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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
C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:32373258,
research and development stages. 
2015
Keywords: amorphous solid dispersion (ASD); bioavailability; dissolution; formulation; polymer; poorly water soluble compound;
solubility; spray drying (SD); stability; supersaturation

INTRODUCTION
More than three quarters of new chemical entities in pharmaceutical research are poorly water soluble,1,2 and for those
solution formulations are often unachievable. Even when a
solution can be prepared with high levels of excipients for
pharmacokinetics (PK) studies, it frequently cannot be tolerated during efficacy studies using in vivo disease models.3,4
Complex formulations may produce unacceptable excipientrelated biological effects in toxicology studies.5 Occasionally,
micronized or nanonized suspensions can solve these problems with minimal amounts of excipients. However, they often cannot offer adequate exposure because of their slow and
incomplete dissolution.5,6 When poor water solubility is because of the lipophilicity of a compound, formulations such as
Abbreviations used: API, active pharmaceutical ingredient; ASD, amorphous
solid dispersion; BCS, biopharmaceutics classification system; BMS, Bristol
Myers Squibb company; CAP, cellulose acetate phthalate; CP, coprecipitation;
CVD, centrifuge vacuum drying; DDS, dynamic dielectric spectroscopy; DMA,
dimethyacetamide; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; DSC,
differential scanning calorimetry; Eudragit E, L, S, FS, polymethacrylates; FD,
freeze-drying; GI, gastrointestinal; HME, hot-melt extrusion; HPC, hydroxypropyl cellulose; HPLC, high-performance liquid chromatography; HPMC, hydroxypropyl methylcellulose; HPMCAS-L, -M, -H, hydroxypropylmethyl cellulose
acetate succinate L grade, M grade, and H grade; HPMCP, hydroxypropyl methylR
cellulose phthalate; HTP, high-throughput; KSD, KinetiSol
dispersing; MBP,
microprecipitated bulk powder; MiCoS, miniaturized coprecipitation screening;
NME, new molecular entity; PEG, polyethylene glycols; PK, pharmacokinetics; PLM, polarized light microscopy; PVAP, polyvinyl acetate phthalate; PVP,
polyvinylpyrrolidone; PVP/VA 64, polyvinylpyrrolidone-vinyl acetate copolymer;
RE, rotary evaporation; RH, relative humidity; SC, solvent casting; SCF, spincoated film; SD, spray drying; SE, solvent evaporation; SEM, scanning electron
microscopy; SLS, sodium lauryl sulfate; ssNMR, solid-state nuclear magnetic
resonance; Tg , glass transition temperature; Tm , melting temperature; UV,
ultraviolet; XRPD, X-ray powder diffraction.
Correspondence to: Yan He (Telephone: +781-434-3581; Fax: +781-466-3788;
E-mail: Yan.he2@sanofi.com)
Journal of Pharmaceutical Sciences, Vol. 104, 32373258 (2015)


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

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


delivery systems (SNEDDS, SMEDDS, SEDDS), liposomes,
and so on may be viable options, but their utility is limited as the drug loading is typically low in these types of
systems.
In an amorphous solid dispersion (ASD), the solubility of the
drug substance is improved by disrupting its crystalline lattice
to produce a higher energy amorphous form. Compared with
other enabling solubilization approaches, an ASD can hold a
much higher dose for low-solubility active pharmaceutical ingredients (APIs). ASDs improve bioavailability by maintaining
supersaturation in the gastrointestinal (GI) tract. When supersaturation is sustained, the absorption of a compound can
be maximized to be greater than that of a saturated solution.7
Furthermore, the solubility differences among crystalline physical forms (e.g., polymorphs) are eliminated because they are
converted to the amorphous form. This is particularly beneficial for compounds in the research stage when the form is
not clearly defined. ASDs are usually well tolerated in animal disease models and are acceptable to toxicologists as their
polymer carriers are derived from GRAS (generally regarded as
safe) excipients. Commonly used excipients for forming ASDs
are cellulose derivatives such as hydroxypropyl methylcellulose
(HPMC), hypromellose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxy ethyl cellulose, hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose, ethyl
cellulose, carboxymethyl ethyl cellulose, chitosan, cyclodextrin and derivatives, lactose, poloxamers, polyvinylpyrrolidone
(PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA
64), polyvinyl acetate phthalate (PVAP), polymethacrylates
(Eudragit E, L, S, FS), and polyethylene glycols (PEG) derivatives. These polymers are biologically inert and minimally
absorbed.

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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
R
dispersing (KSD), drum drying,
extrusion (HME), KinetiSol
freeze-drying (FD), rotary evaporation (RE), spray congealing,
coprecipitation (CP), cogrinding, spin-coated film (SCF), centrifuge vacuum drying (CVD), supercritical fluid technology,
electrostatic spinning, and microwave technology.813 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 processing. 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 available 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 pharmaceutical R&D. FD can be a good choice when the solvent is water. 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 3050 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 prepare ASD in discovery when drug substance is only available
in limited quantities because the screening requires only milligrams 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 instruments 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.1517
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 development is often achievable and preferred.
The objective of this review is to assess current understanding of the chemistry of ASDs, how it is utilized, and what limits
its applications. The main focus will be on what physicochemical properties of the API determines a candidates 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 104:32373258, 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 bioavailability was reported over 50 years ago. In 1960, sulfathiazole was orally administrated to humans in a eutectic mixture
with urea.18 The absorption and excretion of the eutectic mixture was higher than that of sulfathiazole alone. The authors
proposed that this new formulation method provided microscopic intimate contact of fine crystallites, which gives an improved 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 (fusion), SE, or a melting-solvent method. Since then, solid dispersion has become a platform to overcome the low-bioavailability
barrier for poorly water-soluble compounds.2,1924 In this platform, the dispersion can be a single amorphous phase mixture
of an active drug with polymer(s), a crystalline mixture of active 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 Zografi 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 drugs solid-state physical stability by
reducing its molecular mobility and increasing its glass transition 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 disrupting intermolecular interactions in the drugs crystal lattice
and forming drugpolymer 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 believed 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 energy state. Its dissolution is more extensive and faster because
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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 crystalline form, R is the molar gas constant, and T is the testing
temperature (K).
Spray Drying

