ADR-12895; No of Pages 10

Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Recent advances in co-amorphous drug formulations☆

Swapnil Jayant Dengale a, Holger Grohganz b, Thomas Rades b,⁎, Korbinian Löbmann b
a
Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India
b
Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Co-amorphous drug delivery systems have recently gained considerable interest in the pharmaceutical field be-
Received 6 October 2015 cause of their potential to improve oral bioavailability of poorly water-soluble drugs through drug dissolution en-
Accepted 9 December 2015 hancement as a result of the amorphous nature of the material. A co-amorphous system is characterized by the
Available online xxxx
use of only low molecular weight components that are mixed into a homogeneous single-phase co-amorphous
blend. The use of only low molecular weight co-formers makes this approach very attractive, as the amount of
Keywords:
Co-amorphous
amorphous stabilizer can be significantly reduced compared with other amorphous stabilization techniques. Be-
Solid dispersion cause of this, several research groups started to investigate the co-amorphous formulation approach, resulting in
Poorly soluble drugs an increasing amount of scientific publications over the last few years. This study provides an overview of the co-
Molecular interactions amorphous field and its recent findings. In particular, we investigate co-amorphous formulations from the view-
Increased dissolution point of solid dispersions, describe their formation and mechanism of stabilization, study their impact on disso-
lution and in vivo performance and briefly outline the future potentials.
© 2016 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. What are co-amorphous formulations? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Technologies for the preparation of co-amorphous systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Mechanism of physical stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1. Amorphous solubility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.2. Glass transition temperature (Tg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3. Intermolecular interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.4. Intimate mixing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. Dissolution properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6. In vivo performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7. Concluding remarks and future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction
The development of amorphous drug delivery systems has been
widely investigated in academia and by the pharmaceutical industry
to overcome the poor aqueous solubility of many drugs. Briefly, the
same solid material can be crystalline or amorphous, where amorphous
drugs exhibit a significantly higher solubility and dissolution rate than
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Amorphous
pharmaceutical solids”.
⁎ Corresponding author.
E-mail address: thomas.rades@sund.ku.dk (T. Rades).
their crystalline counterpart [1]. The main drawback of using pure
amorphous highly soluble drugs is their physical instability with respect
to their inherent tendency to recrystallize into the poorly soluble crys-
talline form as they are thermodynamically unstable [2].
As only pure amorphous drugs often appear non-feasible in drug de-
livery systems, a major focus within amorphous research and develop-
ment is the stability of the amorphous form through the use of
excipients. Several approaches have been introduced in previous stud-
ies, including polymer-based glass solutions, mesoporous silica and
co-amorphous formulations. Of them, the co-amorphous strategy has
recently gained considerable interest in the pharmaceutical field as it
provides opportunities to overcome shortcomings associated with the

http://dx.doi.org/10.1016/j.addr.2015.12.009
0169-409X/© 2016 Elsevier B.V. All rights reserved.

Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
2 S.J. Dengale et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx
other two approaches. The objective of this study is to provide an over-
view on the state of the art of co-amorphous drug formulations.
2. What are co-amorphous formulations?
Polymer-based glass solutions, mesoporous silica and co-amorphous
formulations all come under the term glass solutions, which itself is a
subcategory of solid dispersions. The use of this expression is very in-
consistent in the pharmaceutical field; therefore, this section provides
a short guidance to the complex classification of solid dispersions.
The term solid dispersion was defined by Chiou and Riegelman [3] in
1971 as “a dispersion of one or more active ingredients in an inert carri-
er at the solid state prepared by the melting (fusion), solvent, or
melting-solvent method.” According to this definition, solid dispersions
can be classified according to their number of solid-state phases and the
physical state of these phases. As presented in Table 1, solid dispersions
can be very diverse, including eutectic mixtures, solid solutions, glass
solutions and glass suspensions. A more detailed description of the dif-
ferent types of solid dispersions is provided by Chiou and Riegelman [3]
and Laitinen et al. [4]
Glass solutions, that is, single amorphous phase systems, are often
referred to as amorphous solid dispersions (ASD) and can further be
subdivided according to the excipients that stabilize the amorphous
drug. Vaka et al. differentiated them into polymeric and non-
polymeric excipients, where the former can further be classified into
ionic and non-ionic polymers [5]. The group of non-polymeric excipi-
ents can further be divided into mesoporous silica-based glass solutions
and those containing only low molecular weight components, the so-
called co-amorphous formulations (Scheme 1).
To date, polymer-based ASDs are by far the most investigated ASDs.
Thus, the term solid dispersion is highly connected to the use of poly-
mers in stabilizing amorphous drugs. This is misleading as solid disper-
sions are a rather large group of different types of solid mixtures
(Table 1). Thus, for a clearer differentiation, ASDs with polymeric excip-
ients are called polymer-based glass solutions in this study.
In polymer-based glass solutions, polymeric carriers are used to sta-
bilize the amorphous drug and improve its solubility and dissolution
rate [6]. In these systems, stabilization of the drug in its amorphous
form is achieved by several factors. One key aspect is the solubility of
the drug in the amorphous polymer [7,8]. Below its limit of solubility,
the drug is molecularly dispersed in the amorphous polymer and stabi-
lized by physical separation of the molecules between the polymer
chains. Most polymeric carriers have a high glass transition temperature
(Tg), and thus increase the Tg (while reducing the molecular mobility)
of the drug in the glass solution compared to that in its pure amorphous
form [9]. Furthermore, intermolecular interactions between the drug
and functional groups of the polymer have been found to play a role
in the stabilization mechanism [10]. However, limited drug solubility
in large polymeric excipients often increases the dosage and does not
necessarily make the formulation very stable against recrystallization
[11–13]. Another drawback is the hygroscopic nature of many polymer-
ic carriers, which results in absorption of moisture. The absorbed mois-
ture acts as a plasticizer, thus reducing the Tg and increasing mobility,
which in turn can result in phase separation and recrystallization [13].
Thus, despite an active research interest, polymer-based glass solutions
have led to only a few marketed products [5,14].
Table 1
Classification of solid dispersions (reproduced from ref. [4]).
Solid dispersion Number of phases Physical state of phase(s)
Eutectic mixture 2 C/C
Solid solution 1 C
Glass solution 1 A
Glass suspension 2 A/A or A/C
Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
Scheme 1. Classification of co-amorphous mixtures within glass solutions based on the
choice of the stabilizing agent.
In mesoporous silica-based glass solutions, the drugs are
amorphized by adsorption onto the surface of the silica particles,
which consists of a matrix of pores with diameter between 2 and
50 nm [15]. On the one hand, stabilization of the amorphous drug is
achieved through molecular interactions between the drug and the
functional groups of the silica matrix [16,17]. On the other hand, crystal-
lization is inhibited physically by the pore diameter of the materials,
which may be smaller than the size of a crystal nucleus of the drug
[18]. However, the main drawbacks of mesoporous silica-based glass so-
lutions are their production, which predominantly involves the use of
organic solvents for drug loading [18], and often a limited loading capac-
ity of only 20%–30% [19].
The co-amorphous drug formulation approach is characterized by
the combination of two or more low molecular weight components
that form a homogeneous amorphous single-phase system [20,21]. In
order to differentiate glass solutions comprising only small molecules
from those with stabilizing polymers or mesoporous silica matrices,
Chieng et al. coined the term ‘co-amorphous’ in 2009 [22]. Using this ap-
proach, it was proposed that the amount of stabilizing excipient (if
used) can be drastically reduced due to the low molecular weight of
the co-amorphous co-former. Two types of co-amorphous principles
have been proposed so far, namely drug–drug combinations and
drug–excipient mixtures [21]. In the first type, two pharmacologically
relevant drugs intended for multidrug therapies are combined, where
both drugs stabilize each other in the amorphous form. Thus, both
drugs act as an active component and stabilizing excipient at the same
time. As a result of the stable amorphous system, both of the poorly sol-
uble drugs achieve a higher solubility and dissolution rate. In the second
type, low molecular weight excipients such as amino acids are used to
prepare stable and quick-dissolving co-amorphous drug–excipient
