Laitinen, IJP, 2013, Emerging Trends in Stabilization of Amorphous Drugs PDF

International Journal of Pharmaceutics 453 (2013) 6579
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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Review
Emerging trends in the stabilization of amorphous drugs

Riikka Laitinen a, , Korbinian Lbmann a,b , Clare J. Strachan a,c , Holger Grohganz b , Thomas Rades a,b
a
School of Pharmacy, University of Otago, P.O. Box 913, Dunedin 9054, New Zealand
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
c
Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
b
a r t i c l e
i n f o
Article history:
Received 23 February 2012
Received in revised form 20 April 2012
Accepted 23 April 2012
Available online 28 April 2012
Keywords:
Amorphous drug
Stability
Co-amorphous
Mesoporous
Solubility
Dissolution
a b s t r a c t
The number of active pharmaceutical substances having high therapeutic potential but low water solubility is constantly increasing, making it difcult to formulate these compounds as oral dosage forms.
The solubility and dissolution rate, and thus potentially the bioavailability, of these poorly water-soluble
drugs can be increased by the formation of stabilized amorphous forms. Currently, formulation as solid
polymer dispersions is the preferred method to enhance drug dissolution and to stabilize the amorphous
form of a drug.
The purpose of this review is to highlight emerging alternative methods to amorphous polymer dispersions for stabilizing the amorphous form of drugs. First, an overview of the properties and stabilization
mechanisms of amorphous forms is provided. Subsequently, formulation approaches such as the preparation of co-amorphous small-molecule mixtures and the use of mesoporous silicon and silica-based
carriers are presented as potential means to increase the stability of amorphous pharmaceuticals.
2012 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Formation and properties of amorphous compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Stability of amorphous drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Binary co-amorphous mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Co-amorphous indomethacin/ranitidine hydrochloride systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Co-amorphous naproxen/cimetidine systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Co-amorphous naproxen/indomethacin systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.
Co-amorphous simvastatin/glipizide systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mesoporous systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
The increasing number of new chemical entities (NCEs) with
poor aqueous solubility in the drug development pipeline has led
to exploration of effective means to overcome their low bioavailability as a consequence of poor solubility (Engers et al., 2010;
Kawabata et al., 2011). Converting crystalline drug compounds to
Corresponding author. Tel.: +64 3 479 7275; fax: +64 3479 7034.
E-mail addresses: riikka.laitinen@otago.ac.nz (R. Laitinen),
korbinian.loebmann@otago.ac.nz (K. Lbmann), clare.strachan@otago.ac.nz
(C.J. Strachan), hgr@farma.ku.dk (H. Grohganz), thomas.rades@otago.ac.nz
(T. Rades).
0378-5173/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2012.04.066
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their amorphous counterparts is one of the most promising tools,

compared e.g. to simple micronization (Kesisoglou et al., 2007)
or salt formation (Serajuddin, 2007) which have many practical
limitations.
The amorphous state is the highest energy form of a solid
material with no long-range molecular order. As a result of their
high internal energy, amorphous materials generally have greater
molecular motion and enhanced thermodynamic properties compared to the crystalline state (leading to higher apparent solubility
and dissolution rate) (Hancock and Zogra, 1997; Kaushal et al.,
2004; Yu, 2001). These benets however, come at a cost and can
be lost easily since the high internal energy and enhanced molecular mobility of amorphous materials are also responsible for their
higher chemical reactivity and a tendency to crystallization, which
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R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579
can happen during manufacturing, storage or dissolution (administration) (Aaltonen and Rades, 2009; Hancock and Parks, 2000;
Hancock and Zogra, 1997; Kaushal et al., 2004). Consequently,
much effort has been put into obtaining a better understanding
of the critical factors in recrystallization and nding methods for
stabilization of amorphous forms of drugs in order to benet from
their solubility and dissolution rate advantages.
Since initially introduced by Sekiguchi and Obi (Sekiguchi and
Obi, 1961), solid polymer dispersions have become the preferred
method to enhance drug dissolution and to stabilize the amorphous
form of a drug (Chiou and Riegelman, 1971; Kaushal et al., 2004;
Leuner and Dressman, 2000; Serajuddin, 1999; Sethia and Squillante, 2003; Vasconcelos et al., 2007; Zheng et al., 2012). There
is an extensive amount of literature available on the mechanisms
how the preparation of a molecular dispersion or glass solution of
the drug in a glassy polymer matrix leads to increased physical
stability of the amorphous drug. Interested readers are encouraged to look at the excellent reviews written over the years, since
this review focuses on emerging alternative methods to amorphous polymer dispersions for stabilizing the amorphous form
of drugs (Janssens and Van den Mooter, 2009; Kaushal et al.,
2004; Leuner and Dressman, 2000; Serajuddin, 1999; Sethia and
Squillante, 2003; Srinarong et al., 2011; Vasconcelos et al., 2007).
Briey, the physical stabilization of the amorphous form of drugs
in solid dispersions has been attributed to several factors. Generally, miscibility of the drug with the polymer is directly related
to the stabilization of an amorphous drug against crystallization,
thus the drug and the polymer should preferably be mixed at
the molecular level, forming a glass solution (Marsac et al., 2009;
Qian et al., 2010; Rumondor et al., 2009). Furthermore, the polymeric carrier generally increases the glass transition temperature
(Tg ) of the glass solution compared to the pure amorphous drug,
lowers the mobility of drug molecules and kinetically acts as a
crystallization inhibitor (Hancock et al., 1995; Janssens and Van
den Mooter, 2009; Van den Mooter et al., 2001). Finally, it is also
generally accepted that intermolecular drugpolymer interactions
are important for the stabilization of the drug in solid dispersions (Janssens and Van den Mooter, 2009; Matsumoto and Zogra,
1999).
However, the relative importance of all of the aspects associated with the stability of solid dispersions is still poorly understood
and these systems are still unable to guarantee the long-term stability of amorphous drugs (Janssens and Van den Mooter, 2009).
Amorphous drugpolymer mixtures are often hygroscopic and in
that case the absorbed moisture reduces the Tg of the system, leading to phase separation and recrystallization (Lu and Zogra, 1998;
Vasconcelos et al., 2007; Rumondor and Taylor, 2010). In addition,
there are difculties with manufacturing and processing of solid
dispersions into dosage forms (Srinarong et al., 2011). Due to the
limited miscibility of some drugs with polymers, large quantities
of polymer are often required for sufcient drug loading, leading
to large bulk volumes of the nal dosage forms (Serajuddin, 1999).
Thus, the number of pharmaceutical products on the market based
on solid dispersions is still limited and their current, relatively slow
entering to the market means that they are unlikely to cope with
the growing number of poorly soluble NCEs in the drug discovery process. It thus appears necessary that alternative ways for the
development of stable amorphous systems and improvement of
their feasibility in pharmaceutical products are needed.
The purpose of this review is to highlight emerging alternative
methods to amorphous polymer dispersions for stabilizing the
amorphous form of drugs. First the general properties of the
amorphous state are briey discussed. The current knowledge on
the stability of amorphous drugs alone is reviewed and nally,
approaches such as co-amorphous small-molecule mixtures
and the use of mesoporous silicon and silica-based carriers are
Fig. 1. Schematic representation of enthalpy (or volume) vs. temperature for a liquid
capable of crystallizing and glass formation. TK is the Kauzmann temperature, Ta
is the aging temperature, Tf is the ctive temperature, Tg is the glass transition
temperature and Tm the fusion temperature. Arrows a, b and c indicate the real
glass approaching the equilibrium glassy state by spontaneous relaxation, heating
the sample near to Tg and subsequent enthalpy recovery to the supercooled liquid
state, respectively.
Source: Modied from Kawakami and Pikal (2005).
presented as potential means to increase the stability of amorphous