Figure 1. Amorphous solid dispersion generates and maintains a supersaturated solution. A: Crystalline drug that has lower solubility.
B: Amorphous drug alone that has higher apparent solubility but precipitates 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 intermolecular 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 NoyesWhitney 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.3032
The mechanism for an ASD to generate and maintain supersaturation in the GI tract is illustrated in Figure 1 using the

spring parachute analogy, which was introduced by Guzman


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

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 concept 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 120C, the temperature of the outlet gas is
usually 60C 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 solvent 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 factor 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 4M8Trix, 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
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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 parameters, such as the melting and glass transition temperatures,
melting enthalpy and entropy, melting viscosity, crystalline
density, molecular size and weight, molecular mobility, flexibility, complexity, number of benzene rings, level of molecular
symmetry, level of branched carbon skeleton, number of rotational bonds, number of electronegative atoms, and number of
hydrogen bonds.5862
The amorphous form of a drug substance can often be generated from its crystalline form. The neat amorphous form of
a compound can also be obtained from condensation of its vapor, 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 conditions with accelerated temperature and humidity. The formation of crystalline material is commonly monitored with polarized 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
coolingheating 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 govern vitrification, formation of nuclei, and crystalline growth.
Crystallization tendencies between molecules of similar structure 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 factors (temperature). The crystallization of Class II compounds
was found to be influenced by competition between thermodynamic 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 publication, 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 melting temperature (Tm ), low melt entropy, low melt viscosity, and
high crystal density.
The Tm , Tg , and their ratio have been used to predict glassforming ability and crystallization tendency, as Tm is a wellaccepted parameter to evaluate the thermodynamic driving
force for crystallization, and Tg is a popular measure to assess 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
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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
BeamanBoyer empirical rule, because Beaman and Boyer applied 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 crystallize 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 compounds with modified versions and refined numbers to predict
glass-forming ability.6972
The reciprocal of the Tg /Tm (K/K) value has been applied
not only to predicting the glass-forming ability and crystallization 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 formulated 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 MK0364, which has Tg 41C, Tm 104C, 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 effect of drug load on in vivo absorption needs to be studied and
confirmed.
Using a single parameter to predict ASD stability may oversimplify 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 algorithm 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 experimentally 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 prediction. When a random selected testing set of 16 compounds was
checked, there was a 75% success rate.
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Table 1. Classification of Glass-Forming Ability and Crystallization Tendency by DSC64,65


Group
Class I
Class II
Class III

Cooling

Reheating

Classification

Crystallization Driving Force

Crystalline
Amorphous
Amorphous

Crystalline
Amorphous

Poor glass former/high crystalline tendency


Good glass former/high crystalline tendency
Good glass former/low crystalline tendency

Thermodynamic
Thermodynamic and kinetic
Pressure

A follow-up study by this group of researchers extended


the prediction with rapidly measured physical properties from
DSC.60 The authors suggested that a decision making on the
selection of amorphous or ASD formulation can be rationalized
based on the molecular weight, and the predicted or experimentally obtained glass transition and recrystallization temperatures. Although low crystallization tendency in the dry state is
recognized as an important factor for the ASD shelf life, low
crystallization tendency in the wet state is crucial to achieve
improved bioavailability.57

POLYMER SCREENING FOR SOLID DISPERSION


Even for compounds that are identified as good glass formers with low crystallization tendencies, their amorphous forms
are still thermodynamically unstable. Incorporating the amorphous form into a polymeric solid dispersion can drastically alter the kinetics of conversion to a crystalline form in both solid
and supersaturated solution states. The physicochemical properties of the drug and the polymer determine how the polymer
interacts with the drug molecule in the ASD. The ideal polymer
plays multiple roles in the dispersion. First, it has the properties to maintain the drugs amorphous state not only during the
manufacturing but also during shipping and storage. Second,
it dissolves rapidly and releases the drug at the absorption site
in the GI tract. It also has the ability to maintain the supersaturated solution for an adequate period to allow absorption.
Furthermore, it may also enhance the permeation of the compound through the GI tract membranes.
The miscibility of the drug and polymer is generally believed
to be the prerequisite condition to form a physically stable ASD.
A miscible dispersion is defined as one single amorphous phase
system, which has one single Tg and no detectable phase separation by analytical techniques, such as DSC, XRPD, infrared
spectroscopy, solid-state nuclear magnetic resonance (ssNMR),
scanning electron microscopy (SEM), dynamic dielectric spectroscopy (DDS), and Raman.24,7377 A great deal of research
efforts have been employed in predicting the compatibility and
the phase stability of drugpolymer mixtures. These studies
are shedding light on the stabilization mechanisms of the amorphous compound in an ASD. However, because of the complexity
of the interactions, deviations of experimental results from theoretical predictions are still ubiquitous. In industry, the selection of the optimal polymer still mainly relies on experimental
screening.2
Theoretical DrugPolymer Miscibility Prediction
It is recognized that there is not a well-established method
available to measure the miscibility between drug and polymer because the polymers viscosity impedes the attainments
of equilibrium. Currently, it can only be estimated by model
prediction.78 The lattice-based FloryHuggins theory,79 expressed in Eq. 2, has been adapted from polymer blends
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to predict the thermodynamic miscibility between drug and


