REVIEW

Amorphous Solid Dispersions: Utilization and Challenges in Drug

Discovery and Development
YAN HE, CHRIS HO

Pre-Development Sciences, LGCR, Waltham, Massachusetts 02451

Received 18 January 2015; revised 12 May 2015; accepted 18 May 2015

Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24541

ABSTRACT: Amorphous solid dispersion (ASD) can accelerate a project by improving dissolution rate and solubility, offering dose escalation
flexibility and excipient acceptance for toxicology studies, as well as providing adequate preclinical and clinical exposure. The prerequisite
physicochemical properties for a compound to form a stable ASD are glass-forming ability and low-crystallization tendency, which can
be assessed using computational tools and experimental methods. Polymer excipient screening by in silico miscibility prediction and
experimental screening techniques is discussed. Improved technologies for polymer screening with minimal quantity of drug substance,
and the scalability of ASD from bench to commercial are reviewed. Considerations of in vitro evaluations, preclinical animal selection, and
the translation of the preclinical results to clinical studies are also discussed. Better understanding of how polymers improve the stability
of the amorphous phase in the solid state and how ASD improves bioavailability have facilitated the applications of ASD ranging from
discovery research to preclinical development and further to commercialization. With the understanding of how ASDs are currently used
in the pharmaceutical industry and what challenges remain to be solved, ASD can be applied to solve drug formulation problems at given
research and development stages.  C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3237–3258,

2015
Keywords: amorphous solid dispersion (ASD); bioavailability; dissolution; formulation; polymer; poorly water soluble compound;
solubility; spray drying (SD); stability; supersaturation

INTRODUCTION lipid-based emulsions, self-emulsifying (nano or micro) drug

delivery systems (SNEDDS, SMEDDS, SEDDS), liposomes,
More than three quarters of new chemical entities in phar-
and so on may be viable options, but their utility is lim-
maceutical research are poorly water soluble,1,2 and for those
ited as the drug loading is typically low in these types of
solution formulations are often unachievable. Even when a
systems.
solution can be prepared with high levels of excipients for
In an amorphous solid dispersion (ASD), the solubility of the
pharmacokinetics (PK) studies, it frequently cannot be toler-
drug substance is improved by disrupting its crystalline lattice
ated during efficacy studies using in vivo disease models.3,4
to produce a higher energy amorphous form. Compared with
Complex formulations may produce unacceptable excipient-
other enabling solubilization approaches, an ASD can hold a
related biological effects in toxicology studies.5 Occasionally,
much higher dose for low-solubility active pharmaceutical in-
micronized or nanonized suspensions can solve these prob-
gredients (APIs). ASDs improve bioavailability by maintaining
lems with minimal amounts of excipients. However, they of-
supersaturation in the gastrointestinal (GI) tract. When su-
ten cannot offer adequate exposure because of their slow and
persaturation is sustained, the absorption of a compound can
incomplete dissolution.5,6 When poor water solubility is be-
be maximized to be greater than that of a saturated solution.7
cause of the lipophilicity of a compound, formulations such as
Furthermore, the solubility differences among crystalline phys-
ical forms (e.g., polymorphs) are eliminated because they are
Abbreviations used: API, active pharmaceutical ingredient; ASD, amorphous converted to the amorphous form. This is particularly bene-
solid dispersion; BCS, biopharmaceutics classification system; BMS, Bristol
Myers Squibb company; CAP, cellulose acetate phthalate; CP, coprecipitation;
ficial for compounds in the research stage when the form is
CVD, centrifuge vacuum drying; DDS, dynamic dielectric spectroscopy; DMA, not clearly defined. ASDs are usually well tolerated in ani-
dimethyacetamide; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; DSC, mal disease models and are acceptable to toxicologists as their
differential scanning calorimetry; Eudragit E, L, S, FS, polymethacrylates; FD,
freeze-drying; GI, gastrointestinal; HME, hot-melt extrusion; HPC, hydrox- polymer carriers are derived from GRAS (generally regarded as
ypropyl cellulose; HPLC, high-performance liquid chromatography; HPMC, hy- safe) excipients. Commonly used excipients for forming ASDs
droxypropyl methylcellulose; HPMCAS-L, -M, -H, hydroxypropylmethyl cellulose are cellulose derivatives such as hydroxypropyl methylcellulose
acetate succinate L grade, M grade, and H grade; HPMCP, hydroxypropyl methyl-
cellulose phthalate; HTP, high-throughput; KSD, KinetiSol R
dispersing; MBP, (HPMC), hypromellose acetate succinate (HPMCAS), hydrox-
microprecipitated bulk powder; MiCoS, miniaturized coprecipitation screening; ypropyl methylcellulose phthalate (HPMCP), hydroxy ethyl cel-
NME, new molecular entity; PEG, polyethylene glycols; PK, pharmacokinet-
ics; PLM, polarized light microscopy; PVAP, polyvinyl acetate phthalate; PVP,
lulose, hydroxypropyl cellulose (HPC), cellulose acetate phtha-
polyvinylpyrrolidone; PVP/VA 64, polyvinylpyrrolidone-vinyl acetate copolymer; late (CAP), methyl cellulose, carboxymethyl cellulose, ethyl
RE, rotary evaporation; RH, relative humidity; SC, solvent casting; SCF, spin- cellulose, carboxymethyl ethyl cellulose, chitosan, cyclodex-
coated film; SD, spray drying; SE, solvent evaporation; SEM, scanning electron
microscopy; SLS, sodium lauryl sulfate; ssNMR, solid-state nuclear magnetic trin and derivatives, lactose, poloxamers, polyvinylpyrrolidone
resonance; Tg , glass transition temperature; Tm , melting temperature; UV, (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA
ultraviolet; XRPD, X-ray powder diffraction. 64), polyvinyl acetate phthalate (PVAP), polymethacrylates
Correspondence to: Yan He (Telephone: +781-434-3581; Fax: +781-466-3788;
E-mail: Yan.he2@sanofi.com) (Eudragit E, L, S, FS), and polyethylene glycols (PEG) deriva-
Journal of Pharmaceutical Sciences, Vol. 104, 3237–3258 (2015) tives. These polymers are biologically inert and minimally

C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association absorbed.

He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015 3237

3238 REVIEW
Amorphous solid dispersions are generally prepared using
methods based on solvent evaporation (SE) or melt cooling.
The processing technologies include spray drying (SD), hot-melt
extrusion (HME), KinetiSol R
dispersing (KSD), drum drying,
freeze-drying (FD), rotary evaporation (RE), spray congealing,
coprecipitation (CP), cogrinding, spin-coated film (SCF), cen-
trifuge vacuum drying (CVD), supercritical fluid technology,
electrostatic spinning, and microwave technology.8–13 HME is
the preferred option in pharmaceutical development because of
the favorable powder properties generated from this technology,
the absence of organic solvents in processing, small footprint of
the equipment, ease of increasing batch size, scalability from
pilot to industrial setting, and suitability of continuous process-
ing. However, the application of HME in discovery research is
limited by the amount of API that is required for screening.
Grams of material are still required to fill the currently avail-
able laboratory-scale extruders. Even larger amounts of API
are required for KSD and drum drying. RE is a good choice for
discovery, but it is not a good option when scale-up is needed
for projects that progress into development. Supercritical fluid
technology, electrostatic spinning, and microwave technology
are still in their infancy and have yet to be proven in pharma-
ceutical R&D. FD can be a good choice when the solvent is wa-
ter. It is not applicable for scale-up when the API and polymer
carriers can only be dissolved in organic solvents. In addition,
the FD process is about 30–50 times more expensive than SD,
which renders FD a cost-ineffective choice for production.14 In
SD, the use of organic solvents is often unavoidable and this
raised issues with potential for residual solvents in the ASD,
safety of the workers, and environmental impact of the exhaust
gas. Nevertheless, SD is usually the technique of choice to pre-
pare ASD in discovery when drug substance is only available
in limited quantities because the screening requires only mil-
ligrams of API. In addition, the development time using SD
is also relatively short and a wide range of polymers can be
used. Spray dryers are available not only as bench-top instru-
ments that can function using only milligrams of API, but also
as commercial scale equipment that can prepare kilogram to
ton quantities of ASDs. They offer facile scalability from drug
discovery to development, to commercial production.15–17
Utilizing spray-dried dispersion in discovery has been a
proven approach to accelerate projects in the pharmaceutical
industry. It opens a new avenue for downstream development,
yet it does not lock the development to this approach. When
more API is available, it is possible for the preparation of ASD to
be switched to other techniques, such as HME or drum drying.
In many cases, ASD is only needed in discovery as an enabling
step. As the project progresses, the drug substance is better
characterized and its solid form is better defined. Switching to
other formulation approach within the next stage of develop-
ment is often achievable and preferred.
The objective of this review is to assess current understand-
ing of the chemistry of ASDs, how it is utilized, and what limits
its applications. The main focus will be on what physicochem-
ical properties of the API determines a candidate’s suitability
for ASD, how the polymer carrier stabilizes the amorphous API
in both dry and wet states, how screening is performed to select
the polymer matrix and optimize drug load, how the selection
criteria for ASDs are applied for projects in the discovery stage
and for later stage products in the pipeline, what should be
considered when a project is progressed to the next stage, what
challenges this drug delivery system poses, and what factors
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
should be considered when this system is evaluated in vitro
and in vivo. A roadmap with the aim to help selection an ASD
system is provided.
BACKGROUND
Solid Dispersion
The first application of a solid dispersion to increase bioavail-
ability was reported over 50 years ago. In 1960, sulfathia-
zole was orally administrated to humans in a eutectic mixture
with urea.18 The absorption and excretion of the eutectic mix-
ture was higher than that of sulfathiazole alone. The authors
proposed that this new formulation method provided micro-
scopic intimate contact of fine crystallites, which gives an im-
proved therapeutic effect of pharmaceutical compounds. They
described a new concept of using a physiologically inactive but
easily soluble compound as a carrier to improve the dissolution,
wettability, and solubility of a poorly soluble active to increase
its absorption. After the carrier is dissolved in the intestinal
fluid, the active is suspended as fine dispersed particles, which
wet better and have much greater surface area for dissolution.
The definition of solid dispersion was further refined by Chiou
and Riegelman19 in their review article published in 1971. They
defined solid dispersion as one or more active ingredients in an
inert carrier or matrix in the solid state prepared by melting (fu-
sion), SE, or a melting-solvent method. Since then, solid disper-
sion has become a platform to overcome the low-bioavailability
barrier for poorly water-soluble compounds.2,19–24 In this plat-
form, the dispersion can be a single amorphous phase mixture
of an active drug with polymer(s), a crystalline mixture of ac-
tive with polymer(s), solid complexes of active with complexing
ligands, or an active dissolved in solid lipid-based excipients.24
Amorphous Solid Dispersion
Among the aforementioned solid dispersions, bioavailability
can be ultimately improved when the active is in an amorphous
form. Two to three decades ago, researchers led by George Zo-
grafi and other pharmaceutical scientists, started to exploit the
solubility advantage of the amorphous forms of drugs in solid
dispersions.25 This type of solid dispersion is specified as ASD.
In ASD, the crystalline drug is converted to its amorphous
form and stabilized by a polymer carrier. The polymer carrier
not only helps to increase dissolution and solubility of the drug,
but also to improve the drug’s solid-state physical stability by
reducing its molecular mobility and increasing its glass tran-
sition temperature (Tg ). It can offer additional benefits when
the compound is only available as its amorphous form. This
strategy has been applied to stabilize the amorphous compound
when it is not chemically stable during storage, shipping, and
manufacture processes.26 It has also been utilized to sustain
supersaturation when the neat amorphous compound alone
cannot.27 The stability of an ASD is likely the result of dis-
rupting intermolecular interactions in the drug’s crystal lattice
and forming drug–polymer interactions. Steric hindrance and
hydrophobic interactions can also retard ASD phase separation
and API form conversion processes.28,29
The improved bioavailability resulting from an ASD is be-
lieved to be the results of the synergic effects of thermodynamic
and kinetic forces. Thermodynamically, there are fewer energy
barriers as the API is in an amorphous form that is a higher en-
ergy state. Its dissolution is more extensive and faster because
DOI 10.1002/jps.24541