pharmaceuticals.
2. Formation and properties of amorphous compounds
Amorphous forms can be prepared either by initially transforming the crystalline material to a thermodynamically stable
non-crystalline form (melt or solution), or by direct solid conversion into an amorphous solid (Craig et al., 1999; Hancock and
Zogra, 1997; Kaushal et al., 2004; Kawakami and Pikal, 2005; Yu,
2001). Generally, the former is carried out by rapid cooling from
the melt (quench-cooling) or rapid precipitation from solution (e.g.
by spray-drying) and the latter by mechanical activation (milling)
(Httenrauch et al., 1985; Ohta and Buckton, 2005).
If we look at a situation where a melt is cooled (demonstrated
by the enthalpy (H) or specic volume (V) vs. temperature diagram
in Fig. 1), we can see that the melt usually crystallizes at Tm , which
leads to a contraction of the system due to a sudden decrease in V
and H. However, if the cooling rate is too fast to permit crystallization, H and V may follow the equilibrium line of the liquid beyond
Tm into the supercooled liquid region without showing any discontinuity in H and V. The supercooled liquid is a non-equilibrium state
relative to the crystalline state, but it is an equilibrium state with
respect to structural changes as a function of temperature (Craig
et al., 1999; Hancock and Zogra, 1997; Kawakami and Pikal, 2005).
Thus, cooling causes direct corresponding changes in structure and
thermodynamic properties in the supercooled liquid material. As
the viscosity of the material increases there is a reduction in the
molecular motions until the molecules move so slowly that they
have no time to rearrange themselves before the temperature is
lowered further. This results in a change of the slope (Fig. 1), and the
material enters the glassy state which again is a non-equilibrium
state. This change in molecular motion is called the glass transition
temperature (Tg ). (Craig et al., 1999; Hancock and Zogra, 1997).
At any given temperature below the Tg , the real glass approaches
asymptotically the equilibrium glassy state by spontaneous relaxation (arrow a in Fig. 1), and when the sample is re-heated to the
Tg (arrow b in Fig. 1), molecular mobility increases and H recovers to the supercooled liquid state as shown by arrow c in Fig. 1
(Kawakami and Pikal, 2005).
The amorphous state is characterized by the absence of

long-range three-dimensional molecular order and has physical properties different from those of its crystalline counterpart
(Hancock and Zogra, 1997; Yu, 2001). As a result of the higher
internal energy, the amorphous form generally has greater molecular motion and enhanced thermodynamic properties compared
to the crystalline state, resulting in higher apparent solubility
(Hancock and Zogra, 1997; Kaushal et al., 2004; Yu, 2001), but also
higher chemical reactivity and the tendency to spontaneously crystallize. However, amorphous solids typically exhibit short-range
order over a few molecular dimensions (e.g. via hydrogen bonding)
and this may be affected by the preparation method and processing
parameters (Craig et al., 1999; Graeser et al., 2009b; Karmwar et al.,
2011b; Patterson et al., 2005). In this regard, differences in molecular structure may also lead to differences in the physical properties
of amorphous solids, including their physical stability (Karmwar
et al., 2011a,b).
3. Stability of amorphous drugs
Since amorphous materials are thermodynamically unstable,
they tend to revert back to a crystalline form over time. Crystallization is basically a result of two independent phenomena,
nucleation and crystal growth and is characterized by a lag time
before stable nuclei are formed, followed by the growth of these stable nuclei into a crystalline state. The temperature dependence of
the kinetic factors and the thermodynamic driving force for nucleation have opposite signs, with thermodynamics and increased
viscosity favoring nucleation at low temperatures and kinetics and
greater molecular motion favoring nucleation at higher temperatures (Bhugra and Pikal, 2008; Craig et al., 1999; Hancock and
Zogra, 1997). Thus, nucleation occurs in the balance of these two
factors and the maximum rate of crystallization occurs somewhere
between Tm and Tg (Craig et al., 1999; Hancock and Zogra, 1997). It
is commonly accepted that storing the amorphous material below
Tg (Tg -50 K rule) should lower the risk of recrystallization due to
lower molecular mobility (Yu, 2001). However, molecular mobility
still occurs below Tg , albeit over longer time periods than above Tg ,
and is often sufcient to result in recrystallization during typical
storage times for pharmaceutical products (Hancock et al., 1995;
Miyazaki et al., 2006; Yoshioka et al., 1994).
It has been suggested that storage at the Kauzmann temperature (TK , Fig. 1, where the entropy of the extrapolated supercooled
liquid equals that of the crystal) would ensure sufcient physical
stability for amorphous materials (Craig et al., 1999; Kaushal et al.,
2004; Kaushal and Bansal, 2008; Yu, 2001). Below TK the translational molecular motions are assumed to be negligible even over
long experimental time scales and thus TK is considered the conservative maximum storage temperature for amorphous formulations
(Kaushal and Bansal, 2008). However, this assumption is only valid
for the theoretical supercooled liquid which is in equilibrium with
its environment. Instead, with real glasses, the temperature ensuring sufcient physical stability should be estimated through the
ctive temperature (Tf ) which is the temperature at which the equilibrium supercooled liquid has the same congurational entropy (or
enthalpy)1 as the real glass at the temperature of interest (Fig. 1).
The real glass would be stable at a storage temperature where the
Tf equals TK (Hancock and Shamblin, 2001). In the example case
shown in Fig. 1, the storage temperature would be much lower
1
The congurational quantities express the thermodynamics of the glassy material with respect to the crystalline state and thus describe the relative tendency
for crystallization. Congurational enthalpy, congurational entropy and congurational free energy represent the thermodynamic drive, barrier and overall force
for crystallization, respectively (Kaushal and Bansal, 2008).
67
than TK . Thus, this approach has only limited practical meaning, as