polymer.73,8084
Ndrug
Npolymer
G
=
ln Ndrug +
lnNpolymer + PNdrug Npolymer
RT
mdrug
mpolymer

(2)

where G, R, and T are the same as in Eq. 1, Ndrug is the volume
fraction of drug, mdrug is the ratio of the volume of the drug to
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 FloryHuggins interaction parameter representing the
difference between the drugpolymer hetero contact interaction, the drugdrug homo contact, and the polymerpolymer
homo contact interactions.
This equation is particularly useful in describing drug
polymer mixing systems because it takes into account the
large size discrepancy between the drug molecule that usually has molecular weight less than 600 Da and the polymer
molecule that usually has molecular weight between 10,000
and 1,500,000 Da. The first two terms in the right side of the
equation represent entropy, which always favors mixing. The
magnitude of the entropy upon mixing is relatively constant
in such systems where small size molecules mix with much
larger molecules. The miscibility of the drugpolymer system is
therefore determined by the FloryHuggins interaction. When
the drugpolymer hetero contact interaction is greater than the
summation of the drugdrug and polymerpolymer homo contact interactions, the value of P will be negative, which means
the system also enthalpically favors mixing, and hence the
drugpolymer system is miscible. In the case that the drug
and the polymer lack significant intermolecular interactions,
enthalpy does not favor mixing. However, the system can still
be miscible if the mixing entropy is sufficient to offset the unfavorable adhesive intermolecular interactions.
This theory serves as a good starting point to understand the
thermodynamics between drug and polymer.80 Although it is a
useful theory for the prediction of drug solubility in polymer
carrier, its limitations are also well-known because this theory
is based on mean-field approximation to facilitate the calculation for placement of a polymer molecule in a partly filled
lattice, the assumptions to generate this equation are based on
polymerpolymer or polymersolvent systems, and the energy
for breaking the crystalline lattice is not included.78,81
Solely based on the chemical structures of the drug and the
polymer, the value of P can be calculated from solubility parameters as in Eq. 3.79,85,86 The solubility parameters for the drug
and the polymer can be estimated from a group contribution
method.81,82,84,87 This method has been incorporated into some
R
software, to
commercial prediction tools, such as the MemFis
allow in silico polymer screening. The accuracy of these in silico
predictions need to be experimentally verified as the lack of predictive power is known when the solubility parameter is used
to predict systems where the interactions are predominated by
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forces other than van der Waals forces. Highly directional interactions (e.g., hydrogen bonding) and long-range interactions
(e.g., ionic interactions) are known to form in drugpolymer
systems.88
P=

L(*drug *polymer )2
RT

(3)

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 dissolution performance remains challenging because it remains
difficult to predict the ability of a polymer to prevent drug crystallization in supersaturated solution. At present, the identification of polymeric carriers that increase dissolution rate and
also stabilize supersaturation remains largely empirical.2 Experimental 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 precipitation from supersaturated solution.29,8991 The polymers of
interest are dissolved in aqueous media, which can be water, buffer, or simulated biorelevant fluid. The drug is dissolved in a water-miscible organic solvent, such as ethanol,
propylene glycol, PEG, dimethylformamide (DMF), dimethyacetamide (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 supernatant that is withdrawn at predetermined time points and
then filtered or centrifuged. As described in the Solvent Evaporation 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 stabilizes the compounds supersaturation. These screening results
alone, however, do not provide information on whether the polymer is capable of forming an ASD with the drug or what the
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

Figure 2. Flow diagram of HTP screening for polymer and drug loading 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 dissolution 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 stabilize 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.9295 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 Tefloncoated 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 different drug load. The contents can also be multiple compounds
for one plate leading to fewer combinations. The test polymers are also each individually dissolved in a suitable organic
solvent and dispensed into these wells. A second polymer or
DOI 10.1002/jps.24541

REVIEW

surfactant can be added if the scope includes ternary or higherorder combinations. After dispensing, the plate is covered and
mixed via vortexing or a method designed for the robotic workstation. Then the solvent is removed, most commonly via vacuum evaporation. A solid film is expected to form at the bottom 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 evaluated for stability for a given time frame, characterized again,
and then used for dissolution testing. The goal of the screening 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 13 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.51,9799 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 Barillaro 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 profiles of the RE scaled-up ASDs correlated well with those obtained 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 50C/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 solubility after 2 weeks stored at 50C/75% RH were evaluated.
The data generated by the HTP method were in good agreement
with that generated from the spray-dried material. HPMCASM with 20% drug load offered the highest solubility improvement. 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 Hickman and Clausius-Clapeyron equations, they concluded that it
only takes 115 s to completely evaporate the organic solvents
in these wells.
Miniaturized Coprecipitation Screening
In this screening technique, the API and polymer stock solutions 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