blends.
3. Technologies for the preparation of co-amorphous systems
Several techniques for the production of amorphous drugs have
been described in the literature. Depending on the mechanism involved,
these techniques can be divided into two types as including thermody-
namic and kinetic disordering processes [23,24]. The thermodynamic
pathway has a thermodynamically stable non-crystalline form as a
starting point, that is, the drug as a melt or in solution. In order to obtain
the amorphous drug, the melt needs to be subsequently vitrified by
rapid cooling, a process called quenching, or the drug needs to be pre-
cipitated from the solution, followed by solvent removal. The kinetic
pathway involves direct solid-state conversion of the crystalline drug
into its amorphous form. This can be achieved by continuously intro-
ducing crystal defects and disorders through shear forces, crushing
and impact during a milling process [2,25]. In general, both mechanisms
have been described for the preparation of amorphous blends [26].
The co-amorphous drug formulation approach is still in its early
stage of development, hence majority of studies focused on the basic
understanding of these systems using laboratory-scale preparative
techniques such as quenching [11,27–37], solvent evaporation [38–47]
and ball milling [28,43,47–57]. All of these techniques are attractive as
they represent fast and easy ways of (co-)amorphization, and are ideal
for screening purposes as only small sample sizes are required. In addi-
tion, quenching offers the possibility to quickly assess the critical
 S.J. Dengale et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx
physicochemical parameters such as Tg, miscibility and recrystalliza-
tion, as the co-amorphous systems can be prepared and analyzed direct-
ly in situ within a differential scanning calorimeter (DSC). However, all
these methods cannot be applied for any type of drug or co-forming ex-
cipient. Quenching is applicable only to compounds that do not degrade
upon melting. Solvent evaporation can be challenging if the poorly
water-soluble components also show poor solubility in organic sol-
vents, or if the two components do not dissolve in the same solvent in
appropriate concentrations, that is, only one component dissolves in or-
ganic solvents and the co-amorphous co-former dissolves in aqueous
solvents. On the contrary, ball milling might not be satisfactorily effi-
cient for the disruption of crystal lattice and thus, might not result in a
complete (co-)amorphization. Therefore, the physicochemical proper-
ties of drugs and excipients usually determine the preparative
technique.
With a view of developing industrially more feasible production
methods, a few studies have reported the use of scalable techniques
for the preparation of co-amorphous formulations including spray-
drying [58], freeze-drying [59] and ultrasound extrusion [60,61]. Fur-
thermore, inkjet printing has been used for the preparation of co-
amorphous indomethacin–arginine systems to obtain fabricated
printed systems that allow flexible and more individualized dosing
and thus, the development of quick-dissolving personalized medicines
[62].
4. Mechanism of physical stabilization
4.1. Amorphous solubility
As mentioned in Section 2, a co-amorphous system is a single-phase
amorphous mixture of two or more low molecular weight components.
For a system to be able to from a single phase, the components in the
blend need to exhibit complete miscibility in the amorphous form. For
thermostable compounds, the miscibility of the components in the mol-
ten state can easily be determined by the phase diagram [11,28,33,36].
By quenching these single-phase melts, one can obtain a single-phase
co-amorphous mixture. Similarly, Marsac et al. showed solubility
using a melting point depression approach, where miscible systems
show a depression of the melting point of the drug and immiscible or
partially miscible systems show little or no such depression [63]. Solu-
bility parameters can be used to check miscibility of thermolabile com-
pounds in the amorphous blend [36,50,51]. Another indicator for the
formation of a homogeneous single-phase co-amorphous blend,
where both components are dissolved in each other, is the observation
of a single Tg [3,64–66]. By contrast, immiscible or partially miscible
components result in two-phase amorphous mixtures, thereby produc-
ing two Tgs [67].
Correspondingly, for polymer-based glass solutions, the thermody-
namic solubility of the drug in the amorphous polymer has been de-
scribed as one of the primary reason for stability; however, many
drugs possess only a limited solubility of the drug in the polymeric car-
rier (often ≤20 wt.%) [68]. When the drug is supersaturated in the poly-
mer, phase separation into drug-rich and/or polymer/excipient-rich
domains may occur, followed by a rapid nucleation and crystal growth.
Similarly, partially miscible or immiscible co-amorphous mixtures that
form a homogeneous phase initially after preparation might show fast
phase separation and crystallization.
4.2. Glass transition temperature (Tg)
Tg of an amorphous material is defined as the temperature at which
the material transforms from its glassy state to a supercooled liquid
state upon heating [2,25]. At the Tg, the material changes from a solid-
like form to viscous liquid-like form, thereby drastically changing its
molecular mobility. Because of the higher molecular mobility, materials
in the supercooled liquid state crystallize at a much higher rate than
Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
3
those in the amorphous glassy state. However, although molecules in
the glassy state are kinetically frozen, they still exhibit motion, albeit
at a much lower rate. This phenomenon is called relaxation, which
helps an amorphous material to crystallize over time into a thermody-
namically stable form even at temperatures much below its Tg. In
order to keep a glassy material in its amorphous form, it is suggested
to store the material at least 50° below the Tg [2,9,64,66,69].
In glass solutions, the Tg of the amorphous multi-component system
