug in the
polymer.
The concept of miscibility is well understood in
polymer physics for polymer blends,20 in which each
polymer component is usually in stable amorphous
state. The major complexity around the miscibility of
a small molecule drug in a solid dispersion is that the
amorphous drug is usually meta-stable relative to the
crystalline state and inclines to crystallize. Thus, the
system would eventually reach equilibrium with
regard to the crystalline drug and the equilibrium
composition of the mixture would be the solubility of
the crystalline drug in the polymer. The measurable
miscibility in the case of drug–polymer dispersion is
therefore associated with a meta-stable equilibrium
different from what was originally defined in polymer
science and requires that the drug stay in the super-
cooled liquid (a liquid at temperature below the
crystalline melting point Tm and above Tg) state
without crystallization (a ‘‘stable’’ meta-stable state,
similar to the situation of coexisting polymorphs21)
within the experimental time frame. Similar to
solubility, miscibility at temperatures close to and
below Tg is only apparent and involves the kinetics of
phase separation and structural relaxation. The
theoretical equilibrium miscibility practically may
only be estimated from extrapolation and modeling.
In the study of polymer blends of two stable
amorphous components, the miscibility behavior is
typically described by the well-known Flory–Huggins
theory,22,23 a lattice-based, statistical mechanics
model where the free energy of mixing is broken into
two parts: an entropy part that always favors mixing
and an enthalpy part that can either facilitate or
prevent mixing, depending on the nature and
intensity of the interaction between the two compo-
nents. At a given temperature, complete, partial, or
zero miscibility can be obtained with attractive
(Flory–Huggins interaction parameter x
0), weak
repulsive (x > 0), or strong repulsive (x  0) interac-
tions, respectively. Here miscibility is the equilibrium
composition of the two components, above which the
free energy of mixing is greater than zero and phase
separation is thermodynamically favorable. The
DOI 10.1002/jps

application of Flory–Huggins theory to the drug–
polymer dispersions has been shown useful while
with limitations as well.24–26
The importance of drug–polymer solubility and
miscibility in the development of amorphous solid
dispersions has been recognized widely. From the
industrial aspect, key questions include, but not
limited to, what the implications of these concepts are
to the physical stability of solid dispersions during
the formulation, process development, and product
shelf-life assessment, and how we could apply the
information to facilitate decision making and prior-
itize resource allocation. It is helpful to address these
questions through a comprehensive examination of a
solid dispersion system, using a working diagram
defined by temperature and drug loading in polymer
(Fig. 1) with the assumption that the system is
partially miscible above Tg (i.e., Tc > Tg). As stated
earlier, only temperature and composition range that
has most practical interest is shown for clarification.
In theory, at drug loadings above the miscibility
curve, phase separation is thermodynamically
favored. At equilibrium, a drug-rich phase coexists
with a polymer-rich phase with two distinguished Tg
values, respectively. Practically, solid dispersions
made by industrial processes such as spray drying
or hot-melt extrusion are typically well mixed
kinetically and only show single Tg initially regard-
less of the drug loading. For simplicity, the Tg values
shown in Figure 1 correspond to the single-phase
dispersion immediately after preparation.
As shown in Figure 1, three data sets, Tg of the solid
dispersion, crystalline drug–polymer solubility, and
Figure 1. A hypothetical diagram consists of drug–poly-
mer solubility, miscibility, and glass transition tempera-
tures of a solid dispersion system. A few notes: (1) the
system is partially miscible with Tc > Tg. (2) The diagram
includes only temperature and composition range of main
practical relevance. (3) Phase separation at drug loadings
higher than miscibility is ignored for simplicity when the Tg
curve is drawn (see text for detail).
DOI 10.1002/jps
DRUG–POLYMER SOLUBILITY AND MISCIBILITY 2943
amorphous drug–polymer miscibility, divide this
diagram into six different zones (labeled I–VI).