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 5C, 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 because 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 210 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 13 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 using 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 composed 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 technology, with very minimal amount of material, drugpolymer
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 particle (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 dissolution profiles.47,105 Even in the case where the miscibility limit is exceeded, rapid drying process still most likely
generates well-mixed drugpolymer systems in spray-dried
products.78 With micro spray dryers becoming increasingly
common in pharmaceutical laboratories, many pharmaceutical 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 BLchi

Labortechinik AG. It offers 40%95% yield


for 30500 mg of material.107110 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
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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 4M8TriX 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 adhesion to the chamber of the small laboratory dryer. Equipped
with ultrasonic nozzles, bench-top spray dryers produce particles 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 development and further to product commercialization.16
As an example, solid dispersions of amlodipine using dextrin 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
R
, which is formulated using amlodipine beproduct Norvasc
sylate salt.106 In another example, an ASD containing a GPR119 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 preclinical 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 research 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 challenging to correlate the in vitro dissolution results to the in vivo
absorption especially for formulations that produce supersaturation, because the in vitro dissolution may not be predictive 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, because complex processes take place simultaneously during their
dissolutions.113
The dissolution method should be developed to fit the purpose at the stage of the development. As pointed out by Newman 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 104:32373258, 2015

consistency. The simulation parameters should include composition 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 characterized. 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 analyzed publications up to 2010, which reported bioavailabilities
using ASDs. Their analysis and discussion focused on 40 studies, 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 analyzed 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 500900 mL media,
88% performed at 50100 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 concentrations 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 contained 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 dissolution profiles of 50% drug-loaded ASDs were close to its theoretically calculated solubility of the neat amorphous drug form.
Within a few minutes after the 10% drug load ASDs were introduced into the dissolution media, the solids disappeared and the
media became turbid. In contrast, the media and the solids remained unchanged throughout the experiment (observed under
cross-polarized microscopy) after the 50% drug load ASDs were
introduced. Dynamic light scattering analysis of the turbid media 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 supersaturation 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 felodipine solutions, dissolution of felodipine neat amorphous form in
the presence of polymer in the medium, and a saturated solution 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

REVIEW

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 remarkably close to the theoretically calculated values. In contrast to
approximately 2.5 times difference in the apparent concentrations 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 difference in the thermodynamic activity of felodipine in solutions
derived from the 10%, 50% drug load ASDs or the neat amorphous 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 researchers 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 Soluplus 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 containing 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, polymerbound and solubilized API, as well as microparticulate structures that were mainly formed by amorphous API. Although
the increased apparent solubility was attributed to the micellization and complexation of solubilized API, the increased permeation rate was accredited to the amorphous API microparticulates, which was described as true supersaturation.31
Some researchers have adapted ASD to improve bioavailability of biopharmaceutics classification system (BCS) IV compounds by incorporating absorption enhancers into the dispersion. Using orthogonal design, nine combinations of ternary
ASDs were prepared for berberine with one of the three polymers, PVP K30, PEG 6000, or F 68 as the carrier, and sodium
caprate as the absorption enhancer.95 The membrane permeability 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 studies confirmed that the preparation that offered the best permeation rate and absorption in the in vitro and in situ studies
had markedly increased bioavailability and significantly improved antidiabetic effect. SLS at the concentration of 0.9% was
added to spray-dried amlodipinedextrin solid dispersion.106
The amount of this tertiary component did not affect the dissolution 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

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, microbiome 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 popular 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 exposure 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 experimenter 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 bioavailability 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 comR
as the reference, it released much
mercial product Sporanox
slower from HPMC-based ASD compared with Eudragit E100
or a mixture of Eudragit E100 and PVPVA64 based ASD. However, 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 understanding of the fundamental mechanisms of how polymers inhibit 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 thermodynamic equilibrium is rarely reached during ASD preparation. 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 excess of their equilibrium solubilities in the polymer to satisfy
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

HPMCAS-M (10%, 25%)

HPMCAS-L, HPMCP
HP55 (35%)

HPMC K100, PVP K90,


HPMCAS-M,
(20%70% in HTP)
(25% in SD)

BMS-B, MW 688.2, Tm
amorphous, Tg 88C,
log P 7.7, pKa 7.6, 9.7

Compound 1, MW 377.5,
Tm 168,173C, Tg 36C,
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)

PVPVA, HPMCAS-M
(40%)

BMS-A, MW 500, Tm
160C, Tg 45C,
neutral

NA

PVP K30, PEG6000, F68


with 3%33% sodium
caprate (13%44%)

Berberine, MW 336.4, Tm
145C, log P 0.05,
neutral

Polymers (Drug Load, %)


Dextrin, dextrin with
0.9% SLS (10%)

Structure

Amlodipine, MW 408.9,
Tm 144C, log P 3.0,
pKa 9.0

Compound

Table 2. Examples of Polymer Selection and ASD Evaluation

HTP SC, SD

SD

SD

Solvent shift,
SD

RE

SD

Method

Solubility (HTP
materials), rat PK (SD
material)

Dissolution, rat PK

Dissolution (10% and


25% drug load), rat
and monkey PK and
TK (25% drug load)

Solubility, dissolution,
dog PK

Solubility, dissolution,
membrane
permeability, in situ
intestinal perfusion,
rat PK