Figure 1. Amorphous solid dispersion generates and maintains a su-
persaturated solution. A: Crystalline drug that has lower solubility.
B: Amorphous drug alone that has higher apparent solubility but pre-
cipitates rapidly. C: ASD with weak parachute polymer that cannot
delay the precipitation of the active to hold the supersaturation long
enough to maximize absorption. D: ASD with strong parachute polymer
that can sustain the supersaturation for absorption.
it does not need energy to disrupt the crystal lattice. Kinetically,
the conversion of the amorphous form back to a crystalline
form is impeded by the polymer. The polymer interacts with
the molecules of the active, keeping them apart by attractive
forces (e.g., hydrogen bonding) and steric hindrance. Its large
surface area can act as a crystallization inhibitor, delaying or
preventing nucleation and crystal growth. Because of the inter-
molecular contacts of the active with the carrier molecules, the
surface area of the active is also maximized to assist in faster
dissolution as described by the Noyes–Whitney equation. The
wetting is improved because the water-soluble polymer helps
facilitate the rapid influx of water into the solid dispersion.
In the presence of the polymer, the dissolution kinetics of the
compound can be greatly improved. Even in the case where
complete dissolution and release of the drug from the dosage
form is not achieved, the absorption can still be improved when
a supersaturated solution is generated and maintained during
its GI tract transit time. ASD can also increase permeation
rate by the spontaneously formed micro- or nanoparticles or
micelles in the GI tract.30–32
The mechanism for an ASD to generate and maintain super-
saturation in the GI tract is illustrated in Figure 1 using the
“spring parachute” analogy, which was introduced by Guzmán
et al.33,34 Depending on the enthalpy and entropy of fusion, the
free energy between the amorphous and crystalline forms of a
compound can be very different. Consequently, the solubility of
the amorphous, as expressed in Eq. 1, can be tens to hundreds
of times greater than that of its crystalline counterpart.35 The
extra free energy in the amorphous form behaves like a spring
to bring the concentration of the active to a level that is higher
than that of its crystalline form. The polymer behaves like a
parachute to keep the concentration from decreasing. A strong
parachute can help hold the transient supersaturated state by
minimizing precipitation of an active during its residence in
DOI 10.1002/jps.24541
REVIEW 3239
the GI tract.
G
Famorphous = e RT × Fcrystalline (1)
where Famorphous is the solubility of the amorphous form,
Fcrystalline is the solubility of the crystalline form, G is the free
energy difference between the amorphous form and the crys-
talline form, R is the molar gas constant, and T is the testing
temperature (K).
Spray Drying
Spray drying is the transformation of a solution feedstock from
a fluid state into a dried particulate form by spraying the feed
into a hot drying medium. The earliest mention of the SD con-
cept was in 1865, and the first detailed description of drying
products in spray form was carried out by Samuel Percy in
a patent granted in 1872.36 The significant utilization of the
SD technology in industries, such as food and detergents, was
not realized until 1920s.37 This technology has been explored
by pharmaceutical scientists since 1970s to reduce the particle
size of drug substances and to convert the crystalline form to
the amorphous form.38
Compared with fusion methods, such as HME, SD is the
technique of choice for thermally sensitive compounds as the
drying droplets are at a lower temperature and the drying time
is short.39 Although the temperature for the inlet drying gas
may be as high as 120°C, the temperature of the outlet gas is
usually 60°C or lower. In fact, the actual temperature of the
evaporating droplets is even lower because of the cooling effect
caused by the latent heat of vaporization. The drying time is
extremely short, on the order of milliseconds.
A large volume of solvent is often required to prepare an ASD
by SD as the hydrophobic drug, and the hydrophilic carrier has
to be dissolved in a common volatile solvent. Although finding
the common solvent remains challenging, the efficiency of sol-
vent removal in SD is greatly improved over the traditional
methods, such as RE.40 Compared with a film generated from
SE and a dispersion prepared by ball milling, the drug and the
polymer are mixed better at the molecular level in dispersions
produced by SD.30,41
The availability of the instrumentation is an important fac-
tor driving the utilization of a technology. Access to a spray
dryer certainly enables formulation scientists to apply this
technology in early research. In the last 20 years, bench-top
micro spray dryers, such as Buchi B-90, B-290, B-191, B-190,
Niro SDmicro, Anhydro SPX, ProCepT 4M8, and ProCepT 4M8-
Trix, have become standard tools in most major pharmaceutical
research and development laboratories. The utilization of SD
has been implemented in pharmaceutical companies such as
Addex,42 Abbott,43,44 Bristol Myers Squibb company (BMS),45,46
Merck,5,47 Novartis,48 Pfizer,49,50 Roche,13,51,52 Sanofi,53,54 and
Vortex.55
COMPOUND GLASS-FORMING ABILITY AND
CRYSTALLIZATION TENDENCY
Before ASD can be explored as an option to deliver a compound,
it is important to know whether the compound has suitable
physicochemical properties. Researches have suggested that
the properties of being a good glass former with low tendency to
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
3240 REVIEW
recrystallize are the key criteria for determining the potential
for a crystalline drug to be formulated as an ASD.2,8,56,57
These properties can be experimentally evaluated.57 They
can also be predicted based on measured or calculated parame-
ters, such as the melting and glass transition temperatures,
melting enthalpy and entropy, melting viscosity, crystalline
density, molecular size and weight, molecular mobility, flexi-
bility, complexity, number of benzene rings, level of molecular
symmetry, level of branched carbon skeleton, number of rota-
tional bonds, number of electronegative atoms, and number of
hydrogen bonds.58–62
The amorphous form of a drug substance can often be gen-
erated from its crystalline form. The neat amorphous form of
a compound can also be obtained from condensation of its va-
por, vitrification of its melt mass, or breakage of a crystalline
form by milling or grinding.63 Once the amorphous property is
confirmed, its stability can be evaluated under stressed condi-
tions with accelerated temperature and humidity. The forma-
tion of crystalline material is commonly monitored with polar-
ized light microscopy (PLM), X-ray powder diffraction (XRPD),
or differential scanning calorimetry (DSC).
At the early stage of a project, the access to material is often
limited. With a minimum amount of drug substance, a quick
assessment using modulated DSC with a predefined heating–
cooling–heating cycle was developed by Baird et al.64 On the
basis of the vitrification and recrystallization behaviors in the
cycle, 51 randomly selected organic molecules were classified
into three classes, as summarized in Table 1. The cooling and
reheating rates are critical in this screening, because they gov-
ern vitrification, formation of nuclei, and crystalline growth.
Crystallization tendencies between molecules of similar struc-
ture were found to vary significantly. The understanding of
the driving force for crystallization in each class of compounds
was further investigated by Kawakami et al.65 with a dataset
of seven compounds. For Class I compounds, the crystallization
feature was determined to be dominated by thermodynamic fac-
tors (temperature). The crystallization of Class II compounds
was found to be influenced by competition between thermo-
dynamic and kinetic factors. Although the crystallization of
compounds in this group is still dominated by temperature,
the transformation is perturbed by steric hindrance that can
be measured as local pressure. There is a large energy barrier
for compounds in Class III to nucleate, which leads to a low
probability for them to crystallize. The dominant factor for the
crystallization of compounds in this group is pressure. It was
also concluded that for the compounds in the high-crystalline
tendency groups, Class I and II, the initiation time for their
crystallization could be generalized as a function of the ratio of
Tg to T (the storage temperature), Tg /T. In a recent publica-
tion, Trasi et al.62 investigated glass stability and concluded
that the following physicochemical properties can contribute
to fast crystal growth rates: low molecular weight, high melt-
ing temperature (Tm ), low melt entropy, low melt viscosity, and
high crystal density.
The Tm , Tg , and their ratio have been used to predict glass-
forming ability and crystallization tendency, as Tm is a well-
accepted parameter to evaluate the thermodynamic driving
force for crystallization, and Tg is a popular measure to as-
sess the kinetic barriers of the amorphous. The relationship
of Tg and Tm was first identified by Kauzmann.66 He pointed
out the 2/3 rule, which he stated as a glass transformation
event with sudden drop in the specific heat and the thermal
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
expansion coefficient when a supercooled liquid is cooled below
approximately 2/3 of its normal freezing point (K). However,
the relationship of Tg /Tm = 2/3 was later recognized as the
Beaman–Boyer empirical rule, because Beaman and Boyer ap-
plied it to polymer chemistry and their publications led to a
greater awareness of this relationship.67,68 The ratio of Tg /Tm
reflects both the thermodynamic and kinetic driving forces. A
compound with a high Tm value has strong tendency to crystal-
lize because of the large thermodynamic driving force, whereas
a compound with a low Tg value has low kinetic barrier for
molecular diffusion. This relationship has been widely applied
to polymer materials, alloy materials, and pharmaceutical com-
pounds with modified versions and refined numbers to predict
glass-forming ability.69–72
The reciprocal of the Tg /Tm (K/K) value has been applied
not only to predicting the glass-forming ability and crystal-
lization tendency of a compound, but also to selecting drug
loading in ASD.56,71 In the study reported by Friesen et al.,56
139 compounds were selected for ASDs because their Tm /Tg
(K/K) values were less than 1.6 (the reciprocal of this value
makes Tg /Tm ˜ 2/3). These compounds were divided into three
groups. The first group has the least tendency to crystallize
with Tm /Tg value less than 1.25. The second group has higher
tendency to crystallize with the Tm /Tg value between 1.25 and
1.4. The third group has even higher tendency with the Tm /Tg
value between 1.4 and 1.6. Using HPMCAS as the polymer
carrier, the first group compounds were successfully formu-
lated as ASD with 50% drug load, the second group compounds
were formulated with 35%–50% drug load, and the third group
compounds were formulated with 10%–35% drug loading. The
success of developing ASD for MK-0364 using hydroxypropyl
methylcellulose acetate succinate L grade (HPMCAS-L) was
also attributed to the good glass formation ability of MK-
0364, which has Tg 41°C, Tm 104°C, and Tm /Tg (K/K) 1.20.47
Though the physical stability with the defined drug load can
be predicted for ASD using the relationship of Tm /Tg , the ef-
fect of drug load on in vivo absorption needs to be studied and
confirmed.
Using a single parameter to predict ASD stability may over-
simplify the reality. However, this ratio can serve as a quickly
accessible starting point to understand whether a compound
may be a suitable candidate for ASD, as Tm s and Tg s for known
compounds are abundant in the literature and can be easily
measured for new compounds using a modulated DSC with a
small amount of API.
In the absence of experimental data input, sophisticated
computational tools can also provide initial insights. An al-
gorithm solely based on calculated molecular descriptors was
developed by Mahlin et al.59 to predict glass-forming ability. The
input for this model was 245 variables obtained from DragonX
(Talete, Italy) using partial least squares projection to latent
structure discriminant analysis. The response variables were
glass former (assigned value 0) and nonglass former (assigned
value 1). This model suggested that larger molecules with a low
number of benzene rings, low level of molecular symmetry, and
branched carbon skeleton and electronegative atoms have the
ability to form a glass. The glass formation prediction was ex-
perimentally verified on a training set of 16 compounds whose
amorphous forms were generated using SD, melt quenching, or
mechanical activation. Only one compound failed in the predic-
tion. When a random selected testing set of 16 compounds was
checked, there was a 75% success rate.
DOI 10.1002/jps.24541
 REVIEW 3241