for many materials TK lies near to refrigeration temperatures (Yu,
2001).
As stated in a review by Bhugra and Pikal (2008), crystallization
of an amorphous material is a complex phenomenon governed by
more than one factor. Factors affecting nucleation and/or crystal
growth can be expected to have an effect on the overall crystallization behaviour. Known factors affecting crystallization of the
amorphous state can be categorized as thermodynamic (congurational entropy, enthalpy or Gibbs free energy) (Marsac et al.,
2006; Zhou et al., 2002), kinetic (molecular mobility, for which the
glass transition temperature (Tg ) or structural relaxation time is
often used as an indicator) (Andronis and Zogra, 1997; DiMartino
et al., 2000; Grzybowska et al., 2010) or molecular (e.g., hydrogen bonding interactions) (Ambike et al., 2005; Fukuoka et al.,
1989; Kaushal et al., 2008). Furthermore, parameters such as
moisture content (Hancock and Zogra, 1994) and the methods
and conditions employed for generation of the amorphous form
(including for example its thermal history) (Graeser et al., 2009a;
Karmwar et al., 2011a,b; Patterson et al., 2005; Qi et al., 2008;
Savolainen et al., 2007) have also been reported to inuence crystallization behaviour. These factors are presented in more detail in
Table 1. Generally, the molecular mobility of the amorphous phase
is considered as the main factor governing physical stability. Furthermore, compounds with high Tg s, high congurational entropy
barriers, high TK s and low molecular mobilities are expected to
show the highest stability (Zhou et al., 2002).
The Tg -50 K rule is useful with respect to -relaxation
that requires a cooperative motion of multiple molecules and
therefore has a large energy barrier associated with it. However,
local non-cooperative motion has a signicantly smaller energy
barrier and continues to occur at lower temperatures, giving
rise to the -relaxation process (Table 1), also referred to as
JohariGoldstein relaxations (Johari, 1973; Johari and Goldstein,
1970). In contrast to -relaxations, they generally follow Arrhenius
kinetics and are characterized by activation energy values that are
much smaller than those of -relaxations (Dranca et al., 2009).
Characterization of -relaxation is important for understanding
their role in determining physical stability since usually amorphous pharmaceuticals are stored well below their Tg , i.e. in the
temperature region where relaxation is either predominately or
exclusively driven by the -process. Characterization is usually
conducted with dielectric spectroscopy, but calorimetric characterization has also been carried out (Dranca et al., 2009; Vyazovkin
and Dranca, 2005). Local mobility has been reported to correlate
with the crystallization kinetics of some glass formers. Vayazovkin
and Dranca (2005) found that indomethacin underwent a relaxation at temperatures as low as 20 C. The activation energy
of the -relaxation was found to be several times smaller than that
of the -relaxation and the nucleation of indomethacin was found
to take place in the temperature region of the -relaxation, which
thus could have contributed to the nucleation of indomethacin.
The authors concluded that amorphous pharmaceuticals could be
physically stable below the temperature region of the -relaxation,
which in the case of indomethacin was around 30 C. A comparison of local and global mobility has been conducted for sucrose
and trehalose in a study by Dranca et al. (2009). They found that
amorphous trehalose had a higher activation energy barrier for
-relaxation compared to sucrose due to its lower free volume.
The activation energy of -relaxations was found to increase with
annealing temperature due to increasing cooperative motions and
this increase was larger in sucrose than in trehalose. The temperature at which -relaxation was detected for a given annealing
time was much lower for sucrose indicating that progression of
local motions to global motions occurred at lower temperatures in
sucrose than in trehalose. Thus, amorphous sucrose, even if stored
68
Table 1
Factors found to correlate with the physical stability of amorphous forms of drugs.
Factor
Indicator
Observed impact on stability
Ref.
Glass transition
temperature (Tg )
Stability increases with increasing Tg . Polymers with high

Tg increase the kinetic stability of amorphous drugs.
However, often Tg alone cannot predict the crystallization
tendency of a compound.
Bansal et al. (2010);

Bhattacharaya and
Syrayanarayanan (2009);
Zhou et al. (2002)
Structural relaxation
(-relaxation)
Short relaxation times in the region of Tg correlate with a

signicant rate of crystallization of amorphous
indomethacin.
Structural relaxation seems to be responsible for
recrystallization of celecoxib when stored at room
temperature.
The strong crystallization tendency of amorphous
griseofulvin can be accounted for by its moderate to small
congurational entropy and relatively high molecular
mobility (relaxation). The rate of crystallization shows
better correlation with molecular mobility at temperatures
above Tg (there is change in crystallization mechanism
below Tg ).
Andronis and Zogra