Dissolution, membrane
permeability, rat PK

Selection Criteria

All ASDs increased solubility and


dissolution while 1:1:6
berberinesodium
capratePEG6000 performed the
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.
More solubility was increased by
HPMCAS-M in solvent shift. In
both nonsink and sink dissolutions,
PVPVA ASD performed better.
Better dog PK was obtained from
HPMCAS-M ASD.
ASD with 10% and 25% drug load
dissolved 90% drug in 7 min and
25 min, respectively. Satisfactory
and dose-proportional exposure was
obtained in rat and monkey
toxicology studies.
HPMCAS-L ASD crystallized in the
vehicles of suspension formulation.
HPMCP ASD increased 7-fold AUC
from crystalline suspension in
dissolution and exposure in rat PK.
Solubility was increased the most by
HPMCAS-M, followed by HPMC
K100, then PVP K90. Solubility was
the highest at 20% drug load and is
reduced with increasing loading in
all cases. ASD with 25% drug load
provided satisfied rat PK.

Permeability was better from the


ternary ASD. Rat PK was also
better and comparable to market
product.

Performance

Continued

51,100

27

112

95

106

Reference

3246
REVIEW

DOI 10.1002/jps.24541

DOI 10.1002/jps.24541

HPMC E5 and E50, PVP


K12 and K90, Eudragit
L 100-55, HPMCP 55
and 55S (33%)

MiCoS

Eudragit L100 and


L10055, HPMCAS-L,
(20%, 35%, 50%)
HPMCP HP-55, Eudragit
L100 and L100-55,
HPMCAS-L (10%,
20%, 30%, 40%, 50%)

Itraconazole, MW 705.6,
Tm 166C, Tg 50C,
log P 5.7, pKa 3.7

RE,

HPMC, PVP (10%, 50%),

HME

FD, SD, CVD

MiCoS

SD, HME,

PVP K30, HPLCAS-L


(25%, 33%, 50%),

Dissolution, rat PK,

Effect of manufacture
process, rat PK

XRPD characterization,
solid stability,
dissolution

XRPD characterization

Dissolution, diffusion,
solution NMR

Dissolution

Dissolution

Nucleation rate

SCF, RE

RE

Crystallization tendency,

Selection Criteria

SCF

Method

Same as above,
(2%590%)

PVP K29/K32, HPMC,


HPMCAS-M
(75%97%),
Same as above, (75%)

Polymers (Drug Load, %)

HPMCAS-M (20%)

Structure

Griseofulvin, MW 354.8,
Tm 216C, Tg 88C,
log P 3.0, neutral

Glyburide, MW 494.0, Tm
169C170C, Tg 65C,
log P 3.1, pKa 13.7

Felodipine, MW 384.3, Tm
147C, Tg 45C, log P
4.8, pKa 2.7

Compound

Table 2. Continued

Among pH-independent polymers,


HPMC was a better stabilizer than
PVP, while increasing molecular
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.

Only L100 at drug load 40% and 50%


did not form ASDs. Although
L100-55 ASDs offered the best solid
stabilities, HPMCAS-L ASDs
offered the best dissolutions.
They offered comparable dissolution
profiles and similarly improved rat
PK.

These polymers equally effectively


reduced nucleation rate in the
absence of moisture.
Equally effectively reduced nucleation
rate at 75% RH, PVP absorbs more
water and caused the tendency of
phase separation.
HPMCAS-M produced the highest
extent of supersaturation, followed
by HPMC, then PVP.
HPMCAS-L produced higher drug
released rates and better
wettability. In both polymer
matrixes, SD materials were
released faster.
Although there is a higher apparent
dissolution from the 10% drug load
ASDs, a similar maximum
thermodynamic activity of the
dissolved drug was detected from all
ASDs.
All polymers at all drug loads formed
ASDs.

Performance

Continued

122

121

101

101

113

120

93

92

28

Reference

REVIEW

3247

He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

Compound

Table 2. Continued

Structure
Ultra-rapid
freezing

HME

Solvent shift

KSD

SD

HPMC 2910, Eudragit


E100, mixture of
Eudragit
E100-PVPVA64 at
70/30 (40%)
HPMC E3, E50, F50, and
HPMCAS-L, M, H
(10,000x of equilibrium
solubility)

HPMCAS-L, M, H, and
HPMCAS-L, H with
Carbomer 974P (33%)

PVP K17, HPMCAS-L


(10%)

Method

CAP and PVAP (33%,


50%, 67%)

Polymers (Drug Load, %)

He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

Molecular mobility

Dissolution, rat PK

Precipitation inhibition,

Dissolution, clinical

Dissolution, rat PK

Selection Criteria
CAP provided greater degree and
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.
Eudragit E100, mixture of Eudragit
E100-PVPVA64 released drug
instantaneously, whereas HPMC
released much slower in dissolution.
However, HPMC performed the best
in clinical.
HPMCAS family provided greater
stabilization of supersaturation,
and the stabilization within each
family was directly related to the
number of hydrophobic functional
groups: HPMCAS H>ML, HPMC
E50>F50E50.
In dissolution: HPMCAS-LM>H.
C974P reduced AUC for L, but
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.
HPMCAS-L acted as an
anti-plasticizer of global mobility. It
was substantially more effective
than PVP in inhibiting
crystallization.