Table 1. Classification of Glass-Forming Ability and Crystallization Tendency by DSC64,65

Group Cooling Reheating Classification Crystallization Driving Force

Class I Crystalline – Poor glass former/high crystalline tendency Thermodynamic

Class II Amorphous Crystalline Good glass former/high crystalline tendency Thermodynamic and kinetic
Class III Amorphous Amorphous Good glass former/low crystalline tendency Pressure

A follow-up study by this group of researchers extended to predict the thermodynamic miscibility between drug and
the prediction with rapidly measured physical properties from polymer.73,80–84
DSC.60 The authors suggested that a decision making on the
selection of amorphous or ASD formulation can be rationalized G Ndrug Npolymer
based on the molecular weight, and the predicted or experimen- = ln Ndrug + lnNpolymer + PNdrug Npolymer (2)
RT mdrug mpolymer
tally obtained glass transition and recrystallization tempera-
tures. Although low crystallization tendency in the dry state is
recognized as an important factor for the ASD shelf life, low where G, R, and T are the same as in Eq. 1, Ndrug is the volume
crystallization tendency in the wet state is crucial to achieve fraction of drug, mdrug is the ratio of the volume of the drug to
improved bioavailability.57 the lattice site, Npolymer is the volume fraction of polymer, mpolymer
is the ratio of the volume of the polymer to the lattice site, and
P is the Flory–Huggins interaction parameter representing the
POLYMER SCREENING FOR SOLID DISPERSION difference between the drug–polymer hetero contact interac-
tion, the drug–drug homo contact, and the polymer–polymer
Even for compounds that are identified as good glass form-
homo contact interactions.
ers with low crystallization tendencies, their amorphous forms
This equation is particularly useful in describing drug–
are still thermodynamically unstable. Incorporating the amor-
polymer mixing systems because it takes into account the
phous form into a polymeric solid dispersion can drastically al-
large size discrepancy between the drug molecule that usu-
ter the kinetics of conversion to a crystalline form in both solid
ally has molecular weight less than 600 Da and the polymer
and supersaturated solution states. The physicochemical prop-
molecule that usually has molecular weight between 10,000
erties of the drug and the polymer determine how the polymer
and 1,500,000 Da. The first two terms in the right side of the
interacts with the drug molecule in the ASD. The ideal polymer
equation represent entropy, which always favors mixing. The
plays multiple roles in the dispersion. First, it has the proper-
magnitude of the entropy upon mixing is relatively constant
ties to maintain the drug’s amorphous state not only during the
in such systems where small size molecules mix with much
manufacturing but also during shipping and storage. Second,
larger molecules. The miscibility of the drug–polymer system is
it dissolves rapidly and releases the drug at the absorption site
therefore determined by the Flory–Huggins interaction. When
in the GI tract. It also has the ability to maintain the super-
the drug–polymer hetero contact interaction is greater than the
saturated solution for an adequate period to allow absorption.
summation of the drug–drug and polymer–polymer homo con-
Furthermore, it may also enhance the permeation of the com-
tact interactions, the value of P will be negative, which means
pound through the GI tract membranes.
the system also enthalpically favors mixing, and hence the
The miscibility of the drug and polymer is generally believed
drug–polymer system is miscible. In the case that the drug
to be the prerequisite condition to form a physically stable ASD.
and the polymer lack significant intermolecular interactions,
A miscible dispersion is defined as one single amorphous phase
enthalpy does not favor mixing. However, the system can still
system, which has one single Tg and no detectable phase sepa-
be miscible if the mixing entropy is sufficient to offset the un-
ration by analytical techniques, such as DSC, XRPD, infrared
favorable adhesive intermolecular interactions.
spectroscopy, solid-state nuclear magnetic resonance (ssNMR),
This theory serves as a good starting point to understand the
scanning electron microscopy (SEM), dynamic dielectric spec-
thermodynamics between drug and polymer.80 Although it is a
troscopy (DDS), and Raman.24,73–77 A great deal of research
useful theory for the prediction of drug solubility in polymer
efforts have been employed in predicting the compatibility and
carrier, its limitations are also well-known because this theory
the phase stability of drug–polymer mixtures. These studies
is based on mean-field approximation to facilitate the calcu-
are shedding light on the stabilization mechanisms of the amor-
lation for placement of a polymer molecule in a partly filled
phous compound in an ASD. However, because of the complexity
lattice, the assumptions to generate this equation are based on
of the interactions, deviations of experimental results from the-
polymer–polymer or polymer–solvent systems, and the energy
oretical predictions are still ubiquitous. In industry, the selec-
for breaking the crystalline lattice is not included.78,81
tion of the optimal polymer still mainly relies on experimental
Solely based on the chemical structures of the drug and the
screening.2
polymer, the value of P can be calculated from solubility param-
eters as in Eq. 3.79,85,86 The solubility parameters for the drug
Theoretical Drug–Polymer Miscibility Prediction
and the polymer can be estimated from a group contribution
It is recognized that there is not a well-established method method.81,82,84,87 This method has been incorporated into some
available to measure the miscibility between drug and poly- commercial prediction tools, such as the MemFis R
software, to
mer because the polymer’s viscosity impedes the attainments allow in silico polymer screening. The accuracy of these in silico
of equilibrium. Currently, it can only be estimated by model predictions need to be experimentally verified as the lack of pre-
prediction.78 The lattice-based Flory–Huggins theory,79 ex- dictive power is known when the solubility parameter is used
pressed in Eq. 2, has been adapted from polymer blends to predict systems where the interactions are predominated by

DOI 10.1002/jps.24541 He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015

3242 REVIEW

forces other than van der Waals forces. Highly directional in-
teractions (e.g., hydrogen bonding) and long-range interactions
(e.g., ionic interactions) are known to form in drug–polymer
systems.88

L(*drug − *polymer )2
P= (3)
RT

where R, T, and P are the same as in Eqs. 1 and 2, L is the

volume per lattice site, and * is the solubility parameter for the
drug, *drug , and for the polymer, *polymer .
When the calculation was coupled with experimental data,
much improved predictions can be achieved. The experimental
data can be the melting point depression in the mixture of
the drug and the polymer or solubility of the drug in a lower
molecular weight analog of the polymer.73,80,81,83

Experimental Screening
Although there are improved techniques for the prediction of
the solid-state stability of ASD, the prediction of ASD disso-
lution performance remains challenging because it remains
difficult to predict the ability of a polymer to prevent drug crys-
tallization in supersaturated solution. At present, the identifi-
cation of polymeric carriers that increase dissolution rate and
also stabilize supersaturation remains largely empirical.2 Ex-
perimental screening of a polymer is typically unavoidable.

Solvent Shift
The solvent shift technique, also known as cosolvent or solvent
quench method, is traditionally used to evaluate the ability
of a polymer to attain supersaturation and to prevent precip-
itation from supersaturated solution.29,89–91 The polymers of
interest are dissolved in aqueous media, which can be wa-
ter, buffer, or simulated biorelevant fluid. The drug is dis-
solved in a water-miscible organic solvent, such as ethanol,
propylene glycol, PEG, dimethylformamide (DMF), dimethyac-
etamide (DMA), N-methylpyrrolidone, 1,4-dioxane, or dimethyl
sulfoxide (DMSO). In addition to organic solvent, an acidic drug
can be dissolved in alkaline media, such as sodium hydroxide
solution, and a basic drug can be dissolved in acidic media, such
a hydrochloric acid solution. The drug solution is then added
dropwise into the aqueous media containing the test polymer.
The target can be a predetermined drug concentration or until
precipitation is noticed. The final solution contains a minimal
amount of organic solvent, and the drug concentration should
be greater than its solubility in the media. The precipitation
(appearance of turbidity) can be monitored visually or detected
via nephelometry or by a focus beam reflectance measurement.
The concentration of drug in solution can be monitored by an
in situ fiber optical probe, or measured by ultraviolet (UV) or
high-performance liquid chromatography (HPLC) using super-
natant that is withdrawn at predetermined time points and
then filtered or centrifuged. As described in the Solvent Evap-
oration and Casting section, this screening can be performed
in a high-throughput (HTP) fashion with robotic automation
using multiwell plates. The best-performing polymer is the one
that offers the highest drug concentration in solution for the
longest time. The results help to select the polymer that stabi-
lizes the compound’s supersaturation. These screening results
alone, however, do not provide information on whether the poly-
mer is capable of forming an ASD with the drug or what the
Figure 2. Flow diagram of HTP screening for polymer and drug load-
ing by solvent casting and dissolution method.
optimum drug load will be. Even in the case where the polymer
can form an ASD with the compound, the dissolution behavior
of the ASD can diverge sharply from the screening results. For
example, in one solvent shift study, the AUC of itraconazole in
a buffer solution with hydroxypropyl methylcellulose acetate
succinate H grade (HPMCAS-H) was about seven times that
in buffers with HPMCAS-M or HPMCAS-L. However, the dis-
solution AUC from the ASD that was made with HPMCAS-H
was only about 2% of that from the ASDs that were made with
HPMCAS-M or HPMCAS-L. Although the rank order to stabi-
lize itraconazole supersaturated solution from the solvent shift
method was H > M ≈ L, the rank order to promote dissolution
from ASD was L ≈ M  H.29
Solvent Evaporation and Casting
When a drug ASD needs to be produced to assess its dissolution
behavior, a rotary evaporator becomes a useful tool as it is
available in almost every research laboratory.92–95 As a thin
film is formed after the SE, this method can be referred to
as solvent casting (SC). A film can also be cast on a Teflon-
coated glass plate or a silicon chip after rapid spinning.41,96
This screening can be performed in a HTP manner.51,97,98
The HTP SC process is schematically depicted in Figure 2.
The test compound is dissolved in a suitable organic solvent
as stock solution and dispersed into each well of a 96-well
plate. The contents can be the same compound for the entire
plate with the same or different volume for the same or differ-
ent drug load. The contents can also be multiple compounds
for one plate leading to fewer combinations. The test poly-
mers are also each individually dissolved in a suitable organic
solvent and dispensed into these wells. A second polymer or