Since amorphous drug has higher chemical potential
than its crystalline counterpart, the drug–polymer
miscibility (solubility of amorphous drug) is always
higher than the crystalline drug–polymer solubility.
Out of these data sets, Tg values of solid disper-
sions, which define the boundary between the
equilibrium liquid (Zones II, IV, and VI) and glass
(I, III, and V) can be obtained experimentally by
thermal analysis without ambiguity. Many times Tg
of a binary solid dispersion can also be estimated with
reasonable accuracy by weight average theories like
Fox or Gordon–Taylor equations with small positive
or negative deviations due to drug–polymer interac-
tions.24,27,28
It is generally recognized that Tg represents a
kinetic boundary of molecular mobility. Here we
assume that the width (temperature range) of this
boundary is zero and thus to the right of the Tg curve
in Figure 1 is the equilibrium liquid where structural
relaxation occurs rapidly and solubility and misci-
bility can be measured at equilibrium. To the left of
the Tg curve is the nonequilibrium, glassy region,
where molecular mobility is low and structural
relaxation occurs slowly in the experimental time
scale. Thus, equilibrium solubility and miscibility
cannot be strictly defined or experimentally mea-
sured. Below Tg, the stability of the solid dispersions
relies heavily on the kinetics of phase separation and/
or crystallization instead of thermodynamics. In fact,
it has been proposed that at T < Tg  508C, the
molecular mobility can be neglected and the amor-
phous solids are stable enough over a period of years.3
The solubility curve is the boundary between the
thermodynamically stable (Zones I–II) and unstable
(Zones III–VI) regions, which defines the maximum
drug loading that can be mixed with the polymer
without worrying about crystallization or phase
separation. Zones I and II are therefore the safe
regions, within which any drug concentration and/or
temperature fluctuation of solid dispersions will not
destabilize the system. In fact, even if the drug starts
as crystalline material, the thermodynamic driving
force in Zones I and II is to dissolve the crystalline
drug in the polymer. For example, in the design of hot-
melt extrusion process, the selection of a processing
temperature at certain drug loading within Zone II
ensures thermodynamically the complete dissolution
of the drug in the polymer, assuming the dissolution
rate is fast enough at T > Tg (hot-melt extrusion in
Zone I is usually not feasible because of the high
viscosity in the glassy state).
If the drug is relatively stable without crystal-
lization as a super-cooled liquid, the amorphous
drug–polymer miscibility curve (should it be obtained
with confidence) might represent a meta-stable
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
2944 QIAN, HUANG AND HUSSAIN
boundary similar to the situation in regular solution
crystallization: above miscibility (Zones V and VI),
spontaneous phase separation would drive the
destabilization of solid dispersions while below
miscibility but above solubility (Zones III and IV), a
local fluctuation of drug concentration might be
necessary to cause the destabilization. In this
argument, the miscibility curve might shine lights
on potential strategies to enhance drug loading and
stability of a solid dispersion, if crystallization can be
prevented in the mixture. Above miscibility, there is
no thermodynamic barrier to prevent the system from
destabilization (thus Zone VI should be avoided at
anytime) and a solid dispersion can only be stabilized
kinetically (e.g., storage at temperatures sufficiently
below Tg, Zone V). A solid dispersion below miscibility
might be able to maintain its thermodynamically
meta-stable status both below and above Tg depend-
ing on the crystallization behavior of the drug.
Especially in Zone III, a solid dispersion may be
stabilized both thermodynamically (below miscibility)
and kinetically (low molecular mobility below Tg).
Although still controversial, the drug–polymer mis-
cibility might be an important consideration for the
physical stability of a solid dispersion, especially
when a homogeneous amorphous mixture can be
obtained during processing. Table 1 summarizes the
different properties of the six zones according to their
physical nature and destabilization driving force.