Performance

Continued

76

29

29

119

123

Reference

3248
REVIEW

DOI 10.1002/jps.24541

DOI 10.1002/jps.24541

RE
MiCoS

Eudragit L100 and


L100-55, HPMCAS-L
(20%, 35%, 50%)

HPMCP HP-55, Eudragit


L100-55, HPMCAS-L
(40%)

Vemurafenib, MW 489.9,
Tm 272C, Tg
105C107C, log P
3.0, neutral
MBP

HTP SC, RE

Solid stability,
dissolution, human PK

Dissolution

XRPD characterization

Crystallization and phase


transition kinetics

Dissolution, monkey PK

Dissolution, rat and dog


PK

Selection Criteria

Performance

All three grade of PVP with all three


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.
All formed ASDs, only Eudragit
L100-55 and HPMCAS-L ASDs
were stable. HPMCAS-L ASD
provided better dissolution profile
and offered fivefold increased
exposure from crystalline form.

Eudragit L100-55 at 20% drug load,


and HPMCAS-L at 20% and 35%
drug load formed ASDs.

HPMCAS-M performed the best,


followed by HPMC, then PVP.

Eudragit E PO with Cremorphor EL


performed better than others in
dissolution. It offered exposure
similar to lipid-based formulation,
less variability, and acceptance to
toxicology studies.
PVP/VA 64 with both Tween 80 and
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.

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.

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)

Phenytoin, MW 252.3, Tm
295C, log P 1.4, pKa
8.3 (acidic)

HTP SC, HME,


SD

PVP, HPMC, HPMCAS-M


(50%)

MK-0364, MW 516.0, Tm
104C, Tg 41C, log P
6.3, pKa 0.7

HTP SC, RE

Method

Nifedipine, MW 346.3,
Tm 173C, Tg 45C,
log P 2.3, pKa 3.9

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%)

Structure

LCQ-789, MW 476.9, Tm
194C, Tg 105C, log P
5.4, pKa 2.5

Compound

Table 2. Continued

124

97

101

94

47

48

Reference

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He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

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REVIEW

the dose requirement.24,125127 Given time, the amorphous drug


in these ASDs will ultimately revert to a crystalline form. Some
ASDs, however, have successfully advanced to commercial products and many more are in the pipeline because not only the
bioavailability is optimized, but also the requisite pharmaceutical stability is achieved when the polymer and manufacturing
conditions are carefully selected.
In an attempt to improve ASD physical stability, increasing
the dispersions Tg has been the focus of many studies.76 Before
the introduction of more powerful analytical techniques to analyze 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 interactions 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 temperature XRPD. Besides miscibility between the drug and the polymer, 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 recognized as the unavoidable third component in hydrophilic polymeric dispersion systems at ambient condition.127 With consideration of the impact on amorphous drug "- and $-relaxations
from both temperature and humidity, the prediction of longterm 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 accelerated 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 protect 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. Dissolution 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.

formulations in late-stage development and marketed products 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 patients. 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 regimen needed to take 1600 mg vemurafenib, which required ingesting 32 capsules.130 The reformulation of vemurafenib succeeded 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

vemurafenib (Zelboraf ).124,131 Furthermore, using a less thermally 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 application of this technology to their reformulation. Besides oral delivery, 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.133135 ASD can also be applied in injectable formulations

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 utilized in NMEs as well as new formulations for lifecycle management. 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 preclinical is only 33 in this search, the actual number of preclinical
products employing ASDs is likely much higher as the majority 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 pharmaceutical companies. Among these, over 50 programs have advanced
to clinical trials.
R

Product and Pipeline


In addition to the improved dissolution kinetics, flexibility in
dosing, and acceptance in toxicology studies in the discovery and early development stages, the number of ASD-based
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

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

Griseofulvin
Telaprevir
Etravirine

Verapamil HCl
Ritonavir/ lopinavir

Ivacaftor
Itraconazole
Nimesulide
Ritonavir
Posaconazole
Itraconazole
Tacrolimus
Troglitazone
Itraconazole
Ibuprofen

Vemurafenib

Gris-Peg
Incivek
Intelence

Isoptin SR
Kaletra

Kalydeco
Lozanoc
Mesulid fast
Norvir
Noxafil
Onmel
Prograf
Rezulin
Sporanox
Thomaflex Meltrex

Zelboraf

NME

NME
NF
NF
NF
NF
NF
NME
NME
NF
NF

NF
NF

NF
NME
NME

NF
NF
NME
NF

NME/NF

ins

s
ins
ins
ins
ins
ins
ins
ins
ins
ins
ins
ins
vss

ins
ins
ins

ins
vss
vss
ins

WS

IV

II
IV
II
II/IV
IV
II
IV
II
IV
II
II
IV
II

IV
II
IV

II
III
II
II

BCS

HPMCAS

HPMCAS
HPMCP
$CD
PVP
HPMCAS
HPMC
HPMC
HPMC
HPMC
Nd

HPC/HPMC
PVP

HPMC
HPMC
PVP
PEG6000/
Poloxamer 188
PEG 6000
HPMCAS
HPMC

Polymer

MBP

SD
SD
Mech.
HME
SD, HME
HME
KDS
HME
SD
HME

HME
HME

Melt
SD
HME

WG
CP
SE
CA, SD

ASD
Method

Tablet

Tablet
Capsule
Tablet
Tablet
Tablet
Tablet
Capsule
Tablet
Capsule
Tablet

Tablet
Tablet

Tablet
Tablet
Tablet

Capsule
Tablet
Capsule
Tablet

Dosage
Form

Cancer

Cystic fibrosis
Infections, fungal
Pain
Infections, HIV/AIDS
Infections, fungal
Infections, OM
Organ trans.
Diabetes
Infections, fungal
Pain