He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015 DOI 10.1002/jps.24541


surfactant can be added if the scope includes ternary or higher-
order combinations. After dispensing, the plate is covered and
mixed via vortexing or a method designed for the robotic work-
station. Then the solvent is removed, most commonly via vac-
uum evaporation. A solid film is expected to form at the bot-
tom of the well. The plate can be characterized by techniques
such as PLM, SEM, XRPD, or Raman. As described by Chiang
et al.,51 the plates can be prepared as duplicates with one for
characterization and stability studies while the other is used
for solubility studies. When only one plate is prepared, the plate
can first be characterized for amorphous contents, then evalu-
ated for stability for a given time frame, characterized again,
and then used for dissolution testing. The goal of the screen-
ing is to select a polymer that can form solid dispersion with
the testing compound to improve its dissolution. When a buffer
is added to the plate, the solid film will be hydrated, and the
dissolution of the compound can be facilitated with shaking or
stirring. At a predefined time point, usually 1–3 h, the contents
are transferred to filter plates and the filtrates are diluted with
an organic solvent to prevent further precipitation, and finally
the concentrations are measured by UV or HPLC.
The screening can be modified along the process line at any
step to accommodate the needs of the project.51,97–99 This HTP
screening method has been adapted by many contract research
and manufacturing organizations, such as Evonik and Bend
Research, to screen polymers for customers. In the work of Bar-
illaro et al.,97 HTP was performed on binary combinations of
phenytoin with polymer or surfactant at drug loadings of 10%,
20%, or 40%. Three polymers at all three tested drug loads
that provided dissolution greater than 90% after 30 min were
selected for scale-up using the RE method. The dissolution pro-
files of the RE scaled-up ASDs correlated well with those ob-
tained from HTP screening.97
Chiang et al.51 reported that SD was used to successfully
scale up an ASD based on HTP screening results. In their
study, HTP screening was performed on four model compounds
with loadings of 10%–70% using HPMC K100, HPMCAS-M,
or PVP K90 as the carrier. Duplicate plates were prepared.
Full characterization was performed on the plates that were
stored at 50°C/75% RH (relative humidity) for 2 weeks. The
HTP screening method was validated by a low-solubility b-Raf
kinase inhibitor, Compound A. The physical stability and sol-
ubility after 2 weeks stored at 50°C/75% RH were evaluated.
The data generated by the HTP method were in good agreement
with that generated from the spray-dried material. HPMCAS-
M with 20% drug load offered the highest solubility improve-
ment. In a separate publication, the spray-dried Compound
A with 25% drug load in HPMCAS-M offered much improved
bioavailability.100 The authors attributed the success of scaling
up the HTP method to SD by the rapid evaporation in their
HTP experimental conditions. A high-vacuum system and heat
were utilized to ensure rapid solvent removal. Using the Hick-
man and Clausius-Clapeyron equations, they concluded that it
only takes 1–15 s to completely evaporate the organic solvents
in these wells.
Miniaturized Coprecipitation Screening
In this screening technique, the API and polymer stock solu-
tions are prepared in a common water miscible solvent, such
as DMA, DMSO, or DMF. They are mixed at predefined drug
loading ratios. The mixtures are then dispersed in a dropwise
DOI 10.1002/jps.24541
REVIEW 3243
manner into 1 mL glass vials, which are inserted in the wells of
a 96-well plate, as in Figure 2. The vials are filled with acidified
water (e.g., 0.01 N HCl), chilled at 5°C, and stirred to produce
fine microprecipitated bulk powder (MBP). The suspensions
are next transferred to filter plates, washed, dried, and then
follow the same steps as in Figure 2, where the powder can be
characterized, dissolved, and analyzed.101
The MBP preparation was adapted from a general CP
method by using enteric polymers.13 This method is suitable
for drugs that are not amendable to HME, SD, RE, or FD be-
cause of high Tm , thermal instability, or low solubility in volatile
organic solvent and water. Although the laboratory-scale MBP
experiment requires at least 100 mg API to test one condition,
this integrated miniaturized system can be used to screen ASDs
with as little as 2–10 mg API per sample.101
Single Droplet Drying
Some research laboratories are working with the single droplet
drying technology to produce amorphous forms with even lower
drug substance requirements for screening.
Aerodynamic, electromagnetic, and acoustic levitation have
been explored to develop amorphous drug on single droplet
individually dried particles.102,103 Drug solutions that have a
propensity for forming viscous fluids have been screened on an
acoustic levitator by SE or laser heating.104 During levitation,
droplets with 1–3 mm diameters are introduced and dried while
floating freely in the gas phase. The drying process is similar
to the SD process as the droplets do not contact any surface.
Therefore, the extrinsic heterogeneous nucleation is avoided
and the results are expected to be reproduced in scaling up us-
ing SD.103 The individually dried droplets of griseofulvin with
2.5% and 20% drug load in PEG 6000 mixtures were levitated
in a drying kinetics analyzerTM .105 Their physical and chemical
properties were compared with bulk spray-dried powders com-
posed of the same ratios of the griseofulvin and PEG 6000. The
characterizations were performed by atomic force microscopy
imaging and confocal Raman microscopy. For the same drug
load, it was found that the individually dried particles were
equivalent to the bulk spray-dried powders. Using this tech-
nology, with very minimal amount of material, drug–polymer
combinations can be screened to simulate SD. However, only
a few pharmaceutical laboratories are currently equipped with
such instrumentation. Literature on the use of the single par-
ticle (or droplets) to screen formulations is limited.
Spray Drying
Although both SD and SC produce materials via SE, the films
and the spray-dried particles can produce very different dis-
solution profiles.47,105 Even in the case where the miscibil-
ity limit is exceeded, rapid drying process still most likely
generates well-mixed drug–polymer systems in spray-dried
products.78 With micro spray dryers becoming increasingly
common in pharmaceutical laboratories, many pharmaceuti-
cal scientists choose to directly screen formulations using SD
technology.5,42,45,106
The B-90 is the fourth generation of laboratory-scale spray
dryer from BL̈chi Labortechinik AG. It offers 40%–95% yield
for 30–500 mg of material.107–110 Therefore, 30 mg of compound
with 20% drug load in polymer can be screened using Buchi
B-90 to generate about 75 mg product with the assumption of
50% yield. The Bend Mini Spray Dryer from Bend Research
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
3244 REVIEW
Inc. is able to provide 82% yield on 50 mg batch size, with 10%
and 25% drug load, using 5 mL solvent.27 The ProCepT 4M8-
TriX states a greater than 90% yield from as little as 1 mL
of solution. The introduction of ultrasonic nozzles to bench-top
spray dryers has improved their capabilities for formulation
screening. Compared with the two-fluidic nozzle configuration,
an ultrasonic nozzle offers the advantage of spraying very small
amounts of solution with better yield by avoiding solution ad-
hesion to the chamber of the small laboratory dryer. Equipped
with ultrasonic nozzles, bench-top spray dryers produce par-
ticles with the size, morphology, and powder properties that
closely resemble those from large spray dryers. This adaption
certainly helps streamline scale up from research to develop-
ment and further to product commercialization.16
As an example, solid dispersions of amlodipine using dex-
trin as the matrix with or without the permeability enhancer
sodium lauryl sulfate (SLS) were manufactured by using a
Buchi 190 mini spray dryer. The best-performing dispersion
demonstrated a comparable rat PK profile to the marketed
product Norvasc R
, which is formulated using amlodipine be-
sylate salt.106 In another example, an ASD containing a GPR-
119 agonist was selected as a preclinical candidate formulation,
which was prepared by a SD process using the ProCepT micro
spray dryer. The formulation selection was based on solid-state
stability of the ASD upon storage, physical stability of the ASD
suspension in dosing vehicle, dissolution in biorelevant media,
rat PK profile, and the acceptance of the excipients for preclin-
ical toxicity studies.5
PERFORMANCE OF SOLID DISPERSION
Once solid dispersion is identified as the enabling drug delivery
tool for a drug candidate and a polymer or polymer mixture is
selected through screening, the solid dispersion containing the
compound can be prepared by a selected processing technique.
SD and HME are the most commonly used processes in re-
search and development, respectively. The solid-state stability
can be evaluated under stressed conditions with accelerated
temperature and elevated RH. The performance of the drug
dispersion is determined by the rate and extent of drug release
as measured by in vitro dissolution and confirmed by in vivo
exposure.
In Vitro Evaluation
Dissolution
Dissolution is the most widely accepted tool to predict in vivo
biological performance of a formulation.24 It remains challeng-
ing to correlate the in vitro dissolution results to the in vivo
absorption especially for formulations that produce supersat-
uration, because the in vitro dissolution may not be predic-
tive of precipitation or fully demonstrate the driving force for
absorption generated by the solubilizing power of such drug
delivery systems.111,112 This is especially true for ASDs, be-
cause complex processes take place simultaneously during their
dissolutions.113
The dissolution method should be developed to fit the pur-
pose at the stage of the development. As pointed out by New-
man et al.,24 during the discovery and early phases of drug
development, the dissolution conditions need to be carefully
designed to closely simulate the GI tract environment in order
to predict in vivo performance, not to control batch to batch
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
consistency. The simulation parameters should include compo-
sition of the medium, pH of the medium, dose to GI fluid volume
ratio (with the introduction of the whole intended dosage form
in the dissolution medium), and the exposure (experimental)
time. The pH of the medium at the end of experiment should be
measured. The precipitate, if there is any, should be character-
ized. Meanwhile, nonsink condition should be used, although
using sink condition is common practice when dissolution is
performed for quality control of conventional formulations.114
The commentary authored by Newman et al.24 thoroughly ana-
lyzed publications up to 2010, which reported bioavailabilities
using ASDs. Their analysis and discussion focused on 40 stud-
ies, where the drug is in an amorphous form and the polymer
is the main component of the dispersion (interested readers
are urged to consult the article for details). The authors ana-
lyzed all of the reported dissolution conditions and found that
71% of them used Apparatus II vessels, 92% used nonspecific
or nonsink condition, 90% performed in 500–900 mL media,
88% performed at 50–100 rpm, 50% used media with pH close
to neutral, 79% used buffer or water, and 21% used simulated
gastric fluid or simulated intestinal fluid without enzymes. The
dissolution media were widely varied in composition with pH
from 1.2 to 7.2.
In one study, felodipine ASDs were prepared with HPMC as
the carrier.113 The controlling factor in their dissolution was
found to change from the physicochemical properties of the
polymer to the solubility of the amorphous drug layer when
the drug load in the ASD was increased from 10% to 50%.
The generality of the conclusion was verified by studies of the
same percentage drug-loaded ASDs with either felodipine or
indomethacin as the drug and either HPMC or PVP as the
carrier. Using a UV dip probe detector, the peak concentra-
tions in the dissolution profiles of the ASDs with 10% drug
load showed full release from the introduced solids. The study
was performed using various amounts of ASD solids that con-
tained the equivalent felodipine concentration of 30, 60, and
90 :g/mL. However, the dissolutions of the ASDs with 50%
drug load were much less with only about 6% release from the
introduced solids. The felodipine concentrations in the disso-
lution profiles of 50% drug-loaded ASDs were close to its theo-
retically calculated solubility of the neat amorphous drug form.
Within a few minutes after the 10% drug load ASDs were intro-
duced into the dissolution media, the solids disappeared and the
media became turbid. In contrast, the media and the solids re-
mained unchanged throughout the experiment (observed under
cross-polarized microscopy) after the 50% drug load ASDs were
introduced. Dynamic light scattering analysis of the turbid me-
dia revealed the formation of nanoparticles. The UV spectra
analysis of these particles indicated that they were crystalline
nanoparticles of felodipine, which were precipitated from the
supersaturated solutions. In order to verify the degree of su-
persaturation in the dissolution of the ASD, a diffusion study
using a dialysis membrane was performed on the dissolution
of these ASDs, along with artificially supersaturated felodip-
ine solutions, dissolution of felodipine neat amorphous form in
the presence of polymer in the medium, and a saturated so-
lution of crystalline felodipine. The equilibrium solubility of
the felodipine crystalline form is about 1 :g/mL, which was
used as the reference. The artificial supersaturated solutions
were added at concentrations of 5 and 10 :g/mL in the donor
chambers and their resultant measured relative fluxes were 4.8
and 10, respectively. The measured values and their ratios to
DOI 10.1002/jps.24541