(1997); Grzybowska et al.
(2010); Zhou et al. (2008)
Local mobility
(-relaxation)
-relaxation is generally associated with faster motion on

a smaller length scale than -relaxation and is not
necessarily coupled with the motions associated with the
glass transition. The - and the -relaxations merge at a
particular temperature (Tb ) above the Tg at which the
relaxations times become identical.
DSC has been employed for probing -relaxations in
pharmaceutical glasses annealed at temperatures around
0.8Tg , in order to estimate the low temperature limit of
-relaxation, i.e. the temperature below which amorphous
drugs would remain practically stable.
Bhugra and Pikal (2008);

Bhattacharaya and
Syrayanarayanan (2009);
Vyazovkin and Dranca
(2006)
Entropic barrier for

crystallization
Congurational
entropy
Often found to be the best thermodynamic parameter to

predict crystallization.
The rigidity of the molecule reduces the number of
possible conformations leading to low congurational
entropy which favors crystallization from the amorphous
state. The strong crystallization tendency of amorphous
griseofulvin, for example, can be accounted for by its
moderate to small congurational entropy and relatively
high molecular mobility.
Graeser et al. (2009b);

Zhou et al. (2002, 2007,
2008)
Enthalpic driving force
Congurational
enthalpy
The increased nucleation rate of nifedipine compared to

felodipine was shown to partially originate from a greater
thermodynamic driving force for crystallization (i.e. higher
congurational enthalpy).
Marsac et al. (2006)
Gibbs free energy
Often poorer predictor for crystallization than

congurational entropy.
Graeser et al. (2009b);

Zhou et al. (2002)
Amorphous materials with similar Tg values might show

different stability proles due to variations in hydrogen
bonding of the molecules within the materials.
The differences in the thermodynamic behavior and
physical stability of celecoxib, valdecoxib, rofecoxib, and
etoricoxib in their amorphous forms arise from the
differences in their interaction patterns at the molecular
level.
The increased nucleation rate of nifedipine relative to
felodipine was shown to partially originate from
differences in hydrogen bonding strength between the
crystalline and amorphous forms, i.e. as nifedipine
crystallizes, the hydrogen bonding strength increases.
The stability and very low enthalpy recovery of glassy
simvastatin could be attributed to strong inter-molecular
hydrogen bonding.
Ambike et al. (2005);

Fukuoka et al. (1989);
Kaushal et al. (2008);
Marsac et al. (2006)
The presence of moisture in storage conditions increases

molecular mobility and may plasticize the material
sufciently to lower the Tg to that of the storage
temperature (crystallization rate increases and
crystallization temperature decreases).
Even small variations in sample handling (mechanical
stress) of the generated amorphous state can result in
signicant differences in crystallization behavior.
Bhugra et al. (2008);

Hancock and Zogra
(1994); Miller and
Lechuga-Ballesteros
(2006); Newman et al.
(2008)
Factors on the molecular level

Molecular mobility
Overall
thermodynamic
driving force
Hydrogen bonding
Factors independent of the molecule

Environmental stress
Humidity, mechanical
stress and temperature
69
Table 1 (Continued)
Factor
Indicator
Observed impact on stability
Ref.
Preparation method
Melting, solvent
evaporation and
mechanical activation
methods
All preparation methods result in different thermal

histories and different mechanical stresses introduced into
the material and produce different degrees of relaxation
(molecular mobility).
Differences in the physical stability of amorphous forms of
simvastatin prepared by different techniques were
reected in their mobility and thermodynamic
parameters. Quench-cooled (QC) simvastatin has been
found to be more stable than cryo-milled simvastatin. In
addition, a larger particle size range of QC simvastatin was
found to be more stable than a smaller particle size range.
The ranking of amorphous indomethacin samples with
respect to stability has been found to be: quench cooled
amorphous samples > cryo-milled (-form) > spray
dried > ball milled
(-form) > ball milled (-form) = cryo-milled (-form)
which correlated with the relaxation time values of the
samples.
Bhugra and Pikal (2008);

Graeser et al., 2009a,b;
Karmwar et al. (2011b);
Patterson et al. (2005);
Zhang et al. (2009)
Preparation conditions
Cooling rate,
processing
temperature,
processing time
Structural differences between amorphous indomethacin

samples, quench cooled at different rates were found. The
physical stability of the samples was found to increase as a
function of cooling rate.
Different inlet temperatures used in spray-drying of
cefditoren pivoxil led to differences in the orientation of
molecules at the particle surface, which were signicant
enough to alter the stability in stressed conditions.
Bhugra et al. (2008);

Karmwar et al. (2011a);
Ohta and Buckton (2005)
at temperatures lower than Tg -50 K, is less stable due to the larger

effect of temperature variation on the global mobility.
The term pseudo-polyamorphism has been suggested by
Hancock et al. (2002) to describe glassy amorphous materials
that have different energetic states as a result of different conditions of production and storage. Differences in thermal, structural
and physical properties of amorphous forms prepared by different techniques have been suggested to lead to different molecular
mobility for the same drug in differently prepared samples (Graeser
et al., 2009a). Karmwar et al. (2011b) used melt-quenching, spraydrying, ball milling and cryo-milling as preparation methods for
amorphous indomethacin. They observed that when performing a
principal component analysis (PCA) analysis of the Raman spectra
measured from these amorphous samples, the samples clustered
in the scores plot according to the preparation method. In addition,
the shapes of the amorphous halos, obtained by XRPD, were found
to vary depending on the preparation method. These differences
were suggested to originate from different molecular conformations and intermolecular interactions in the samples. However,
physical stability of the samples was not found to be directly
affected by structural variations, but instead, ranking of stability
of the amorphous forms prepared by different methods could be
predicted by determining the relaxation time values.
Btker et al. (2011) used atomic pair-wise distribution function (PDF) and multivariate data analysis (MVDA) to determine
the optimal cryo-milling time for amorphization of solids. MVDA
carried out on the PDF data, assessing the structural disorder in
indomethacin induced by cryo-milling, revealed that the incremental differences in indomethacin milled for different times got
increasingly smaller for the extended cryo-milling times and after
120 min of milling time no further effect from cryo-milling was
observed. Furthermore, the physical stability was found to increase
as a function of the cryo-milling time up to 120 min but cryo-milling
for longer time periods resulted in no further improvement in physical stability.
Karmwar et al. (2011a) also prepared amorphous indomethacin
by melt-quenching employing different cooling rates. PCA of the
Raman spectra of the various amorphous forms revealed that the
samples clustered in the scores plot according to the cooling rate,