Hypertension
Infections, HIV/AIDS

Infections, fungal
Infections, hepatitis C
Infections, HIV/AIDS

Organ trans.
Organ trans.
Cancer, chemo se
Hyperlipidemia

Therapeutic
Category

2011

2012
nd
nd
2010
2013
2010
1994
1997
1992
nd

1997
2005

1975
2011
2008

2013
2010
1985
2007

FDA

2012

2012
2012
nd
2010
2014
ND
2006
nd
nd
2005

1986
2006

nd
2011
2008

2007
2003
2009
nd

EU

nd

US8410274
US6881745
nd
US7364752
US20110123627
US7081255
EP0240773
nd
US5633015
nd

nd
US7364752

nd
US8431615
US7887845

US6440458
US6004973
US4087545
US7658944

Formulation
Patent

Vertex
Mayne
Novartis
AbbVie
Merck
Merz
Astellas
Pfizer
Janssen
BoehringerIngelheim
Roche

Astellas
Novartis
Valeant
Santarus
Veloxis
Pedinol
Vertex
Johnson &
Johnson
Abbott
AbbVie

Company

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.

Tacrolimus
Everolimus
Nabilone
Fenofibrate

Molecule

Advagraf/Astagraf XL
Certican/Zortress
Cesamet capsules
Fenoglide

Product
Name

TM

Table 3. Examples of Marketed Amorphous Dispersion Products for Oral Delivery (Source: PharmaCircle

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delivery system is that this higher energy state poses challenges in manufacture, shipping, storage, and dissolution. Although understanding of this drug delivery system has greatly
improved in recent years, there are many questions that remain. Understanding the molecular interactions between the
drug and the polymer carrier in the solid state of the ASD and
in supersaturated solution still need to be further elucidated
to enhance the predictability of ASD physical and chemical
stability and in vivo performance. Further basic research will
certainly boost the applications of ASDs to new levels, and potentially enable previously undevelopable drug candidates to
benefit patients.
Can a Polymer be Selected Without Making an ASD?
Polymer selection has been thoroughly discussed in both theoretical predictions and experimental screening. Although the
physical stability of the solid-state ASD can be predicted by
theoretical calculations, the performance of ASD still largely
requires experimental evaluation.
High-throughput solvent casting is the method of choice of
some major pharmaceutical companies and it frequently provides predictable guidance to select an ASD.48,51,98 Instrumentation limitations persist as many laboratories are not equipped
with automated systems. In addition, when the preparation is
scaled from HTP screening to laboratory-scale production, the
properties of the product sometimes cannot be reproduced because of the change in thermal history. In scale-up, the process
can be altered from film casting to SD or melt extrusion or other
techniques. The mechanism varies from solvent-based to meltbased, or to mechanical-based or vice versa.30,114 When an ASD
of felodipine was prepared using PVP K30 or HPMCAS-L as
the carrier, the drug was released faster from the spray-dried
product than from hot-melt extruded product.120 As the crystallization of felodipine happens rapidly in the solid once the
ASD contacts the aqueous medium, the thermal history has
important implication on how the polymer interacts with the
compound.128
Although the stability of the ASD is important, improved
bioavailability is the key criterion of an ASD. The in vivo performance is determined by many factors, including crystallization tendency of the compound in solid form upon contacting
the GI fluid, dissolution of the amorphous drug, dissolution of
the polymer, interaction of the drugpolymer in both solid and
solution, precipitation of the supersaturated drug in its crystalline form, and so on. When the performance is dominated by
the polymers ability to generate and maintain supersaturation,
such as in the case of BMS-A, the solvent shift method can give
a reliable prediction.112 When the ASD performance is mainly
contributed by the interaction between drug and polymer to
generate and hold the supersaturation, the ASD may have to
be prepared for screening. When the kinetics during ASD manufacture do not significantly contribute to the properties of the
ASD, the polymer can be screened without manufacturing the
ASD or the ASD produced by any manufacturing process may
be used.51,121 A study of griseofulvin on HPMCAS-M matrix
using small-scale bench processes, namely, fast evaporation,
lyophilization, and SD, demonstrated that each of these techniques is reliable, comparable, and suitable to generate ASD
material without large investment in time and API quantity.121
However, when the thermal history of the manufacturing
process significantly contributes to the ASD properties, the
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015