the reference indicated that the experimental design accurately
discriminated between solution concentrations. The measured
solubility of the neat amorphous form in the donor chamber
was about 10 :g/mL and its solution activity calculated from
the flux value across the dialysis membrane was about nine
times to that of crystalline form. These results were remark-
ably close to the theoretically calculated values. In contrast to
approximately 2.5 times difference in the apparent concentra-
tions in the donor chambers, the flux of the ASDs (11 and 10
for the 10% drug load and 50% drug load, respectively) were
similar. These results indicate that there is no significant dif-
ference in the thermodynamic activity of felodipine in solutions
derived from the 10%, 50% drug load ASDs or the neat amor-
phous API. A solution NMR study on the dissolutions of these
ASDs confirmed the diffusion results. Although the finding in
this research is intriguing, a further investigation on in vivo
exposure of these ASDs would be very helpful to shed light on
understanding how the nanoparticles in the low drug-loaded
ASD, and the unchanged amorphous compound in the high
drug-loaded ASD affect the bioavailability.
Permeation
The permeation rate of ASDs has been evaluated by some re-
searchers because they believe this delivery system may also
alter the permeation rate of a drug. The intracellular uptake
of 9-nitrocamptothecin was significantly increased on Caco-2
cells when its freeze-dried ASD with a drug load of 6% in Solu-
plus was studied. The increased permeation rate was attributed
to the spontaneously formed homogenous nanosized micellar
structures.32 One study on an ASD prepared by HME contain-
ing 5% of the model compound ABT-102 in polymer PVP/VA 64
and surfactants Tween 80, pluronic 188, and sucrose palmitate,
led to a controversial discovery. After dissolution of the ASD, it
was found the medium contained free API, micelles, polymer-
bound and solubilized API, as well as microparticulate struc-
tures that were mainly formed by amorphous API. Although
the increased apparent solubility was attributed to the micel-
lization and complexation of solubilized API, the increased per-
meation rate was accredited to the amorphous API micropar-
ticulates, which was described as true supersaturation.31
Some researchers have adapted ASD to improve bioavail-
ability of biopharmaceutics classification system (BCS) IV com-
pounds by incorporating absorption enhancers into the disper-
sion. Using orthogonal design, nine combinations of ternary
ASDs were prepared for berberine with one of the three poly-
mers, PVP K30, PEG 6000, or F 68 as the carrier, and sodium
caprate as the absorption enhancer.95 The membrane perme-
ability of these preparations was assessed using Caco-2 cells,
and the intestinal absorption was examined in situ using rat
small intestine. The in vivo bioavailability and bioactivity stud-
ies confirmed that the preparation that offered the best perme-
ation rate and absorption in the in vitro and in situ studies
had markedly increased bioavailability and significantly im-
proved antidiabetic effect. SLS at the concentration of 0.9% was
added to spray-dried amlodipine–dextrin solid dispersion.106
The amount of this tertiary component did not affect the dis-
solution of amlodipine. However, the permeation rate of the
ternary ASD was increased on Caco-2 study. Consequently, the
exposure of this ternary ASD in rats was increased compared
with the neat amlodipine powder, and the binary amlodipine–
dextrin ASD.
DOI 10.1002/jps.24541
REVIEW 3245
In Vivo Evaluation
Preclinical
The selection of a preclinical animal model is critical because
significant variations in drug absorption can be caused by
differences in aspects of anatomical, physiological, luminal
fluid contents, gastric emptying, metabolic, biochemical, mi-
crobiome compositions, and so on.115 In the aforementioned
commentary,24 four animal species were found in the studies
analyzed: dog (50%), rat (30%), rabbit (18%), and monkey (2%).
In literature published after 2010, rat appears as a more pop-
ular model.27,32,42,97,116,117 Other species found in ASD in vivo
evaluations are mouse, minipig, and pig.24,118
In order to generate data that can help predict human expo-
sure and enable human dosage estimation, a clinically relevant
animal model should be selected with clearly defined selection
of gender, fed or fasting state, and so on. If fasted, the experi-
menter needs to define the fasting time prior to dosing and after
dosing. If fed, the experimenter needs to control the diet. In the
survey performed by Newman et al.,24 80% of the bioavailabil-
ity studies were performed under a fasted state, whereas free
food access was allowed for 7% studies and 9% studies were
performed under a defined fed state.
Clinical
The ultimate goal of developing an ASD formulation is to obtain
satisfactory exposure in human clinical trials and eventually
patients.
There is no doubt that in vitro and in vivo evaluations are
necessary for formulation selection in order to advance the most
appropriate formulation for clinical trials. Both experimental
design and data analysis require care. When itraconazole ASD
with 40% drug load was evaluated in dissolution using the com-
mercial product Sporanox R
as the reference, it released much
slower from HPMC-based ASD compared with Eudragit E100
or a mixture of Eudragit E100 and PVPVA64 based ASD. How-
ever, in a clinical study, the best bioavailability measured by
AUC and Cmax was obtained from the HPMC-based ASD.119
DISCUSSIONS
Achievements
As demonstrated in this review, academic researchers and
industrial pharmaceutical scientists have shaped our under-
standing of the fundamental mechanisms of how polymers in-
hibit and/or retard the amorphous to crystalline phase change
in both the solid state and in supersaturated solutions. Table 2
lists some examples that have been discussed in this paper.
ASD Solid-State Physical Stability
Stabilization of an amorphous drug in an ASD is extremely
important because the dissolution and exposure would not be
improved if the drug reverted to its crystalline form. Even in the
case where the drug and the polymer are miscible, their ther-
modynamic equilibrium is rarely reached during ASD prepara-
tion. The solid is arrested in a metastable state regardless of
whether it is rapidly cooled from the melt, rapidly evaporated
from solution, or obtained from other techniques. In addition,
as long as a supersaturated single phase dispersion is achieved,
pharmaceutical ASDs are often prepared with drug loads in ex-
cess of their equilibrium solubilities in the polymer to satisfy
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015

Table 2. Examples of Polymer Selection and ASD Evaluation
Compound Structure
Amlodipine, MW 408.9,
Tm 144°C, log P 3.0,
pKa 9.0
Berberine, MW 336.4, Tm
145°C, log P 0.05,
neutral
BMS-A, MW 500, Tm
160°C, Tg 45°C,
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
neutral
BMS-B, MW 688.2, Tm
amorphous, Tg 88°C,
log P 7.7, pKa 7.6, 9.7
Compound 1, MW 377.5,
Tm 168,173°C, Tg 36°C,
log P 3.7, pKa 1.9, 3.3
Compound A, MW 425.4,
log P 1.8, pKa 2.2, pKa
8.5 (acidic)
DOI 10.1002/jps.24541
3246
REVIEW
Polymers (Drug Load, %) Method Selection Criteria Performance Reference
Dextrin, dextrin with SD Dissolution, membrane Permeability was better from the 106
0.9% SLS (10%) permeability, rat PK ternary ASD. Rat PK was also
better and comparable to market
product.
PVP K30, PEG6000, F68 RE Solubility, dissolution, All ASDs increased solubility and 95
with 3%–33% sodium membrane dissolution while 1:1:6
caprate (13%–44%) permeability, in situ berberine–sodium
intestinal perfusion, caprate–PEG6000 performed the
rat PK best. It provided 3×, 4×, and 5×
increase in permeability, perfusion,
and rat oral bioavailability. No rank
order of polymer can be concluded
because of the experimental design.
NA PVPVA, HPMCAS-M Solvent shift, Solubility, dissolution, More solubility was increased by 112
(40%) SD dog PK HPMCAS-M in solvent shift. In
both nonsink and sink dissolutions,
PVPVA ASD performed better.
Better dog PK was obtained from
HPMCAS-M ASD.
HPMCAS-M (10%, 25%) SD Dissolution (10% and ASD with 10% and 25% drug load 27
25% drug load), rat dissolved 90% drug in 7 min and
and monkey PK and 25 min, respectively. Satisfactory
TK (25% drug load) and dose-proportional exposure was
obtained in rat and monkey
toxicology studies.
HPMCAS-L, HPMCP SD Dissolution, rat PK HPMCAS-L ASD crystallized in the 5
HP55 (35%) vehicles of suspension formulation.
HPMCP ASD increased 7-fold AUC
from crystalline suspension in
dissolution and exposure in rat PK.
HPMC K100, PVP K90, HTP SC, SD Solubility (HTP Solubility was increased the most by 51,100
HPMCAS-M, materials), rat PK (SD HPMCAS-M, followed by HPMC
(20%–70% in HTP) material) K100, then PVP K90. Solubility was
(25% in SD) the highest at 20% drug load and is
reduced with increasing loading in
all cases. ASD with 25% drug load
provided satisfied rat PK.
Continued
 Table 2. Continued

Compound Structure Polymers (Drug Load, %) Method Selection Criteria Performance Reference

DOI 10.1002/jps.24541
Felodipine, MW 384.3, Tm PVP K29/K32, HPMC, SCF Crystallization tendency, These polymers equally effectively 28
147°C, Tg 45°C, log P HPMCAS-M reduced nucleation rate in the
4.8, pKa 2.7 (75%–97%), absence of moisture.
Same as above, (75%) SCF, RE Nucleation rate Equally effectively reduced nucleation 92
rate at 75% RH, PVP absorbs more
water and caused the tendency of
phase separation.
Same as above, RE Dissolution HPMCAS-M produced the highest 93
(2%5–90%) extent of supersaturation, followed
by HPMC, then PVP.
PVP K30, HPLCAS-L SD, HME, Dissolution HPMCAS-L produced higher drug 120
(25%, 33%, 50%), released rates and better
wettability. In both polymer
matrixes, SD materials were
released faster.
HPMC, PVP (10%, 50%), RE, Dissolution, diffusion, Although there is a higher apparent 113
solution NMR dissolution from the 10% drug load
ASDs, a similar maximum
thermodynamic activity of the
dissolved drug was detected from all
ASDs.
Eudragit L100 and MiCoS XRPD characterization All polymers at all drug loads formed 101
L100–55, HPMCAS-L, ASDs.
(20%, 35%, 50%)
Glyburide, MW 494.0, Tm HPMCP HP-55, Eudragit MiCoS XRPD characterization, Only L100 at drug load 40% and 50% 101
169°C–170°C, Tg 65°C, L100 and L100-55, solid stability, did not form ASDs. Although
log P 3.1, pKa 13.7 HPMCAS-L (10%, dissolution L100-55 ASDs offered the best solid
20%, 30%, 40%, 50%) stabilities, HPMCAS-L ASDs
offered the best dissolutions.
Griseofulvin, MW 354.8, HPMCAS-M (20%) FD, SD, CVD Effect of manufacture They offered comparable dissolution 121
Tm 216°C, Tg 88°C, process, rat PK profiles and similarly improved rat
log P 3.0, neutral PK.
Itraconazole, MW 705.6, HPMC E5 and E50, PVP HME Dissolution, rat PK, Among pH-independent polymers, 122
Tm 166°C, Tg 50°C, K12 and K90, Eudragit HPMC was a better stabilizer than
log P 5.7, pKa 3.7 L 100-55, HPMCP 55 PVP, while increasing molecular
and 55S (33%) weight promotes supersaturation.
Among enteric-coating polymers,
Eudragit was better than HPMCP.
Only HPMC E50 and EUdragit L
100-55 ASD were evaluated in rats;
they both performed well.
REVIEW