suggesting structural differences between the differently cooled
samples. The physical stability of the samples was found to increase
as a function of increasing cooling rate. It was suggested that differences in the non-isothermal crystallization processes for the
differently cooled samples may be governed by nucleation (number
of nuclei) and that decreasing cooling rates lead to a higher number
of nuclei in the resulting amorphous material, since it has been in
the super cooled liquid state for a longer time period.
Unfortunately, studies of the crystallization behaviour are often
focused on only one or a few compounds or to understanding
the impact of one single parameter among many affecting crystallization. As a consequence, there are different opinions on the
relative importance of the underlying physical factors that govern
the amorphous stability during formation and on storage. Thus, in
order to gain a more general understanding, Baird et al. (2010),
Graeser et al. (2009b) and Van Eerdenbrugh et al. (2010) have
reported attempts to investigate larger datasets. In the study by
Graeser et al. (2009b), the relaxation time, fragility index and
congurational thermodynamic properties (enthalpy, entropy and
Gibbs free energy) were calculated and correlated to the actual stability behaviour, obtained for 12 drugs, prepared in situ in the DSC
instrument by cooling from the melt (Graeser et al., 2009b). A reasonable correlation between the thermodynamic parameters and
the stability above Tg was found, with the congurational entropy
having the strongest correlation. In contrast, below Tg no clear
relationship between the relaxation time and fragility and physical stability existed, indicating that stability predictions on the
basis of relaxation time (mobility) alone are inadequate. It was suggested that stability above the glass transition temperature may not
necessarily be related to the stability below Tg and that congurational entropy may only serve as a limited predictor of stability.
In the studies by Baird et al. (2010) and Van Eerdenbrugh et al.
(2010) principal component analysis (PCA) was utilized to investigate and classify the glass-forming ability and glass stability of a
set of 40 structurally diverse compounds. Amorphous samples were
prepared by cooling from the melt in a DSC and by rapid solvent
evaporation using spin coating. Their observations suggested that
70
under such conditions of rapid solidication, crystallization was

governed mainly by the inherent properties of the compound, such
as molecular weight and number of rotatable bonds, regardless of
the preparation method. Thus, molecules with more complex and
exible structures have a lower crystallization tendency.
The use of computational models capable of predicting properties of amorphous materials from the chemical structure of
the compounds could be a way to gain a better understanding
of the amorphous forms of drugs. Mahlin et al. (2011) created
a model of glass-forming ability, based on calculated molecular descriptors, through PLS-DA (partial least squares projection
to latent structure discriminant analysis) in which 16 drug-like
molecules were included. Compounds likely to gain in apparent solubility by the transformation to an amorphous form were
selected and these were experimentally determined to be either
able or not able to form the glassy state by three different methods (spray-drying, quench-cooling and mechanical activation). The
experimental results were used together with calculated molecular
descriptors to develop a class model discriminating between these
two groups. In total, 10 of the 16 compounds were determined
experimentally to be good glass formers and the PLS-DA model
correctly sorted 15 of the compounds using only four molecular
descriptors. The model obtained was challenged with an external
test set and correctly predicted the glass-forming ability with an
accuracy of 75%. The authors concluded that the PLS-DA model
developed was applicable for the identication of compounds that
have the potential to be designed as amorphous formulations.
The model showed, as did the study of Van Eerdenbrugh et al.
(2010) that a successful transformation of compounds to an amorphous form strongly depends on the inherent glass-forming ability
of each compound and, to a lesser extent, on the amorphization
method. The descriptors having importance for the assessment of
the glass-forming ability were found to be the number of benzene
rings, branching of the carbon skeleton, the molecular symmetry and the distribution of electronegative atoms in the molecule.
It was suggested that the negative effect of an increased number of benzene rings on glass-forming ability might be related to
that fact that such molecules are generally planar and at and
for this reason, are quite easily packed in a crystal where strong
van der Waals interactions exist between the benzene rings in
the different layers of the crystal. Furthermore, highly branched
and less symmetric molecules form an amorphous form more
easily due to a complex interaction pattern, with a large number of possibilities for the formation of intermolecular bonds. In
addition, the signicance of distribution of electronegative atoms
reects the importance of hydrogen bonding pattern (Mahlin et al.,
2011).
4. Binary co-amorphous mixtures