is usually found between the Tgs of the individual components. This re-
lationship is described by the Gordon–Taylor equation as follows:
w1 T g1 þ Kw2 T g2
T g12 ¼
w1 þ Kw2
where Tg12 is the Tg of the amorphous mixture, Tg1 and Tg2 represent the
Tgs of the respective individual components, w1 and w2 represent the
respective weight fractions and K is a constant. It is thus not surprising
that the inclusion of drugs into polymeric carriers with high Tg, such
as PVP, has been shown to improve physical stability due to the in-
creased Tg of the polymer–drug blend compared with the Tg of the
pure amorphous drug [25]. This anti-plasticizing effect of polymers is
one of the key characteristics of polymer-based glass solutions.
Compared with polymeric excipients, low molecular weight compo-
nents, that is, majority of drugs, usually have a comparatively low Tg. As
co-amorphous systems contain only low molecular weight molecules,
the possibility of anti-plasticization is limited. Nevertheless, this princi-
ple has been shown in several cases of co-amorphous formulations. In
particular, the use of amino acids as co-amorphous excipients has
been shown to result in relatively high Tgs in co-amorphous blends,
for example, with the drugs carbamazepine and indomethacin [51].
The developed co-amorphous binary and ternary drug–amino acid sys-
tems exhibited excellent physical stability over at least 6 months,
whereas the pure amorphous drugs recrystallized within 7 days. Not
only the increase of Tg, but also the increased stability of the systems
are attributed to molecular interactions between the drugs and amino
acids [53]. In particular, tryptophan exhibited excellent co-forming
and anti-plasticizing properties similarly to a co-amorphous system, be-
cause of its high Tg of approximately 140 °C [52,56]. Furthermore, for
strong ionic interactions between the components, the Tg of the co-
amorphous systems can be much higher than those of the individual
components [53,70]. Hence, elevated Tg of co-amorphous mixtures
over their individual amorphous compounds has been discussed as
one of the factors for improved physical stability of these systems.
4.3. Intermolecular interactions
Many studies showed that co-amorphous systems exhibit a higher
physical stability than the individual amorphous drugs. Because the Tg
of co-amorphous systems is usually found in between the Tgs of the in-
dividual components, Tg alone cannot explain the increase of physical
stability. However, such an increase is attributed to several factors,
including molecular interactions between the components in the co-
amorphous mixture. The majority of studies on the co-amorphous for-
mulation approach have attributed the physical stability of such sys-
tems to intermolecular interactions such as hydrogen bonding and/or
π–π interactions [17,22,28,29,36,38,39,41–43,46,51,57].
In individual amorphous components, the molecules are often ar-
ranged in a certain short-range molecular order, which is reflected in
molecular interactions between like molecules, such as the formation
of homodimers in amorphous indomethacin or naproxen [37]. The
homodimers are often found similarly in the crystalline state of the
drugs and thus, recrystallization in the pure amorphous form occurs
usually at a rather high rate. On the contrary, in the co-amorphous
blend, this molecular short-range order gets disturbed in favor of the
formation of intermolecular interactions between dissimilar molecules,
that is, the two different components in the co-amorphous blend. Such a
4 S.J. Dengale et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx
formation of heterodimers is shown in several studies of co-amorphous
formulations, such as naproxen/indomethacin, ritonavir/quercetin and
cimetidine/piroxicam systems [36,42,46]. For such a system to recrys-
tallize, it is suggested that the intermolecular bonds within the hetero-
dimer must be broken, followed by a rearrangement of molecules to
form homodimers and the subsequent establishment of long-range
order in the crystal lattice. This cascade is ongoing for a considerably
longer timescale, leading to a reduced likelihood of recrystallization
and thus, prolonged physical stability of the co-amorphous systems
[20,21,56]. Furthermore, the formation of even stronger ionic interac-
tions has been described for co-amorphous systems. Yamamura et al.
prepared co-amorphous systems of cimetidine with indomethacin and
diflunisal, and found salt formation between the imidazole ring of ci-
metidine and carboxyl groups of indomethacin and diflunisal [38,39].
Strong molecular interactions have also been shown to occur in
drug–excipient mixtures [11,30,32,47]. In particular, the use of amino
acids as excipients has recently shown strong potential to stabilize
drugs in the co-amorphous form [51–53,56,58,70]. This approach was
originally based on the assumption that drugs interact at the molecular
level with amino acids at their respective target sites (receptor proteins)
in the body and thus, may also be able to interact with amino acids in a
co-amorphous mixture [51]. For this purpose, binary and ternary co-
amorphous systems comprising indomethacin and carbamazepine
with a set of amino acids (receptor and non-receptor) were prepared
by ball milling and found to be stable for at least 6 months at 40 °C.
The physical stability of the indomethacin/arginine system was attribut-
ed to ionic interactions between the carboxylic acid group of indometh-
acin and the guanidine moiety of arginine. For the tryptophan/
carbamazepine system, hydrogen bonding and π–π interactions have
been found responsible for the increased physical stability. However,
obvious differences exist between the anticipated interactions based
on in vivo binding and actual interactions in the co-amorphous mix-
tures. Unlike in vivo binding where only the side chains of the amino
acids are able to interact with the drug, it was found that the whole
amino acid molecule, that is, side chain as well as head group interacted
with the drug in the co-amorphous states [21,51].
Such intermolecular interactions in the solid state have been inves-