Continued

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3247
 3248
REVIEW

Table 2. Continued

Compound Structure Polymers (Drug Load, %) Method Selection Criteria Performance Reference

CAP and PVAP (33%, Ultra-rapid Dissolution, rat PK CAP provided greater degree and 123
50%, 67%) freezing extent of supersaturation in
dissolution. The performance order
on drug load was 33%>50%>67% in
both polymers. Only 33% in CAP
was dosed in rats, which doubled
exposure as compared with
R
Sporanox pellets.
HPMC 2910, Eudragit HME Dissolution, clinical Eudragit E100, mixture of Eudragit 119
E100, mixture of E100-PVPVA64 released drug
Eudragit instantaneously, whereas HPMC
E100-PVPVA64 at released much slower in dissolution.
70/30 (40%) However, HPMC performed the best

He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015

in clinical.
HPMC E3, E50, F50, and Solvent shift Precipitation inhibition, HPMCAS family provided greater 29
HPMCAS-L, M, H stabilization of supersaturation,
(10,000x of equilibrium and the stabilization within each
solubility) family was directly related to the
number of hydrophobic functional
groups: HPMCAS H>ML, HPMC
E50>F50E50.
HPMCAS-L, M, H, and KSD Dissolution, rat PK In dissolution: HPMCAS-LM>H. 29
HPMCAS-L, H with C974P reduced AUC for L, but
Carbomer 974P (33%) improved AUC for H. Only 33% in
HPMCAS-L with and without
C974P were dosed in rats, they both
R
performed better than Sporanox
pellets. C974P reduced exposure.
PVP K17, HPMCAS-L SD Molecular mobility HPMCAS-L acted as an 76
(10%) anti-plasticizer of global mobility. It
was substantially more effective
than PVP in inhibiting
crystallization.

Continued

DOI 10.1002/jps.24541
 Table 2. Continued
DOI 10.1002/jps.24541
Compound
LCQ-789, MW 476.9, Tm
194°C, Tg 105°C, log P
5.4, pKa 2.5
MK-0364, MW 516.0, Tm
104°C, Tg 41°C, log P
6.3, pKa 0.7
Nifedipine, MW 346.3,
Tm 173°C, Tg 45°C,
log P 2.3, pKa 3.9
Phenytoin, MW 252.3, Tm
295°C, log P 1.4, pKa
8.3 (acidic)
Vemurafenib, MW 489.9,
Tm 272°C, Tg
105°C–107°C, log P
3.0, neutral
Tg and Tm are from published literature; log P and pKa are from literature or calculated using ACD v12 (Advanced Chemistry Development, Inc.).
PVAP, polyvinyl acetate phthalate; SC, solvent casting; TK, toxicokinetics.
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
Structure Polymers (Drug Load, %)
Eudragit E PO, Eudragit
L 100, PEG 8000,
HPC-L, HPMC, PEG
4000, PEG 8000, or
PVP K30 with
surfactant (10%)
HPMCP HP-55,
HPMCAS-L, Eudragit
L100-55, or PVP/VA 64
with or without
surfactant (10%)
PVP, HPMC, HPMCAS-M
(50%)
Eudragit L100 and
L100-55, HPMCAS-L
(20%, 35%, 50%)
PVP K12, K17, VA64,
PEG6000, Lutrol F68,
F127, Eugragit E100,
Kolliphor HS15,
Gekucire 44/14, Brij
35, 58, Myrj 49, (10%,
20%, 40% in HTP SC)
(11%, 33% in SE)
HPMCP HP-55, Eudragit
L100-55, HPMCAS-L
(40%)
Method Selection Criteria Performance Reference
HTP SC, RE Dissolution, rat and dog Eudragit E PO with Cremorphor EL 48
PK performed better than others in
dissolution. It offered exposure
similar to lipid-based formulation,
less variability, and acceptance to
toxicology studies.
HTP SC, HME, Dissolution, monkey PK PVP/VA 64 with both Tween 80 and 47
SD Span 80, or VitE TPGS by HME,
HPMC by SD. HMPMCAS-L by SD
offered promising and similar
exposure in monkey. HMPMCAS-L
by SD was physically most stable.
RE Crystallization and phase HPMCAS-M performed the best, 94
transition kinetics followed by HPMC, then PVP.
MiCoS XRPD characterization Eudragit L100-55 at 20% drug load, 101
and HPMCAS-L at 20% and 35%
drug load formed ASDs.
HTP SC, RE Dissolution All three grade of PVP with all three 97
drug load from HTP performed the
best with over 90% phenytoin
dissoluted within 30 min. The worst
performance came from the
combination with Myrj 49. They
were scaled up by SE and the
release profile of laboratory-scale
ASD was similar to that from HTP
films.
MBP Solid stability, All formed ASDs, only Eudragit 124
dissolution, human PK L100-55 and HPMCAS-L ASDs
were stable. HPMCAS-L ASD
provided better dissolution profile
and offered fivefold increased
exposure from crystalline form.
REVIEW
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3250 REVIEW
the dose requirement.24,125–127 Given time, the amorphous drug
in these ASDs will ultimately revert to a crystalline form. Some
ASDs, however, have successfully advanced to commercial prod-
ucts and many more are in the pipeline because not only the
bioavailability is optimized, but also the requisite pharmaceu-
tical stability is achieved when the polymer and manufacturing
conditions are carefully selected.
In an attempt to improve ASD physical stability, increasing
the dispersion’s Tg has been the focus of many studies.76 Before
the introduction of more powerful analytical techniques to ana-
lyze phase separation in ASD, a distinctive single Tg was widely
accepted as reliable proof of the homogeneity of the amorphous
mixture at the molecular level.127 In recent years, the interac-
tions between the drug and polymer in the mixture has been
much more thoroughly examined and better understood with
the availability of instruments such as ssNMR, DDS, Raman,
synchrotron radiation, high-speed DSC, and variable tempera-
ture XRPD. Besides miscibility between the drug and the poly-
mer, many other mechanisms have been proposed to explain
how the amorphous form of a drug is stabilized by a polymer
in ASDs. In some studies, the polymer was found to stabilize
the drug in ASD by modifying its "- or $-relaxation (or both
simultaneously) and consequently delay crystallization onset
time or decrease crystallization rate constant.76
In addition to temperature, moisture is another factor that
has profound impact on the stability of ASD. Water is recog-
nized as the unavoidable third component in hydrophilic poly-
meric dispersion systems at ambient condition.127 With consid-
eration of the impact on amorphous drug "- and $-relaxations
from both temperature and humidity, the prediction of long-
term stability (up to 17 months) was achieved and verified by a
statistical method developed using mid-term stability data (up
to 3 months) from normal and stressed conditions with acceler-
ated temperatures and elevated relative humidities.53
Generating and Maintaining Supersaturation
Many factors that contribute to the stabilization of the drug in
the solid state of the ASD likely also play a role to maintain
supersaturation in the solution.
The understanding of polymer interactions with amorphous
solids in an aqueous medium to help generate and maintain
supersaturated concentration is also improving.93,94,128 Upon
contact of the ASD with aqueous media, some polymers pro-
tect the amorphous solid drug by impeding its crystallization
and some polymers dissolve rapidly to increase media viscosity
or interfere the nucleation of the dissolved drug to prevent it
from precipitating out in the supersaturated solution. In some
cases, solid polymers swell to facilitate water uptake and wet
the API. In other cases, polymers dissolve and form micro- or
nanoparticles to facilitate fast dissolution of the API. Disso-
lution of a compound from an ASD to generate and maintain
a supersaturated solution is a complicated process. To simplify
the process of understanding how polymers perform in aqueous
media, neat amorphous compounds have been used to evaluate
polymer effects by dissolving polymers in the media prior to
addition of the amorphous compound.
Product and Pipeline
In addition to the improved dissolution kinetics, flexibility in
dosing, and acceptance in toxicology studies in the discov-
ery and early development stages, the number of ASD-based
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
formulations in late-stage development and marketed prod-
ucts is growing because of the ASD properties that are well
suited for preparation of conventional oral dosage forms, such
as tablets, and capsules.129
In one case, a novel ASD technology was employed to rescue
vemurafenib clinical trials.13 When this new molecular entity
(NME) was brought to clinical trials, investigators were excited
by this breakthrough for treatment of late-stage melanoma pa-
tients. At the end of Phase I, the trial had to be halted because
of low absorption from capsules that were formulated from the
crystalline form of this drug. Patients in the highest dose regi-
men needed to take 1600 mg vemurafenib, which required in-
gesting 32 capsules.130 The reformulation of vemurafenib suc-
ceeded with the development of MBP technology, which led to
manufacture this compound as a stable ASD. With more than
fivefold increased exposure in the ASD, the dose was reduced
to four tablets twice a day with each tablet containing 240 mg
R
vemurafenib (Zelboraf ).124,131 Furthermore, using a less ther-
mally stressed nonsolvent process, KSD technology recently
demonstrated the feasibility to manufacture this drug as an
ASD with improved efficiency and reduced cost.132 With ASD
technology, the clinical trials were resumed, and the bench to
bedside translation of this breakthrough medicine was realized
to save the lives of melanoma patients.
While new therapeutic options can be brought to patients
with the application of ASD in NME formulations, the economic
potential of existing drugs can also be improved with applica-
tion of this technology to their reformulation. Besides oral de-
livery, ASD has also been exploited in injectable formulations.
The most frequent applications in injectable formulation are to
modify the release profiles of existing drugs. Modified release
profiles can be realized by forming ASD in microspheres using
SD.133–135 ASD can also be applied in injectable formulations
R
to improve dissolution. Abraxane is an injectable ASD dosage
form that was approved by US FDA and EU in 2005 and 2008,
respectively. This product is supplied as a lyophilized powder
in which amorphous paclitaxel forms a solid dispersion with
human albumin.136,137
There are increasing numbers of products in pharmaceutical
pipelines that are formulated with amorphous solid dispersed
TM
APIs. A query of the PharmaCircle database138 in March 2015
revealed 76 products in the pipeline that are formulated as
ASDs. These data show that amorphous dispersions are uti-
lized in NMEs as well as new formulations for lifecycle man-
agement. Of the 27 globally marketed amorphous dispersion
products, nine were in NME submissions. Some examples of
the marketed ASD products used for oral administration are
listed in Table 3. The FDA and EU approval dates are included
when available.
Even though the confirmed products in research and preclin-
ical is only 33 in this search, the actual number of preclinical
products employing ASDs is likely much higher as the major-
ity of studies in pharmaceutical research are not published.
The search also revealed that Bend Research Inc. alone had
manufactured over 350 compounds in ASDs for pharmaceuti-
cal companies. Among these, over 50 programs have advanced
to clinical trials.
Challenges and Remaining Questions
As the improved bioavailability using ASD stems from the
higher energy of the amorphous form, a caveat of this drug
DOI 10.1002/jps.24541
DOI 10.1002/jps.24541
TM
Table 3. Examples of Marketed Amorphous Dispersion Products for Oral Delivery (Source: PharmaCircle )