Two concentration values, C1 and C2 as shown in
Figure 1, are of particular interest. C1 is the drug
solubility in polymer at Tg. A solid dispersion
formulated at C1 would be thermodynamically stable
at temperatures above Tg while may be kinetically
stable below Tg. Therefore, C1 may represent the
highest drug loading to be adopted in a solid
dispersion that could withstand temperature fluctua-
tion across Tg during storage and downstream
processing, with minimal stability risk. C2, the
miscibility of the drug in the polymer at Tg, may
have a similar implication with respect to the solid
dispersion formulation design, if the drug can remain
amorphous during the time frame of formulation
processing and storage. Since C2 is higher than C1, it
may be of practical importance when extremely high
Table 1. Thermodynamic Nature and Destabilization Driving Force for Solid Dispersions in Zones I–VI of Figure 1,
Assuming All Solid Dispersions Were Homogeneously Mixed Initially
Zone Thermodynamic Nature
I Thermodynamically stable glass
II Thermodynamically stable liquid
III Supersaturated glass
IV Supersaturated liquid
V Supersaturated and immiscible glass
VI Supersaturated and immiscible liquid
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
drug loading is necessary to satisfy the dose require-
ment.
It is worth noting that Figure 1 represents a system
where the drug is partially miscible with the polymer
across the relevant temperatures. In cases where the
drug and the polymer are completely miscible at these
temperatures (e.g., indomethacin–PVP, nifedipine–
PVP25,26), the miscibility curve would shift to the left
and may not cross the Tg curve. Practically, the
miscibility line then will not appear in the working
diagram, while similar discussions as above still hold
for a simplified system with four zones (I–IV).
DRUG–POLYMER SOLUBILITY AND
MISCIBILITY: CHALLENGES IN DETERMINATION
Although drug–polymer solubility and miscibility are
important in solid dispersion development, no well-
established method is currently available to measure
them. In both of the measurements, one difficulty is
the high viscosity of the polymer that makes the
system hard to reach equilibrium. On the other hand,
at temperatures near and below Tg, the system goes
on continuously slow relaxation to reach equilibrium
and therefore the equilibrium solubility and misci-
bility can only be estimated by model prediction. In
this section of the commentary, we will first go
through some literature reports on the measurement
of drug–polymer solubility above or close to Tg
followed by the discussion of miscibility assessment
by various techniques and model application.
So far there is no literature report for the direct
experimental measurement of the solubility of a
crystalline drug in a polymer at temperatures below
Tg. This is because the crystallization is extremely
slow to achieve drug–polymer equilibrium in a glassy
state. In fact, it was shown by Tao et al.29 that
crystalline drug–polymer equilibrium can be approxi-
mately reached in the time of months even at
temperatures well above Tg and in the presence of
crystalline seeds. In that study a DSC method was
proposed to determine the drug–polymer solubility
through direct measurement of the melting point of
the crystalline drug in the presence of the polymer
Destabilization Driving Force
None
None
Crystallization of supersaturated drug
Crystallization of supersaturated drug
Amorphous phase separation, crystallization of supersaturated drug
Amorphous phase separation, crystallization of supersaturated drug
DOI 10.1002/jps

(i.e., the equilibrium melting point of the mixture at
this composition). This method involves sufficient
blending of the drug and the polymer through
cryomilling, followed by DSC scanning with multiple
slow ramping rates (18C/min or slower). The melting
end-set extrapolated to 08C/min ramping rate was
recorded as the equilibrium melting temperature.
The merit of this method is that it does not involve any
model prediction and can be used for most drug–
polymer systems. The major limitation is that only
solubility at temperatures 308C above Tg could be
obtained with confidence, while at lower tempera-
tures the system becomes too viscous to achieve
dissolution equilibrium in the timescale of DSC
measurement. Prior to Tao et al.’s work, Vasantha-
vada et al.30,31 measured the solubility of trehalose in
dextran and PVP in the presence of moisture. The
solubility was determined on the basis of the Tg
change as a function of the mixture composition and
moisture content. The study was actually done in a
three-component system and the measurement tem-
perature was much more above the Tg of the system.