From the previous discussion it can be concluded, that the
crystallization process of amorphous materials is still not well
understood and there are only limited approaches to ensure stability for an amorphous drug alone. It has been known for a
long time that addition of certain excipients, such as surfactants,
anti-plasticizers and other crystallization inhibitors can offer a
signicant improvement in the physical stability of amorphous
drugs. Recently, interest toward the potential of binary amorphous
systems, comprising of small molecules instead of polymers, has
increased. It has been reported that small molecules, such as citric
acid, sugars, urea, and nicotinamide can be used as carriers in solid
dispersions (Ahuja et al., 2007; Lu and Zogra, 1998; Masuda et al.,
2012).
Citric acid has been found to form amorphous binary mixtures
with indomethacin and acyclovir through hydrogen bonding
interactions (Lu and Zogra, 1998; Masuda et al., 2012). Formation

of the amorphous molecular acyclovircitric acid mixture led to
a signicant improvement of skin permeation ux of the amorphous form from PEG ointment in vitro compared to crystalline
acyclovir (Masuda et al., 2012). In addition, citric acid anhydrate
(CAA) was also found to form physically stable amorphous blends
when melt-quenched with paracetamol (Hoppu et al., 2007). The
mixtures had Tg -values of room temperature or lower, higher
paracetamol content resulting in higher Tg -values. The 1:1 (w/w)
mixture was found to be the most stable mixture, with a miscible
structure remaining for two years when stored at 25 C and dry
conditions (Hoppu et al., 2009, 2007). The increased stability of the
mixtures was attributed to hydrogen-bond interactions between
the phenol group of paracetamol and the carboxylic acid group of
CAA and the alcohol group of CAA with paracetamol, as suggested
by 13 C NMR measurements (Schantz et al., 2009).
Descamps et al. (2007) co-milled mixtures of lactose and
mannitol, and lactose and budesonide with a ball mill. The components milled together had very different Tg values, i.e. mannitol
13 C/lactose 111 C and lactose 111 C/budesonide 90 C. Molecular level mixing was achieved for lactose/budesonide irrespective of
the molar ratio (the highest experimentally applied molar fraction
of budesonide was 0.65). This behavior was found to be consistent
with the fact that the two compounds could be fully amorphized
when separately milled. The Tg of the mixture as a function of the
molar fraction of budesonide was found to obey the GordonTaylor
relationship. In contrast, molecular level lactose/mannitol mixtures
were only obtained with a mannitol fraction lower than 0.44 and
in this concentration range Tg vs. mannitol concentration was well
described by the GordonTaylor law. Interestingly, it was found
that for larger mannitol fractions the state obtained after milling
was a mixture of lactose/mannitol glass solution and crystalline
-mannitol. Extrapolation of Tg vs. mannitol fraction revealed that
for mannitol fractions >0.50 the glass transition temperature of the
lactose/mannitol glass solution became close to the milling temperature. It was suggested that in these conditions, the molecular
mobility of the glass solution was high enough to induce the crystallization of mannitol, which acts as a plasticizer in the mixture
during the milling process. When the Tg of the mixture reached the
milling temperature, further amorphization of mannitol was probably counterbalanced by a rapid recrystallization to the -form,
leading to a steady state concentration of mannitol in the glass
solution.
Yamamura et al. combined two drug molecules and found that
cimetidine formed an amorphous binary mixture with the nonsteroidal anti-inammatory drugs (NSAIDs) naproxen (Yamamura
et al., 1996), indomethacin (Yamamura et al., 2000) and difunisal
(Yamamura et al., 2002) upon precipitation from ethanol solution. Spectroscopic studies (1H NMR, 13C NMR and FTIR) suggested
that the formation of amorphous cimetidine/naproxen and cimetidine/indomethacin precipitates was possible due to non-bonding
intermolecular interactions between the imidazole ring of cimetidine and the carbonyl group of the NSAIDs (Yamamura et al., 2000,
1996). However, as a result of a study with difunisal (Yamamura
et al., 2002) this nding was later revised to the amorphous precipitates being obtained due to salt formation between cimetidine
and NSAIDs molecules upon precipitation instead of non-bonding
interactions. The results suggested that cimetidine may be a potential amorphous carrier for acidic drugs due to salt formation, which
also resulted in an increased solubility of the NSAIDs (Yamamura
et al., 2002, 2000).
The concept of formation of amorphous binary drug mixtures
has been later developed further and in addition to formation of
stable amorphous systems (Table 2), it can be seen as a potential way of preparing candidates for new formulations intended
for combination therapy.
71
Table 2
Formulation of co-amorphous mixtures and key observations for them.
Component 1
Component 2
Preparation
method
Observed
interactions
Stability
characteristics
Dissolution
improvement
Ref.
Naproxen
Non-steroidal
anti-inammatory
drug (NSAID)
Cimetidine
H2 -receptor antagonist
Co-milling for
60 min at 4 C.
1:1 molecular
interaction
between the
imidazole ring of
cimetidine and the
carboxylic acid
moiety of
naproxen.
1:1 mixture was

stable for 33 days
at 4 C, 25 C and
40 C (dry
conditions).
Alles et al. (2009)
Indomethacin
NSAID
Ranitidine
hydrochloride
H2 -receptor antagonist
Co-milling for
60 min at 4 C.
1:1 mixture was

stable for 30 days
at 4 C and 25 C
(dry conditions).
Naproxen
NSAID
Indomethacin
NSAID
Quench-cooling
1:1 molecular
interaction
between the
carbonyl and/or
the benzoyl group
of indomethacin
and the aci-nitro
group of ranitidine
hydrochloride.
Formation of a
naproxenindomethacin
heterodimer.
A four-fold increase in
the intrinsic
dissolution rate of
naproxen and a two
fold increase in the
dissolution rate of
cimetidine.
Synchronized
dissolution.
NA
Simvastatin
Anti-hyperlipidaemic
Glipizide
Anti-diabetic
Ball milling (BM)

and cryo-milling
(CM)
No observed
interactions.
1:1 mixture
remained
amorphous for 21
days at 4 C and
25 C (dry
conditions).
The storage
stability increased
as a function of Tg .
The most stable
mixtures (1:1 and
1:2 CM mixtures)
were stable for
over two months in
all storage
conditions.
Over seven-fold
increase in the intrinsic
dissolution rate of
indomethacin
compared to crystalline
form. Synchronized
dissolution (dissolves
as heterodimer).
The dissolution rate of
glipizide was improved
upon formation of
co-amorphous
simvastatin-glipizide
mixtures and even in
the case of amorphous
physical mixtures,
whereas dissolution
rate of simvastatin was
unaffected.
Chieng et al. (2008,

