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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
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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
DOI 10.1002/jps.24541
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3239
the GI tract.
G
Famorphous = e RT Fcrystalline
(1)
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.
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Cooling
Reheating
Classification
Crystalline
Amorphous
Amorphous
Crystalline
Amorphous
Thermodynamic
Thermodynamic and kinetic
Pressure
(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
He and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES 104:32373258, 2015
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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)
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
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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
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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
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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
HPMCAS-L, HPMCP
HP55 (35%)
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
Berberine, MW 336.4, Tm
145C, log P 0.05,
neutral
Structure
Amlodipine, MW 408.9,
Tm 144C, log P 3.0,
pKa 9.0
Compound
HTP SC, SD
SD
SD
Solvent shift,
SD
RE
SD
Method
Solubility (HTP
materials), rat PK (SD
material)
Dissolution, rat PK
Solubility, dissolution,
dog PK
Solubility, dissolution,
membrane
permeability, in situ
intestinal perfusion,
rat PK
Dissolution, membrane
permeability, rat PK
Selection Criteria
Performance
Continued
51,100
27
112
95
106
Reference
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DOI 10.1002/jps.24541
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MiCoS
Itraconazole, MW 705.6,
Tm 166C, Tg 50C,
log P 5.7, pKa 3.7
RE,
HME
MiCoS
SD, HME,
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%)
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
Performance
Continued
122
121
101
101
113
120
93
92
28
Reference
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3247
Compound
Table 2. Continued
Structure
Ultra-rapid
freezing
HME
Solvent shift
KSD
SD
HPMCAS-L, M, H, and
HPMCAS-L, H with
Carbomer 974P (33%)
Method
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
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MiCoS
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
Dissolution, monkey PK
Selection Criteria
Performance
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.
Phenytoin, MW 252.3, Tm
295C, log P 1.4, pKa
8.3 (acidic)
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
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
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REVIEW
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
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
REVIEW
3251
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REVIEW
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.
3253
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REVIEW
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
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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