screening of the polymer is better performed using the manufacturing method that ultimately will be used to produce
the bulk material for preclinical or clinical development.92,120
In recent years, bench-top spray dryers have often been
used to prepare spray-dried ASD and their appearance in
literature demonstrates their versatility in aiding candidate selection in early research and downstream formulation
development.27,52,106,112,139
Is the Dissolution Method Biorelevant Enough?
The selection of appropriate dissolution conditions is crucial for
the successful in vitro evaluation of an ASD formulation. It is
well recognized that the in vitroin vivo correlation is far from
perfect for this type of formulation.114 In the survey performed
by Newman et al.,24 the relationship between in vitro dissolution and in vivo bioavailability was reported for 78% of the 40
studies examined. In 22% of these studies, the in vitro dissolution failed to offer insight into the in vivo performance. The
authors systemically analyzed how the dissolution results are
influenced by factors including physicochemical properties of
the compound, particle size of the ASD, composition and pH of
the dissolution media, selection of dissolution vessel, dissolution volume, agitation rate, choice of sink to nonsink conditions,
and consideration of dose to solubility ratio.24
Sample preparation is critical for dissolution studies of this
type of formulation. They should be designed based on the in
vivo dosing protocol. If the particle size of the dispersion is to
be controlled for in vivo dosing, for example, sieved to a more
defined particle size range, it should be controlled in the dissolution too. Although solid dosage formulations such as capsules
are preferred in preclinical studies to facilitate animal dosing, ASDs are frequently dosed as suspensions in preclinical
studies, especially when the carrier is an enteric polymer. If a
suspension of the dispersion is planned to be dosed sometime
after preparation, for example, 1 day or 1 week after preparation, the prepared sample should be kept for the same length
of time prior to evaluation via dissolution testing. The role of
the vehicle in this type of suspensions is to maintain the solid
in amorphous form. The physical form of the ASD must also
be evaluated to ensure there is no change after the sample is
prepared.
Because of the metastable nature of this type of dispersion,
it usually does not afford the luxury to prepare a single sample
for a 2-week toxicology study when the formulation is a suspension. The need for extemporaneous preparation for each dose is
common. Stability of at least 2 h is usually preferred, although
some institutes accept half-hour stability.48 If the suspension
stability is unknown, ASD material can be dispersed into the
dosing vehicle immediately prior to dosing.122 The dose to media
volume ratio should also be carefully selected, as precipitation
from supersaturation is a concentration-driven phenomenon.
Other Considerations in Dissolution
The vehicle composition of formulation is important. Tween 80
at a concentration of 0.2%0.5% is routinely used as a wetting agent in suspensions of crystalline material. However, it
reduced the drug release and led to precipitation in a short period of time in the case of an LCQ789 ASD suspension,48 which
is consistent with the authors observations with other research
compounds (unpublished data). In another study, Tween 80
at a concentration of 10% was added in an ASD suspension
DOI 10.1002/jps.24541

REVIEW

formulation because it provided significant solubility improvement 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 dispersion 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 However, 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 solubility is pH dependent, the pH of the suspension vehicle and the
buffer composition should be carefully selected. The preparation 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 important too. It should be set close to physiological temperature.
Although equilibrium solubility increases with elevated temperature and the solubility difference between 25C and 37C is
usually minimal,140,141 the solubility of a neat amorphous compound or ASD may decrease with increased medium temperature because crystallization onset may be earlier, crystallization rate may be faster, amorphous material agglomerates may
be more extensive, and crystalline precipitation from supersaturation 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 translated to the clinical studies. Although disease relevance is often 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 Newman et al.,24 dog and rat are the most favorable choice when
ASDs are dosed. Nonhuman primates have been used in studies of ASDs and they are regarded as useful models in drug
delivery with regard to gastric pH and emptying time, GI agitation intensity, and intestinal transit time.27,142,143 However,
large exposure variability could limit their use when the compound is ionizable or when a pH-dependent polymer is used as
the carrier. The cause of the variability is often the consumption 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

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 reproducibility 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, pHdependent polymers are frequently selected as the carrier because 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 effect need to be included in the considerations of the dissolution
method for preclinical and clinical study designs to fully understand 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 escalation studies because of the higher achievable drug exposure,
inert nature of the polymer and the dosing flexibility of suspension formulation. ASDs can be dosed as simple suspensions
in preclinical studies and early clinical trials, can be formulated 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 acceptability. 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 berberinesodium capratePEG
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 1.83.0 g ASD per day. This
amount of ASD would contain 0.20.4 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 determine whether ASD can be a choice to improve its bioavailability. A compound with low Tm and high Tg would have fewer
obstacles to convert to an amorphous phase and less thermodynamic 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 solubility of the drug in the polymer. Many efforts have been made
for a theoretical prediction. Limited by the inadequate understanding of the mechanisms involved with stabilization, dissolution, 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
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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 automated 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 reproduced 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 minimum of 5 g of drugpolymer 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, enabling 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 candidate does not warrant the compound to stand all ASD processing options. Compounds, such as vemurafenib, cannot stand
HME because of its high Tm and thermal instability and cannot be manufactured by SD because its low solubility in volatile
solvents and water. Some research compounds can be manufactured using SD with relative low solubility in volatile solvents because the amount of ASD needed at this stage is
small. However, after the ASD is proved to be the right concept 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 acceptable processability at scaled-up setting may have to be
explored. Shelf life in pharmaceutics is a relevant term. Although a few months stability is usually sufficient for researchstage 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 prediction of long-term stability from short-term data can help
ensure confidence in the compound transition from preclinical to clinical. Robust batch to batch physical quality reproducibility 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 unapproved 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 approval, 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 104:32373258, 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 dissolution, 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 formulation 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 consideration 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 largescale manufacturing of ASD are more established. FDA approval 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 intellectual property positions accessible through ASDs. The pharmaceutical industry has embraced the idea that the applications of
ASDs are not limited to NMEs, but also been to lifecycle management 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 stability 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 industrial 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 pharmaceutical scientists because of the challenges in manufacturing and physical stability, it has been demonstrated in numerous 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

REVIEW

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 products because of physical and chemical instability to actively
utilizing ASDs to enhance drug absorption by taking advantages 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 sincerely thank Dr. Ed Orton for help in editing this manuscript.

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DOI 10.1002/jps.24541