2009); Yoshioka et al.
(1994)
Lbmann et al. (2011)
Lbmann et al. (2012a)
NA, not analyzed.
4.1. Co-amorphous indomethacin/ranitidine hydrochloride

systems
By using mechanical activation as the preparation method,
Chieng et al. (2009) investigated indomethacin/ranitidine
hydrochloride mixtures (Table 2) whose crystalline to amorphous transformation was found to be faster compared to
individually milled drugs. In both cases, co-amorphous mixtures
were formed with molar ratios of 2:1, 1:1 and 1:2 and single
Tg s were observed for all the co-amorphous mixtures by DSC,
indicating formation of a single, homogenous phase. The experimentally detected Tg s were compared to the theoretical values
obtained from the GordonTaylor equation and in the case of
indomethacin/ranitidine hydrochloride, the theoretical values
were slightly higher. In general, the more ranitidine hydrochloride there was in the mixture, the lower was the Tg . These
co-amorphous mixtures were analyzed with diffuse reectance
infrared Fourier transform spectroscopy (DRIFTS) and it was found
that only the spectrum of 1:1 mixture showed signicant peak
shifts and formation of new peaks, suggesting an interaction
occurring between indomethacin and ranitidine, and that this
occurred at the expense of indomethacins dimer formation.
The analysis of the DRIFTS spectra revealed that the aci-nitro
group of ranitidine hydrochloride and the two carbonyl groups
of indomethacin (benzoyl and carboxylic acid) were involved in
this interaction. The 2:1, 1:1 and 1:2 mixtures were stored at 4 C,
25 C and 40 C under dry conditions (silica gel) up to 30 days. The
XRPD measurements showed that the binary 2:1 and 1:1 mixtures
were more stable than the 1:2 mixture. The 1:1 mixture was found
to be stable for up to 30 days at 4 C and 25 C despite the fact

that it did not have the highest Tg . This was attributed to the 1:1
molecular interaction between the components. In case of the 2:1
and 1:2 mixtures, it was found that the co-amorphous mixtures
crystallized primarily back to the excess component, since the
excess component would not be involved in an above-mentioned
1:1 molecular interaction. Moreover, the 1:2 mixture with excess
ranitidine hydrochloride was found to crystallize faster than the
2:1 mixture with excess indomethacin. This was explained by
the differences in the Tg values of the two mixtures, i.e. the Tg
being higher for the 2:1 mixture, and/or the presence of residual
ranitidine (form 2) nuclei in the 1:2 mixture.
4.2. Co-amorphous naproxen/cimetidine systems
In the case of naproxen/cimetidine (Alles et al., 2009), a coamorphous mixture was achieved upon ball milling for 60 min at
4 C, while milling of naproxen alone did not lead to amorphization (Table 2). The Tg s observed for 2:1, 1:1 and 1:2 mixtures were
found to be considerably higher than the theoretical ones from
the GordonTaylor equation. Again, the Tg s of the co-amorphous
mixtures were closer to the excess component, i.e. the more
naproxen in the mixture the lower was the Tg . The positive deviation of the experimental Tg s form the theoretical values suggested
an interaction between the two molecules. As in the case of
indomethacin/ranitidine hydrochloride, the stability studies (same
conditions as above) showed that the 1:1 co-amorphous mixture
was the most stable, staying in the amorphous state up to approx.
six months in all storage conditions, in spite of not having the
72
highest Tg . Again, crystallization of the excess component of the

mixture was observed with the 2:1 and 1:2 samples. Traces of crystalline naproxen could be found in 2:1 mixtures stored at 25 C
and 40 C after 33 days of storage, but at 4 C this mixture was
stable. Although it had the highest Tg of all mixtures, the 1:2
mixture showed traces of crystalline cimetidine at all temperatures. Raman spectroscopy studies of the most stable mixture (1:1)
revealed a solid state interaction between the imidazole ring of
cimetidine and the carboxylic acid moiety of naproxen similarly to
ndings in FTIR studies with the amorphous naproxencimetidine
co-precipitate, where the N H group of the imidazole ring of cimetidine was found to interact via ionic bonding with the carboxylic
acid group of naproxen (Yamamura et al., 2002, 1996). The authors
concluded that the observed molecular interaction was responsible for the high stability of the 1:1 co-amorphous mixture and
it was also observed to be strong enough to stabilize the system
during dissolution, leading to a four-fold and two-fold increase in
the intrinsic dissolution rates (IDRs) of naproxen and cimetidine,
respectively, compared to their crystalline counterparts. Interestingly, the release-time proles (mg/cm2 ) revealed that the release
of naproxen and cimetidine from the co-amorphous mixture was
synchronized and a pair-wise solvation process was suggested to
be the reason for this.
4.3. Co-amorphous naproxen/indomethacin systems
In a recent publication from Lbmann et al. (2011), a system of
naproxen and indomethacin was investigated. The co-amorphous
mixtures were prepared by quench-cooling at molar ratios of 2:1,
1:1 and 1:2 (Table 2). FTIR and DSC measurements revealed formation of amorphous single-phase systems with all mixture ratios
showing single Tg values. Comparison with theoretical Tg values
from the GordonTaylor equation revealed a negative deviation,
with the 1:1 molar ratio having the highest deviation (2.63 C).
FTIR measurements suggested that a 1:1 molecular interaction
occurred between the molecules and thus it was concluded that
this interaction might play a role in the deviation from the calculated Tg values. Thus, a novel approach to predict the Tg s more
accurately was applied. It was assumed that both drugs at the 1:1
molar ratio may be regarded as an interconnected state through
hydrogen bonding, forming a heterodimer, and thus could be
treated in the GordonTaylor equation as an individual component, with the excess drug representing the second component.
The predicted Tg s using this approach showed signicantly lower
deviations from the experimental values than the originally calculated ones and this approach was also shown to be valid with other
naproxen/indomethacin mixtures in different ratios (Fig. 2).
The results of stability and dissolution studies further supported the assumption of a 1:1 heterodimer formation. It
was observed that the excess component of the 1:2 and 2:1
naproxen/indomethacin mixtures recrystallized in the stability
study, whereas the co-amorphous 1:1 mixture remained amorphous for the entire duration of the stability study (21 days), even
though the Tg was lower than that obtained for the 1:2 mixture.
It was suggested that, due to the formation of a heterodimer,
the co-amorphous 1:1 mixture possesses an intrinsic resistance
toward crystallization. In order to recrystallize, the hydrogen bonds
within the heterodimer have to be broken and subsequently, two
indomethacin molecules have to form a homodimer (Kistenmacher
and Marsh, 1972) and naproxen molecules need to form a chainlike structure (Kim and Song, 1984). In the 1:2 and 2:1 quench
cooled mixtures, the molecular short-range order for the excess
drug is already present and, therefore, they are more readily able
to recrystallize into their corresponding individual crystals.
In addition, the intrinsic dissolution studies showed that the
1:1 co-amorphous mixture released both drugs in a synchronized
Fig. 2. Glass transition temperatures of co-amorphous binary drugdrug mixtures