tigated by Fourier transform infrared spectroscopy [28,30,36,40,41,43,
45–47,49,52–54,71] and solid-state nuclear magnetic resonance
[32–34,38,39,42,56]. Furthermore, a deviation of the experimental Tgs
from theoretical Tgs following the Gordon–Taylor equation can be
used for identifying molecular interactions. The Gordon–Taylor equa-
tion describes the Tg of a homogeneous amorphous blend of two com-
ponents and is based on two important assumptions: (1) ideal free
volume additivity of the two components in the amorphous mixture
and (2) no specific interactions exist between these components
(ideal mixing behavior). As the Gordon–Taylor equation explains the
dependence of Tg on the composition of the amorphous blends with
the aforementioned assumptions, deviations of the calculated values
from experimentally observed ones have been interpreted as the possi-
bility of intermolecular interactions [64,72–75].
A modified use of the Gordon–Taylor equation has been described
for co-amorphous naproxen/indomethacin when the degree of molecu-
lar interactions, for example, the formation of a heterodimer, between
the components is known [36]. In such a case, the deviation of the ex-
perimentally determined Tgs from the theoretical Tgs calculated using
the Gordon–Taylor equation was largest for the co-amorphous system
showing the largest degree of molecular interactions, that is, the hetero-
dimer at 1:1 M ratio. Assuming that the heterodimer is made of one
component, whereas any excess drug represents the second component
in the co-amorphous blends, the theoretical Tgs of the mixtures can be
recalculated. In the above example, an ideal fit of the experimental
values with the theoretical ones using this modified use of the
Gordon–Taylor equation was obtained. This finding suggested that
ideal mixing behavior was observed for the heterodimer and any excess
drug in those mixtures. Therefore, it has been suggested that one should
Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
consider using the interacting adduct between the components in
amorphous blends rather than the pure components when using the
Gordon–Taylor equation. On the contrary, when finding the largest de-
viation from the classical Gordon–Taylor approach by determining the
experimental Tgs over a range of different ratios, one might be able to
identify the co-amorphous blend with the largest degree of interactions
between the components in the mixture.
4.4. Intimate mixing
In some co-amorphous systems, an improved physical stability was
observed as a result of intimate mixing, that is, physical separation of
similar molecules in the homogeneous co-amorphous blend. Simvastat-
in/glipizide systems showed improved physical stability over the indi-
vidual amorphous drugs without any detectable intermolecular
interactions or an increased Tg [50]. Dengale et al. reported similar ob-
servations for ritonavir/indomethacin systems after co-precipitation
followed by solvent evaporation [45]. The recrystallization of these sys-
tems is suspected to be a result of slow demixing and phase separation.
In general, for most co-amorphous systems, a clear separation of the
aforementioned stabilization mechanisms is not possible, but the in-
creased stability is rather the result of a combination of these mecha-
nisms. Together with molecular interactions, Löbmann et al., for
example, attributed the physical stability of co-amorphous systems of
indomethacin and carbamazepine with various amino acids to the
molecular-level mixing of drug with amino acids, their molecular inter-
actions and the increased Tg after ball milling [51,53]. It is important to
mention that solid-state solubility of the components is the first re-
quirement for a co-amorphous blend, whereas increased Tg, molecular
interactions and intimate mixing occur due to the miscibility of the
components in the amorphous blend. Table 2 summarizes the factors
responsible for the increased stability of different co-amorphous
formulations.
5. Dissolution properties
Because of their higher internal energy, amorphous phases possess a
higher solubility and dissolution rate than their crystalline counterparts
[2,20,65,76]. Accordingly, co-amorphous systems have been found to
show improved dissolution behavior not only over their crystalline
counterparts, but moreover also over their individual amorphous
forms (Table 3) [36,45,47,50–52,55,57]. For example, Allesø et al. ob-
served a higher dissolution rate of co-amorphous naproxen/cimetidine
than both crystalline drugs and amorphous cimetidine (a comparison
to amorphous naproxen was not made because of its high instability
and fast recrystallization immediately after preparation). The dissolu-
tion rate of pure amorphous cimetidine was found to be identical to
that of crystalline cimetidine, indicating its recrystallization upon con-
tact with the dissolution medium. However, when co-milled with
naproxen, cimetidine showed a 2-fold increase in dissolution rate with-
out any evidence of recrystallization. The authors suggested that co-
amorphization prevented cimetidine from recrystallization upon
dissolution [57]. Similarly, fast solvent-mediated recrystallization was
observed for pure amorphous lurasidone HCl during dissolution,
which resulted in a faster offset of the dissolution rate than the dissolu-
tion rate of crystalline lurasidone HCl (Fig. 1). Recrystallization was con-
firmed as birefringence on the surface of the intrinsic dissolution
compact. On the contrary, co-amorphous lurasidone HCl/saccharine
showed a continuous fast dissolution (5.6-fold faster than crystalline
lurasidone HCl) for the whole duration of the dissolution experiment
[47]. Unlike pure amorphous lurasidone HCl, birefringence was not ob-
served on the surface of the co-amorphous tablet, indicating the ab-
sence of recrystallization during dissolution. Thus, co-amorphization
does not only increase the dissolution rate of the drug, but can also
help prevent solvent-induced recrystallization upon dissolution. Again,
molecular interactions played a crucial role in this stabilization
 S.J. Dengale et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx 5