Compared with the limited number of studies on
the solubility of crystalline drug in polymers, the
amorphous drug–polymer miscibility has been a
popular topic in the literature. So far the most
common technique used to determine the mixing
state of a solid dispersion is DSC, in which a single Tg
(intermediate of the two Tg values of the two
components) indicates homogeneous mixing while
two Tg values indicate not. Observing the resolution
limitation of the DSC method (30 nm)32 to detect
microstructural phase separation, other techniques
were reported to address the miscibility issues of solid
dispersions. Those include spectroscopic studies such
as IR and Raman;18 isothermal water vapor sorption
combined with modeling;24 spin-lattice relaxation by
solid-state NMR;33–37 X-ray powder diffraction;38,39
thermally stimulated depolarization current;40,41 etc.
These techniques are useful in the study of solid
dispersions at molecular level and the mechanistic
investigation of the drug–polymer interactions. On
the other hand, these techniques focus on the static
mixing state of the system (i.e., whether the two
components are homogeneously mixed) and they do
not elucidate the thermodynamic nature of the
system (i.e., equilibrium miscibility).
Similar to measuring drug solubility in polymers,
the experimental determination of miscibility at
temperatures below Tg is practically hard to achieve.
In addition, amorphous drugs usually tend to crystal-
lize, making the miscibility measurement even more
difficult. Experimental data obtained at tempera-
tures above Tg coupled with modeling have therefore
been shown useful in the study of the thermody-
namics of solid dispersions. Recent work done by
Marsac et al.25 applied the Flory–Huggins theory to
DOI 10.1002/jps
DRUG–POLYMER SOLUBILITY AND MISCIBILITY 2945
estimate the drug–polymer miscibility by the deter-
mination of the interaction parameter x. The free
energy of mixing was then calculated from the Flory–
Huggins equation. In their work, x was determined
either experimentally from melting-point depression
data or derived from the activity of the drug in the low
molecular weight analog of the polymer. Both
methods, however, have limitations and need further
verifications. The x value determined from melting-
point depression is applicable only within a narrow
temperature range near the melting point and cannot
be used as a constant for lower temperature predic-
tion. As observed in polymer science, x is a function of
both temperature and composition that can be
empirically described as below
B
x¼Aþ þ CF þ DF2
T
where A, B, C, and D are constants, T and F are
temperature and composition, respectively.42,43
In the other approach where x at low temperatures
was calculated with the knowledge of the activity
coefficient (g) of the drug in the polymer, g was
derived by solubility measurement of the drug in a
low molecular weight polymer analog (i.e., 1-ethyl-2-
pyrrolidone).26 This method estimates x at the same
temperature that the solubility was measured and
therefore is not limited to high temperature as in the
case of melting-point depression. The model, how-
ever, requires assumptions that are not yet verified in
such systems (e.g., identical interaction between
drug–polymer and drug–monomer), and is also only
applicable to polymers like PVP that has liquid
oligomers.
The g and x values determined from these studies
were also applied for drug–polymer solubility estima-
tion using the solubility equation and bridging x with
g, with the same limitations and assumptions coming
along. As discussed earlier, the experimental ver-
ification of the solubility values resulting from these
modeling studies is difficult, especially at tempera-
tures close to and below Tg, and some inconsistency
was also observed between different studies.29
In conclusion, the current research on the deter-
mination of drug–polymer miscibility and solubility is
overall preliminary and the estimation at low
temperatures is both experimentally and theoreti-
cally challenging. More fundamental understanding
may be necessary for further progress.