Product ASD Dosage Therapeutic Formulation

Name Molecule NME/NF WS BCS Polymer Method Form Category FDA EU Patent Company

Advagraf/Astagraf XL Tacrolimus NF ins II HPMC WG Capsule Organ trans. 2013 2007 US6440458 Astellas
Certican/Zortress Everolimus NF vss III HPMC CP Tablet Organ trans. 2010 2003 US6004973 Novartis
Cesamet capsules Nabilone NME vss II PVP SE Capsule Cancer, chemo se 1985 2009 US4087545 Valeant
Fenoglide Fenofibrate NF ins II PEG6000/ CA, SD Tablet Hyperlipidemia 2007 nd US7658944 Santarus
Poloxamer 188 Veloxis
Gris-Peg Griseofulvin NF ins IV PEG 6000 Melt Tablet Infections, fungal 1975 nd nd Pedinol
Incivek Telaprevir NME ins II HPMCAS SD Tablet Infections, hepatitis C 2011 2011 US8431615 Vertex
Intelence Etravirine NME ins IV HPMC HME Tablet Infections, HIV/AIDS 2008 2008 US7887845 Johnson &
Johnson
Isoptin SR Verapamil HCl NF s II HPC/HPMC HME Tablet Hypertension 1997 1986 nd Abbott
Kaletra Ritonavir/ lopinavir NF ins IV PVP HME Tablet Infections, HIV/AIDS 2005 2006 US7364752 AbbVie
ins II
Kalydeco Ivacaftor NME ins II/IV HPMCAS SD Tablet Cystic fibrosis 2012 2012 US8410274 Vertex
Lozanoc Itraconazole NF ins IV HPMCP SD Capsule Infections, fungal nd 2012 US6881745 Mayne
Mesulid fast Nimesulide NF ins II $CD Mech. Tablet Pain nd nd nd Novartis
Norvir Ritonavir NF ins IV PVP HME Tablet Infections, HIV/AIDS 2010 2010 US7364752 AbbVie
Noxafil Posaconazole NF ins II HPMCAS SD, HME Tablet Infections, fungal 2013 2014 US20110123627 Merck
Onmel Itraconazole NF ins IV HPMC HME Tablet Infections, OM 2010 ND US7081255 Merz
Prograf Tacrolimus NME ins II HPMC KDS Capsule Organ trans. 1994 2006 EP0240773 Astellas
Rezulin Troglitazone NME ins II HPMC HME Tablet Diabetes 1997 nd nd Pfizer
Sporanox Itraconazole NF ins IV HPMC SD Capsule Infections, fungal 1992 nd US5633015 Janssen
Thomaflex Meltrex Ibuprofen NF vss II Nd HME Tablet Pain nd 2005 nd Boehringer-
Ingelheim
Zelboraf Vemurafenib NME ins IV HPMCAS MBP Tablet Cancer 2011 2012 nd Roche

CA, controlled agglomeration; CD, cyclodextrin; ins, practically insoluble; KDS, kneading, drying, and sizing; Mech., mechanical; nd, no data; NF, new formulation for existing drug; OM, onychomycosis; s,
soluble; se, side effects; trans., transplantation; vss, very slightly soluble; WG, wet granulation; WS, water solubility.
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3251
3252 REVIEW

delivery system is that this higher energy state poses chal- screening of the polymer is better performed using the man-
lenges in manufacture, shipping, storage, and dissolution. Al- ufacturing method that ultimately will be used to produce
though understanding of this drug delivery system has greatly the bulk material for preclinical or clinical development.92,120
improved in recent years, there are many questions that re- In recent years, bench-top spray dryers have often been
main. Understanding the molecular interactions between the used to prepare spray-dried ASD and their appearance in
drug and the polymer carrier in the solid state of the ASD and literature demonstrates their versatility in aiding candi-
in supersaturated solution still need to be further elucidated date selection in early research and downstream formulation
to enhance the predictability of ASD physical and chemical development.27,52,106,112,139
stability and in vivo performance. Further basic research will
certainly boost the applications of ASDs to new levels, and po- Is the Dissolution Method Biorelevant Enough?
tentially enable previously undevelopable drug candidates to
The selection of appropriate dissolution conditions is crucial for
benefit patients.
the successful in vitro evaluation of an ASD formulation. It is
well recognized that the in vitro–in vivo correlation is far from
Can a Polymer be Selected Without Making an ASD? perfect for this type of formulation.114 In the survey performed
by Newman et al.,24 the relationship between in vitro dissolu-
Polymer selection has been thoroughly discussed in both the-
tion and in vivo bioavailability was reported for 78% of the 40
oretical predictions and experimental screening. Although the
studies examined. In 22% of these studies, the in vitro disso-
physical stability of the solid-state ASD can be predicted by
lution failed to offer insight into the in vivo performance. The
theoretical calculations, the performance of ASD still largely
authors systemically analyzed how the dissolution results are
requires experimental evaluation.
influenced by factors including physicochemical properties of
High-throughput solvent casting is the method of choice of
the compound, particle size of the ASD, composition and pH of
some major pharmaceutical companies and it frequently pro-
the dissolution media, selection of dissolution vessel, dissolu-
vides predictable guidance to select an ASD.48,51,98 Instrumen-
tion volume, agitation rate, choice of sink to nonsink conditions,
tation limitations persist as many laboratories are not equipped
and consideration of dose to solubility ratio.24
with automated systems. In addition, when the preparation is
Sample preparation is critical for dissolution studies of this
scaled from HTP screening to laboratory-scale production, the
type of formulation. They should be designed based on the in
properties of the product sometimes cannot be reproduced be-
vivo dosing protocol. If the particle size of the dispersion is to
cause of the change in thermal history. In scale-up, the process
be controlled for in vivo dosing, for example, sieved to a more
can be altered from film casting to SD or melt extrusion or other
defined particle size range, it should be controlled in the disso-
techniques. The mechanism varies from solvent-based to melt-
lution too. Although solid dosage formulations such as capsules
based, or to mechanical-based or vice versa.30,114 When an ASD
are preferred in preclinical studies to facilitate animal dos-
of felodipine was prepared using PVP K30 or HPMCAS-L as
ing, ASDs are frequently dosed as suspensions in preclinical
the carrier, the drug was released faster from the spray-dried
studies, especially when the carrier is an enteric polymer. If a
product than from hot-melt extruded product.120 As the crys-
suspension of the dispersion is planned to be dosed sometime
tallization of felodipine happens rapidly in the solid once the
after preparation, for example, 1 day or 1 week after prepara-
ASD contacts the aqueous medium, the thermal history has
tion, the prepared sample should be kept for the same length
important implication on how the polymer interacts with the
of time prior to evaluation via dissolution testing. The role of
compound.128
the vehicle in this type of suspensions is to maintain the solid
Although the stability of the ASD is important, improved
in amorphous form. The physical form of the ASD must also
bioavailability is the key criterion of an ASD. The in vivo per-
be evaluated to ensure there is no change after the sample is
formance is determined by many factors, including crystalliza-
prepared.
tion tendency of the compound in solid form upon contacting
Because of the metastable nature of this type of dispersion,
the GI fluid, dissolution of the amorphous drug, dissolution of
it usually does not afford the luxury to prepare a single sample
the polymer, interaction of the drug–polymer in both solid and
for a 2-week toxicology study when the formulation is a suspen-
solution, precipitation of the supersaturated drug in its crys-
sion. The need for extemporaneous preparation for each dose is
talline form, and so on. When the performance is dominated by
common. Stability of at least 2 h is usually preferred, although
the polymer’s ability to generate and maintain supersaturation,
some institutes accept half-hour stability.48 If the suspension
such as in the case of BMS-A, the solvent shift method can give
stability is unknown, ASD material can be dispersed into the
a reliable prediction.112 When the ASD performance is mainly
dosing vehicle immediately prior to dosing.122 The dose to media
contributed by the interaction between drug and polymer to
volume ratio should also be carefully selected, as precipitation
generate and hold the supersaturation, the ASD may have to
from supersaturation is a concentration-driven phenomenon.
be prepared for screening. When the kinetics during ASD man-
ufacture do not significantly contribute to the properties of the
Other Considerations in Dissolution
ASD, the polymer can be screened without manufacturing the
ASD or the ASD produced by any manufacturing process may The vehicle composition of formulation is important. Tween 80
be used.51,121 A study of griseofulvin on HPMCAS-M matrix at a concentration of 0.2%–0.5% is routinely used as a wet-
using small-scale bench processes, namely, fast evaporation, ting agent in suspensions of crystalline material. However, it
lyophilization, and SD, demonstrated that each of these tech- reduced the drug release and led to precipitation in a short pe-
niques is reliable, comparable, and suitable to generate ASD riod of time in the case of an LCQ789 ASD suspension,48 which
material without large investment in time and API quantity.121 is consistent with the authors’ observations with other research
However, when the thermal history of the manufacturing compounds (unpublished data). In another study, Tween 80
process significantly contributes to the ASD properties, the at a concentration of 10% was added in an ASD suspension