Table 2 proline mixtures. Jensen et al. applied two formulation principles.

Factors increasing physical stability of co-amorphous systems. First, the amorphous form of naproxen was stabilized by co-
System Main type of stabilization Reference amorphization with the high-Tg amino acid tryptophan (see
Cimetidine/Indomethacin Salt formation [39]
Section 4.2) or the strongly interacting amino acid arginine (salt forma-
Cimetidine/Diflunisal Salt formation [38] tion). Second, dissolution improvement was achieved by inclusion of
γ-Indomethacin/Ranitidine hydrochlorideHydrogen bonding [22] the highly soluble amino acid proline, which itself is a poor amorphous
Naproxen/Cimetidine π–π interaction [57] stabilizer [52]. As a result, both ternary mixtures exhibited an increased
Cimetidine/Piroxicam Hydrogen bonding [42]
dissolution rate than the binary naproxen/tryptophan and naproxen/ar-
γ-Indomethacin/Naproxen Hydrogen bonding [36]
Simvastatin/Glipizide Intimate mixing [50] ginine mixtures. However, in a subsequent study, it was shown that the
Ritonavir/Indomethacin Intimate mixing [45] highly soluble co-formers can facilitate the dissolution of a given drug
Acyclovir/Citric acid Hydrogen bonding [41] only to a certain degree [70]. When solubility of the co-former is too
Salt formation and Tg high and/or interactions between the components are not strong
Indomethacin/Arginine [51,53]
increase
Hydrogen bonding, π–π
enough, the highly soluble co-former from the co-amorphous system
Indomethacin/Tryptophan interaction and Tg [51,53] dissolves too fast, leaving the pure amorphous form in the suspension.
increase As a consequence, the drug loses its amorphous stabilizer and is thus,
Hydrogen bonding and prone to recrystallization.
Indomethacin/Phenylalanine [51,53]
π–π interaction
In order to investigate supersaturation of the drug from co-
Hydrogen bonding and
Indomethacin/Phenylalanine/Tryptophan
π–π interaction
[51,53] amorphous formulations, Heikinnen et al. studied the dissolution of dif-
Hydrogen bonding and ferent co-amorphous drug amino acid formulations under non-sink
Carbamazepine/Arginine/Tryptophan [51,53]
π–π interaction conditions in phosphate buffer and bio-relevent media, that is, fasted
Hydrogen bonding and (FaSSIF) and fed state-simulated intestinal fluid (FeSSIF) [55]. All of
Carbamazepine/Phenylalanine/Tryptophan [51,53]
π–π interaction
the investigated systems (simvastatin/lysine, glibenclamide/serine,
Hydrogen bonding and
Carbamazepine/Tryptophan [51,53] glibenclamide/threonine and glibenclamide/serine/threonine) showed
π–π interaction
Salt formation and an increased dissolution rate and long-lasting supersaturation com-
Indomethacin/Arginine/Phenylalanine [51,53]
hydrogen bonding pared with the individual amorphous and crystalline drugs (Fig. 2). In
Naproxen/Indomethacin Hydrogen bonding
the case of glibenclamide, the pure amorphous form provided a similar
Salt formation and
Naproxen/Arginine/Proline
hydrogen bonding
[52] supersaturation as the co-amorphous systems; however, the dissolution
Naproxen/Tryptophan Hydrogen bonding [52] rate of the pure amorphous form was slightly lower (Fig. 2(b)). Provid-
Naproxen/Tryptophan/Proline Hydrogen bonding [52] ed the pure amorphous form exhibited a performance similar to the co-
Naproxen/Arginine Salt formation [52] amorphous blends in this example, it is worth mentioning that the for-
Paracetamol/Citric acid Hydrogen bonding [32]
mation of a co-amorphous form was still beneficial because of the
Indomethacin/Tryptophan π–π interaction [56]
Furosemide/Tryptophan Hydrogen bonding [56] prolonged physical stability of amorphous glibenclamide [54]. Similarly,
Ritonavir/Quercetin Hydrogen bonding [46] Shayanfar et al. showed a long-lasting supersaturation of the two drugs
Lurasidone Hydrochloride/Saccharin Hydrogen bonding [47] atorvastatin and glibenclamide from their respective co-amorphous
Repaglinide/Saccharin Hydrogen bonding [43]
mixtures [40].
Atorvastatin/Carvedilol Hydrogen bonding [40]
Atorvastatin/Glibenclamide Hydrogen bonding [40]
Overall, the dissolution of co-amorphous formulations has been
Curcumin/Artemisin Hydrogen bonding [44] shown to be improved compared with the pure crystalline and amor-
phous drugs. Molecular interactions are again not only proved to be im-
portant for preventing solvent-induced recrystallization, but also
mechanism [36,57,70]. On the contrary, Dengale et al. found that ritona- contributed to a possible synchronized release of components from
vir/indomethacin systems showed an increase in the dissolution rate of the co-amorphous mixtures. The dissolution rate of the poorly soluble
ritonavir due to intimate mixing without intermolecular interactions drug from the co-amorphous blend is dependent on the solubility of
[45]. the co-former and the strength of the molecular interactions between
In addition to enhanced dissolution rates, some co-amorphous mix- drug and co-former. Furthermore, co-amorphous formulations can pro-
tures show a pairwise or synchronized dissolution of the individual vide long-lasting supersaturation.
components due to their short-range molecular order, that is, the for-
mation of heterodimers through hydrogen bonds [36,57]. For co- 6. In vivo performance
amorphous naproxen/cimetidine, it is suggested that pairwise solvation
and their interdependency upon dissolution were responsible for the In order to demonstrate the potential of the co-amorphous formula-
synchronized release. Both are a result of the intermolecular interac- tion approach, the positive in vitro dissolution results also need to be
tions at 1:1 M ratio. Similar findings were also reported for co- reflected in an increased in vivo bioavailability. Although the co-
amorphous naproxen/indomethacin, and again related to the intermo- amorphous technology is a rather new approach for improving amor-
lecular interactions between the two drugs in the mixture [36]. phous stability of drugs and their dissolution, only a limited number of
Because synchronized release of two components from the co- studies have been published on in vivo performance of these systems
amorphous blends appears to result from strong intermolecular interac- [44,46,71]. For example, poorly water-soluble curcumin has been co-
tions between them, it has been suggested that the dissolution rate of a amorphized with artemisin and administered to Sprague Dawley male
poorly soluble drug can be modified by the solubility/dissolution rate of rats for bioavailability analysis [44]. Because of the poor solubility of
the co-amorphous co-former [52,70]. When strong intermolecular in- pure crystalline coumarin, the drug was not detected in the plasma
teractions exist between the two components, the co-former might fa- when administered alone. On the contrary, a considerably high amount
cilitate the dissolution of a given poorly water-soluble drug. In other of coumarin was found when administering it for co-amorphous formu-
words, the dissolution rate of the poorly soluble component depends lation together with artemisin. However, no control groups, that is, pure
on the solubility of the co-former. In this regard, it was found that disso- amorphous coumarin or a physical mixture of coumarin and artemisin,
lution rates of several non-salt-forming co-amorphous indomethacin/ were analysed. Therefore, careful interpretation of these results must be
amino acid systems were dependant on the solubility of the co- exercised, as it is unclear whether the increase in bioavailability was
forming amino acid [51]. A similar approach was reported for ternary solely due to amorphization of coumarin or a result of its co-
co-amorphous naproxen/tryptophan/proline and naproxen/arginine/ amorphous formulation.

Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
6 S.J. Dengale et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Table 3
Comparison of dissolution properties of co-amorphous systems.

Co-amorphous system Individual component Measured dissolution property Dissolution improvement Synchronized release Reference

Crystalline NAP 0.359 ± 0.016* NA

Crystalline CIM 0.669 ± 0.038* NA
Naproxen(NAP)/Cimitidine (CIM) Yes [57]
NAP co-milled 1.49 ± 0.108* 4-fold
CIM co-milled 1.32 ± 0.104* 2-fold
Crystalline IND 0.055 ± 0.002*
Crystalline NAP 0.300 ± 0.001*
Indomethacin (IND)/NAP Yes [36]
IND(NAP:IND 1:1) 0.491 ± 0.012* 9-fold
NAP (NAP:IND 1:1) 0.411 ± 0.003* 1.37-fold
Crystalline SVS 6.7 ± 1.4†
Crystalline GPZ 7.6 ± 2.9†
Simvastatin (SVS)/Glipizide (GPZ) NI [50]
GPZ (SVS:GPZ 1:1 BM) 28 ± 11† 3.7-fold
GPZ (SVS:GPZ 1:1 CM) 24 ± 15† 3.1-fold
Crystalline CBZ 0.034 ± 0.001* NA
CBZ (CBZ: Arginine:Tryptophan) 0.047 ± 0.005* Marginal (b0)
Carbamazepine (CBZ)/Amino acids NI [51]
CBZ (CBZ: Phenylalanine:Tryptophan) 0.041 ± 0.003* Marginal (b0)
CBZ (CBZ: Tryptophan) 0.037 ± 0.001* Marginal (b0)
IND (IND: Arginine: Phenylalanine) 11.19 * 200-fold
IND (IND: Arginine) 12.25 * 200-fold
IND/Amino acids NI [51]
IND (IND:Tryptophan) 0.096 * 1.5-fold
IND (IND:Phenylalanine) 0.175 * 3-fold
Crystalline RTV 0.13† NA
Crystalline IND NR NA
Ritonavir (RTV)/IND NI [45]
RTV (RTV:IND 1:1) 0.56† 4.3-fold
IND (RTV:IND 1:1) NR NR
Crystalline LH 0.0066* NA
Lurasidone HCl (LH)/Saccharine (SAC) NI [47]
LH (LH:SAC) 0.0371* 5.6-fold

NI Not investigated.
NR Not reported.
NA Not applicable.
†
Dissolution rates expressed in μg/ml.
⁎ Intrinsic dissolution rates expressed in mg cm−2 min−1.

In addition to poor solubility, poor intestinal permeability can add to
the low bioavailability of a given drug. Poorly soluble and poorly perme-
able drugs are classified as class 4 drugs in the biopharmaceutics classi-
fication system (BCS) and are particularly problematic, because an
increase in dissolution and solubility only might not result in an in-
creased bioavailability. In this context, poor permeability can be due to
the physicochemical properties of the drug molecule, such as size and
polarity, but often is due to being substrate of the so-called intestinal ef-
flux pumps [77,78]. These efflux pumps are situated in the absorption
cell layer of the intestine and their main purpose is to prevent toxins
from entering the systemic blood circulation. The mechanism of such
Fig. 1. Intrinsic dissolution profiles of co-amorphous lurasidone HCl–saccharin (LH–SAC,
triangles), pure amorphous LH (circles) and crystalline LH (squares) (adapted from ref.
[47]).
a protection involves pumping the toxins back into the intestine. The
process of protecting the body from toxins also extends to many
drugs, as they are also substrates of these efflux pumps. In order to over-
come the challenges associated with poorly soluble drugs that are also
efflux pump substrates, Teja et al. applied the co-amorphous formula-
tion approach to address both problems simultaneously. In particular,
they co-amorphized the poorly soluble and permeable drug talinolol,
an efflux pump substrate, with the efflux pump inhibitor naringin
[71]. Using this approach, they were also able to improve the dissolution
rate of talinolol and simultaneously increase absorption of the drug
through efflux pump inhibition of the co-administered naringin. The
bioavailability of talinolol in wistar rats could thus be significantly im-
proved. The mean AUC(0 − t) from co-amorphous talinolol/naringin
was found to be 5.4-fold higher than the administration of pure crystal-
line talinolol (Fig. 3). In order to study the influence of naringin on the
permeability of talinolol, determination of permeability using the in
situ intestinal closed loop method is further studied. Permeability of
talinolol was found to slightly increase from 2.48 × 10− 5 (control
value without naringin) to 3.16 × 10−5 cm/s when formulated as co-
amorphous talinolol/naringin system. The increase in bioavailability of
talinolol was thus attributed to a combination of increased solubility
from the co-amorphous formulation and the inhibition of naringin by
efflux pump. Again, these findings have to be considered carefully as
no control group using pure amorphous talinolol or a co-
administration of physically mixed naringin was investigated. Thus, a
direct connection to the co-amorphous formulation approach cannot
be drawn.
The same group also investigated the bioavailability of co-
amorphous ritonavir/quercetin, where ritonavir is an efflux pump sub-
strate and quercetin is an efflux pump inhibitor [46]. However, unlike
talinolol/naringin, there was no statistically significant improvement
in the bioavailability (AUC) of ritonavir from its co-amorphous formula-
tion compared with the crystalline control. Although a 5-fold improve-
ment of the in vitro saturation solubility was achieved for ritonavir from
its co-amorphous system, the advantage could not be translated into a

Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
 S.J. Dengale et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx 7

Fig. 2. Powder dissolution profiles of crystalline, amorphous and co-amorphous (a) simvastatin (SVS) and (b) glibenclamide (GBC) formulations indicating long-lasting supersaturation
achieved using the co-amorphous drug–amino acid formulation approach. For clarifying the differences of the dissolution profiles of glibenclamide, a magnification of the first 90 min was
inserted. (Abbreviations: LYS = lysine, THR = threonine, SER = serine, CM = cryomilled, PM = physical mixture) (adapted from ref. [55]).

Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
8 S.J. Dengale et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx
Fig. 3. Mean plasma concentration–time profile for pure talinolol (triangles) and co-
amorphous talinolol/naringin (squares) (adapted from ref. [71]).
significant in vivo outcome. On the contrary, the Tmax value was signifi-
cantly reduced from 6 to 4 h for the co-amorphous formulation com-
pared with pure crystalline ritonavir, indicating improved absorption.
This improvement was again attributed to enhanced solubility and per-
meability due to co-amorphization and efflux pump inhibition. Howev-
er, similar to the aforementioned studies, this study did not investigate
any other controls.
Overall, the few in vivo studies that have been performed using co-
amorphous formulations indicated the potential of the co-amorphous
approach. Nevertheless, there are still some unanswered questions
such as whether the improved bioavailability was due to pure
amorphization of the drug or a result of the co-amorphous formulation
itself. Furthermore, a direct comparison with other amorphous stabili-
zation techniques such as polymer- or silica-based glass solutions
would be interesting.
7. Concluding remarks and future outlook
The co-amorphous technology has established itself as a promising
approach to increase dissolution/solubility of poorly water-soluble
drugs and potentially to improve bioavailability. Although it has poten-
tial to become a platform technology to deal with these drugs, it is still a
new technology and the concept needs to be further established.
Most of the above-mentioned studies were conducted on the funda-
mental understanding of co-amorphous formulations, their stabiliza-
tion mechanism and their behavior during dissolution. However, there
are still many unknowns and it is important to obtain a deeper under-
standing on the mechanisms of working of these systems. For example,
similar to polymer-based glass solutions, the tendency of moisture up-
take may also prove problematic for co-amorphous systems. Most of
the stability studies of co-amorphous mixtures have been conducted
in dry conditions. Thus, it would be interesting to study the effect of
water on the performance of co-amorphous systems.
Particularly, in co-amorphous drug–excipient mixtures, there is no
clear rationale on the suitability of an excipient as a co-former. In studies
using amino acids as excipients, it could be shown that certain amino
acids can be successfully co-amorphized with one drug but not neces-
sarily with another. Therefore, finding a good co-former might be
labor-intensive, given the plethora of different amino acids and other
co-formers.
With respect to co-amorphous drug–drug formulations, it might be
difficult to find a suitable partner molecule with a specific pharmacolog-
ical profile. The regulatory constraints and the compliance of adminis-
tering more than one drug at the same time at a fixed ratio between
the two drugs are other important issues that need to be addressed.
The in vivo studies performed on co-amorphous drug formulations
so far showed a potential in increasing the bioavailability of poorly sol-
uble drugs. However, further investigations are necessary to draw
Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009
better conclusions on their behavior in vivo. For example, the co-
amorphous formulations need to be tested against the individual amor-
phous drugs as well as other competing technologies such as polymer-
and mesoporous silica-based glass solutions.
Down-streaming of the formulations into final dose forms, that is,
capsules or tablets, is another important factor that needs to be con-
sidered in future. For this purpose, more understanding on scalable
production techniques, such as spray-drying and melt-extrusion, is
necessary to make this approach feasible in an industrial set-up.
Furthermore, there is only little knowledge on the processability of
co-amorphous formulations. Amorphous materials have shown
problems with powder flow, pulverization and sticking to punches
in tablet presses [12]. Another issue could be to find a suitable gran-
ulation process. A wet granulation may not be feasible, as the intro-
duced water acts as a plasticizer and can induce crystallization. On
the contrary, using melt granulation, the introduced heat could be
above the Tg of the co-amorphous formulation, which as well may
carry a risk for recrystallization. It has also been reported that amor-
phous materials can have significant problems with disintegration
when formulated into tablets [79,80]. In this context, Lenz et al.
were the first to report a successful tablet formulation using the co-
amorphous approach [58].
Despite the challenges, co-amorphous formulations have been
shown to be a very promising and upcoming technique to stabilize the
amorphous form of drugs, increase the dissolution and bioavailability
of poorly soluble drugs and overcome drawbacks related to other amor-
phous formulation strategies.
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Please cite this article as: S.J. Dengale, et al., Recent advances in co-amorphous drug formulations, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/
10.1016/j.addr.2015.12.009