PRACTICAL CONSIDERATIONS IN INDUSTRIAL
DEVELOPMENT
Currently, the development of solid dispersions in the
industry remains largely trial and error, where a
variety of solid dispersions with different polymer
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
2946 QIAN, HUANG AND HUSSAIN
carriers and drug loadings are prepared and eval-
uated in parallel, with physical stability being on top
of the watching list. This approach, although feasible
in theory, is both time and resource-consuming. A
rational approach that enables the selection of solid
dispersion formulation and storage conditions would
help streamlining the industrial practice.
Figure 1 might be useful to guide a rational
approach for comprehensive comparison of different
solid dispersions side by side based on their physical
stability. To use this figure, the major difficulties
could be the correct estimation of the two thermo-
dynamic parameters, that is, drug–polymer misci-
bility and solubility, as well as the possible
complications with regard to the correlation between
these parameters and the physical stability of a solid
dispersion. On the other hand, kinetics plays a heavy
role in the practical development of solid dispersions.
Typical engineering processes, like spray drying and
hot-melt extrusion, are capable of producing well
mixed systems, which remain as homogeneous
dispersions (e.g., single Tg from DSC) kinetically
stable at temperature below its Tg. In a spray drying
process, drug and polymer are dissolved in a common
solvent and rapidly dried (1 s). As long as appro-
priate solvent and processing conditions are applied,
initial spray dried dispersions would mostly be well
mixed even if the miscibility limit is exceeded.
Similarly in a well-designed hot-melt extrusion
process, drug is dissolved in polymer at high
temperatures (typically close to the melting of the
drug), mixed well by screws and the resultant viscous
solution is quenched to room temperature to form a
homogeneous mixture. These systems, although
might be thermodynamically unstable, may still be
proved kinetically stable enough as long as the mixing
status between drug and polymer can be confirmed
and maintained after manufacturing. The kinetic
effect on the stability of solid dispersions is out of the
scope of this commentary. However, it certainly has
very critical impact on the physical stability and
requires in-depth exploration.
Using Figure 1 in practical applications, one has to
keep in mind that moisture is ubiquitous and water is
always the third component in any solid dispersion. It
is well known that water can bring profound impact
on Tg, solubility, and miscibility. The Tg of a ‘‘wet’’
solid dispersion can be obtained experimentally with
some careful experimental control,28,30,31 or be
estimated using the Fox equation, with the knowl-
edge of water content and Tg of pure water (108 to
1378C).44 Depending on the hygroscopicity of a
drug–polymer system, the moisture content may be
critical for the drug loading limit and stability of the
formulation.
In conclusion, a few practical notifications can be
adopted for the evaluation and development of solid
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
dispersions: (1) obtain Tg of the system and give the
best estimation (e.g., extrapolation) of the drug
solubility in polymer across the relevant temperature
range, (2) keep the drug loading in solid dispersion
below the solubility at Tg (i.e., C1 in Fig. 1) as long as
the dose requirement can be satisfied, (3) in cases of
high-dose requirement, give the best estimation of
drug miscibility in polymer and use miscibility at Tg
(C2 in Fig. 1) as the upper limit of drug loading,
(4) evaluate the hygroscopicity of the solid dispersion
to address the impact of relevant water content,
(5) use information from 1 to 4 combined with other
considerations (e.g., dissolution behavior, in vivo
performance, manufacturing feasibility, etc.) to select
appropriate polymer; (6) manufacture and store solid
dispersion within thermodynamically or kinetically
stable zones (i.e., Zones I, II, III, and V in Fig. 1)
whenever possible, and (7) study the crystallization
kinetics of the drug and the mixture (out of the scope
of this commentary).
With the complexity and controversy around the
determination and implication of drug–polymer
solubility and miscibility, more fundamental investi-
gations are highly desirable to reveal the details of the
destabilization mechanism of amorphous solid dis-
persions and then some industrial standards may be
established for solid dispersion development.
ACKNOWLEDGMENTS
The authors thank Prof. Lian Yu and Dr. Jing Tao
(University of Wisconsin, Madison) for their valuable
inputs and helpful discussions.
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