He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015 DOI 10.1002/jps.24541


formulation because it provided significant solubility improve-
ment for the neat crystalline compound. It was expected that
Tween 80 would act like parachute to delay precipitation from
the supersaturated solution of ASD. Surprisingly, the solid dis-
persion crystallized after 3 h in the media with Tween 80,
whereas it was stable for more than 6 h when Tween 80 was
not present.5
When an ASD is dosed at low concentrations, suspending
agents, such as methylcellulose, may need to be added.5 How-
ever, when ASD is dosed at higher concentrations, water or
buffer without suspending agent may be used as the amount
of polymer released from the ASD can serve as a suspension
agent. Water was selected to suspend the LCQ789 ASD, which
facilitated formulations of 10, 50, and 120 mg/mL of ASD.48
When the compound is pH sensitive or the polymer solubil-
ity is pH dependent, the pH of the suspension vehicle and the
buffer composition should be carefully selected. The prepara-
tion should avoid energetic mixing as it can accelerate reversion
to a crystalline form. The powder can be effectively wetted first
by adding a minimal amount of suspension vehicle and stirring
gently with a spatula.
The dissolution temperature of an ASD formulation is im-
portant too. It should be set close to physiological temperature.
Although equilibrium solubility increases with elevated tem-
perature and the solubility difference between 25°C and 37°C is
usually minimal,140,141 the solubility of a neat amorphous com-
pound or ASD may decrease with increased medium temper-
ature because crystallization onset may be earlier, crystalliza-
tion rate may be faster, amorphous material agglomerates may
be more extensive, and crystalline precipitation from supersat-
uration may also occur sooner.128 Therefore, dissolution at a
biologically relevant temperature is necessary for ASD-based
formulations, whereas dissolution at room temperature can be
acceptable for dosage forms containing crystalline phases.
When food effect is evaluated, the consideration should be
not only the bile salts composition of the media, but also how
the food affects the pH, fluid volume, and the residence time in
each segment of the GI tract.
Can Preclinical Results Translate to Clinical?
During preclinical studies, the selection of animal species is
clearly critical as it determines if the results can be trans-
lated to the clinical studies. Although disease relevance is of-
ten the focus of the animal species selection, the PK profile
of a compound is greatly influenced by the physiology and
anatomy of the animal. As summarized in the survey by New-
man et al.,24 dog and rat are the most favorable choice when
ASDs are dosed. Nonhuman primates have been used in stud-
ies of ASDs and they are regarded as useful models in drug
delivery with regard to gastric pH and emptying time, GI ag-
itation intensity, and intestinal transit time.27,142,143 However,
large exposure variability could limit their use when the com-
pound is ionizable or when a pH-dependent polymer is used as
the carrier. The cause of the variability is often the consump-
tion of a meal that has strong impact on their GI pH profiles.144
In addition, primates are not good models for fed-state studies
because they eat when they choose and often do not eat at the
moment food is provided. The duration of gastric pH elevation
after ingestion of a meal varies considerably in primates, and
intestinal pH is more basic in primates than in humans.27
DOI 10.1002/jps.24541
REVIEW 3253
Other animal species, such as rats, also were reported to
have pH variability in the duodenum and jejunum and this
can be further impacted by food intake.29 Although the degree
of pH variation is less as compared with that of monkeys, high
variability of exposure was still observed when a pH-dependent
soluble polymer was used in the ASD.29,122,145 The reproducibil-
ity was excellent, when fed dogs were dosed with powder in hard
gelatin capsules (with 2% disintegrant added) using different
batches of ASD from MBP.13
Regardless of the potential exposure variation, pH-
dependent polymers are frequently selected as the carrier be-
cause they provide the exposure improvement in much higher
magnitudes and offer the benefit of targeted delivery or delayed
Tmax . The exposure variability and higher probability of food ef-
fect need to be included in the considerations of the dissolution
method for preclinical and clinical study designs to fully under-
stand how they can affect the study outcomes and how they can
be maximally mitigated and controlled.
One of the major benefits of using ASD for preclinical studies
is that it can provide much higher doses in toxicology dose esca-
lation studies because of the higher achievable drug exposure,
inert nature of the polymer and the dosing flexibility of sus-
pension formulation. ASDs can be dosed as simple suspensions
in preclinical studies and early clinical trials, can be formu-
lated and encapsulated as powder in capsule or compressed as
tablets in formulation development, and can provide a clear
development pathway to a commercial product.
The optimal drug loading in an ASD is usually in the range
of 10%–30% as further increasing drug loading can jeopardize
manufacturing stability and shelf life, and also can negatively
impact its dissolution performance.93,121,123 When a high dose is
projected for clinical usage, pill burden can impact clinical ac-
ceptability. The maximum daily doses of acceptable excipients
should also be considered. In a study of berberine, the selected
ASD contained a 1:1:6 ratio of berberine–sodium caprate–PEG
6000.95 On the basis of bioavailability and antidiabetic efficacy
in a type 2 diabetic rat model, it was proposed that this ASD
could decrease the berberine clinical dose to one quarter of 0.9–
1.5 g per day, which would require 1.8–3.0 g ASD per day. This
amount of ASD would contain 0.2–0.4 g sodium caprate per day.
It is important to know whether the total amount of inactive
ingredient dosed is toxicologically and clinically acceptable.
ASD Selection Road Map
The physicochemical properties of the drug substance deter-
mine whether ASD can be a choice to improve its bioavailabil-
ity. A compound with low Tm and high Tg would have fewer
obstacles to convert to an amorphous phase and less thermo-
dynamic driving force for the amorphous form to revert back to
its crystalline form. A good glass former with low crystallizing
tendency is more suitable for forming an ASD.
The selection of the polymer is largely governed by the solu-
bility of the drug in the polymer. Many efforts have been made
for a theoretical prediction. Limited by the inadequate under-
standing of the mechanisms involved with stabilization, disso-
lution, and crystallization in supersaturated solutions of ASD,
the selection of the polymer and the optimization of the drug
load in the ASD remains largely empirical and relies mainly on
experimental screening.2,76
When the API quantity is limited, the selection of polymer is
traditionally screened using solvent quench or SE methods.89,92
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
3254 REVIEW
The evolution of this field has seen the recent introduction of
new methods such as single droplet drying and miniaturized
coprecipitation screening (MiCoS). With the availability of au-
tomated systems, some of these screening techniques can be
adapted to a HTP processes as depicted in Figure 2. These
methods can be used, variously, to screen for the feasibility of
forming an ASD, the stability of the ASD, and the optimum
ASD drug loading as evaluated by stability and dissolution.
Miniaturized spray dryers also have enabled screening with
milligram quantities of API. Many studies have demonstrated
that ASD generated by miniaturized spray driers can be repro-
duced at larger development scale. At present, the application
of nonsolvent process ASD in research and early development
remains challenging because of the constraints of the amount
of drug required for the evaluation. The currently available
batch mode bench top HME instrumentation requires a mini-
mum of 5 g of drug–polymer mixture, whereas more material is
required in the continuous process model. When a technology
breakthrough introduces a scalable miniaturized solvent-free
instrument, such as HME or KSD, to enable the screening of
solvent free ASDs using milligrams of API, the application of
pharmaceutical ASDs will be further accelerated.
Once the compound is identified as an ASD candidate, en-
abling formulations by other approaches cannot be formulated
or the benefit of developing ASD formulation is viewed as
overweighing the benefits of other formulations, the method
of screening might be governed by the practical factors, such
as the amount of API available for feasibility testing, in-house
expertise, and access of instruments. Being a good ASD candi-
date does not warrant the compound to stand all ASD process-
ing options. Compounds, such as vemurafenib, cannot stand
HME because of its high Tm and thermal instability and can-
not be manufactured by SD because its low solubility in volatile
solvents and water. Some research compounds can be manu-
factured using SD with relative low solubility in volatile sol-
vents because the amount of ASD needed at this stage is
small. However, after the ASD is proved to be the right con-
cept for the compound and a larger amount of ASD is needed in
the later stage of the pipeline, the amount of solvent needed
in SD can be a restraint and another process that has ac-
ceptable processability at scaled-up setting may have to be
explored. Shelf life in pharmaceutics is a relevant term. Al-
though a few months stability is usually sufficient for research-
stage compounds up to GLP toxicology studies, a longer time
frame shelf life will be required for clinical studies that can
add another factor for processing selection. The reliable pre-
diction of long-term stability from short-term data can help
ensure confidence in the compound transition from preclini-
cal to clinical. Robust batch to batch physical quality repro-
ducibility of ASD is also important in the application of this
technology.
The emergence of new types of modified polymers, such as
HPMCAS and Soluplus, offer better stability and dissolution
profiles for some drugs. The decision to employ a new unap-
proved excipient is not only a pharmacologic safety risk, but
also a regulatory and business decision. The pioneers using
new polymers for ASDs have a strong advantage in terms of
patent protection. However, in order to gain regulatory ap-
proval, there is a daunting amount of work and expense to
introduce new excipients. Polymer carrier selection criteria
were well discussed in the review article by Janssens and Van
den Mooter.8 Although the stability of the ASD is important,
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:3237–3258, 2015
other considerations should include the safety of the polymer
in animal and humans, suitable properties for the selected
manufacturing processing method, the release profile in disso-
lution, and stability in both solid and supersaturated solutions.
In current pharmaceutical industry practice, ASDs are most
commonly prepared from SD in research and HME is more
preferable in development because of the factors discussed in
the introduction section. An ASD formulation approach would
likely not be appropriate when developing a conventional for-
mulation with acceptable performance is possible. In instances
when an ASD is selected for discovery stage research and a
conventional formulation becomes feasible at the clinical stage,
the transition should be considered as early as possible to avoid
expensive bridging studies in later-stage clinical trials.
Drug loading is often optimized after the ASD is selected as
the delivery technology. The optimization is a balanced consid-
eration of the solid stability, dissolution performance, in vivo
exposure, and pill burden in the final dosage form.
As evident from the literature cited throughout this review
and the data presented in the product and pipeline sections,
the technologies available for screening ASDs have matured
tremendously at this time. Importantly, the processes for large-
scale manufacturing of ASD are more established. FDA ap-
proval of these novel drug products also seems simpler because
the regulators are more comfortable with such formulations.
Companies are seizing the advantages of the unique intellec-
tual property positions accessible through ASDs. The pharma-
ceutical industry has embraced the idea that the applications of
ASDs are not limited to NMEs, but also been to lifecycle man-
agement of existing medications.17 It is now clear that ASD
technology has become an important drug delivery method for
pharmaceutical scientists.
CONCLUSIONS
The successful formulation of an ASD is dependent on its sta-
bility in the solid state and its performance after dosing. The
manufacturing challenges and the phase stability upon storage
are hurdles to the acceptance and wider application of ASD. In
the last two decades, increased efforts from academic and in-
dustrial researchers have pushed the understanding to a new
level regarding the fundamental driving forces of (1) how ASD
works to improve exposure, (2) what are the thermodynamic
and kinetic factors as well as molecular interaction between
drug and polymer for its phase stability in solid state, and (3)
how the supersaturated solution is generated and maintained
in the GI tract.
Manufacturing challenges are also better controlled. With
currently available instruments, in particular bench-top spray
dryers, it is possible to prepare ASD with minimal amount of
material to perform a quick bioavailability study, when other
approaches are exhausted for a poorly water-soluble compound
in the research or early development stages. Although the
choice of technique in marketed product is dominated by HME,
other techniques such as SD, CP, MBP, SE, mechanical milling,
and kneading are also being used.
Despite the fact that ASD is usually the last choice of phar-
maceutical scientists because of the challenges in manufactur-
ing and physical stability, it has been demonstrated in numer-
ous cases that it can be a very effective and powerful approach
to improve exposure and facilitate project progression from lead
DOI 10.1002/jps.24541

optimization, to candidate selection, to full development and
into a commercial product. Improvement in the understanding
of both the solid-state stability of ASDs and the mechanism
of generating and maintaining supersaturation have led the
paradigm shift from avoiding amorphous forms in drug prod-
ucts because of physical and chemical instability to actively
utilizing ASDs to enhance drug absorption by taking advan-
tages of the powerful solubility enhancement that is intrinsic
to the technology.
ACKNOWLEDGMENT
The authors gratefully appreciate Dr. Harvey Lieberman and
Dr. Donglai Yang for their discussions and prereview, and sin-
cerely thank Dr. Ed Orton for help in editing this manuscript.
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DOI 10.1002/jps.24541