between naproxen and indomethacin. The symbols represent the experimentally determined Tg values, the dashed line represents the prediction of the
GordonTaylor equation calculated from the Tg s of the single drugs (no interaction assumed), and the solid line represents the prediction with the 1:1 molar ratio
of the two drugs being a separate component in the Gordon Taylor equation next to
the excess amount of drug (interaction assumed).
Source: Reproduced from Lbmann et al. (2011) with permission of the American
Chemical Society.
manner (with every naproxen molecule also one indomethacin

molecule was dissolved), leading to the conclusion that in fact the
heterodimer was released instead of two individual amorphous
drugs (Fig. 3). A similar observation was made by Alles et al. (2009)
with the co-amorphous mixture of naproxen and cimetidine as
described above. Furthermore, an increased release compared to
the crystalline counterparts and amorphous indomethacin alone
was detected giving an over seven-fold increase in the IDR of
indomethacin compared to crystalline form (Table 2). The authors
suggested that when two drugs are released as a heterodimer, it
might be possible to further increase the dissolution rate by creating a co-amorphous mixture of a Biopharmaceutics Classication
System (BCS class) II drug with a highly soluble partner as demonstrated Alles et al. (2009) by combining naproxen with the BCS
class I drug cimetidine.
Fig. 3. Intrinsic dissolution rate (nmol mL1 min1 ) of the co-amorphous

naproxenindometacin (NAPIND) binary mixture demonstrating a synchronized
drug release due to formation of a heterodimer.
Source: Modied from Lbmann et al. (2011) with permission of the American Chemical Society.
73
4.4. Co-amorphous simvastatin/glipizide systems

In the above discussion, molecular 1:1 interactions have been
shown to be an essential factor with regards to stabilization
and improved drug dissolution from binary co-amorphous drug
mixtures. However, in a recent study using the drug pair simvastatin/glipizide, it was observed that improved stabilization of the
amorphous state can be achieved even when such interactions are
absent (Lbmann et al., 2012a). The simvastatin/glipizide system
was estimated to be immiscible by calculating a FloryHuggins
interaction parameter () of 5.5, indicating lack of favorable interactions (Marsac et al., 2009; Pajula et al., 2010). Nonetheless, it was
observed that ball milling (at molar ratios of 2:1 and 1:1) and cryomilling (at molar ratios of 2:1, 1:1 and 1:2) were able to force the
components to mix at the molecular level producing a single-phase
amorphous system, indicated by a single Tg observed in DSC measurements. The more glipizide in the mixture the higher was the Tg .
The observed Tg s were found to be lower than the theoretical Tg s
predicted by the GordonTaylor equation indicating an overall loss
in the number and strength of hydrogen bonding upon mixing. FTIR
spectra of all co-amorphous mixtures were found to be similar to
the spectra of the corresponding physical mixtures of the individual amorphous drugs (amorphous physical mixtures, APMs). PCA
analysis of the spectral data revealed that the band shifts occurring
in APMs and the co-amorphous mixtures (compared to physical
mixtures of the crystalline drugs) were simply associated with the
formation of amorphous forms of the individual drugs (Fig. 4a,b).
However, differences in stability between molecularly mixed
and physically mixed amorphous simvastatin/glipizide were
observed. Storage at conditions of 25 C/0% RH and 25 C/60% RH
(for the APMs) and at 4 C/0% RH in addition for all other samples revealed that APMs were stable over approximately the same
time period than the co-amorphous mixtures when stored at
25 C/0% RH, but when humidity (60%) was involved, the APMs
remained amorphous for only a few days while the 1:1 and 1:2 coamorphous mixtures were stable for over two months. The order of
increasing stability of co-amorphous mixtures was 2:1 < 1:1 < 1:2,
indicating that stability increased as a function of increasing
amount of glipizide and thus, increasing Tg of the co-amorphous
mixture. Interestingly, this nding was in contrast to what has
been described above for other co-amorphous mixtures and was
attributed to the lack of specic interactions between simvastatin
and glipizide. The better stability of co-amorphous mixtures over
APMs was explained by differences in mixing. In a well-mixed
binary system (such as the co-amorphous mixtures of this study),
where the components are intimately mixed at the molecular level,
only one amorphous phase would be present. In contrast, a system
with more than one amorphous phase present (such as the APMs
of this study) would have different amorphous regions with different simvastatin-to-glipizide ratios. Such differences in composition
lead to differences in recrystallization behavior. In co-amorphous
simvastatin/glipizide systems, stabilization can be considered to
occur similarly as in drugpolymer systems; one amorphous component of the mixture acts as an anti-plasticizing stabilizer (Marsac
et al., 2009), which in this case would be glipizide.
5. Mesoporous systems
The interest toward mesoporous silicon and silica for drugdelivery applications has increased recently. Among other
applications, the use of porous media or adsorbents to produce an
amorphous drug delivery system has been introduced as an alternative to drug/polymer systems in producing stable drug delivery
systems for amorphous drugs (Qian and Bogner, 2012; Simovic
et al., 2011). This will be the focus of this review, but there are
Fig. 4. PCA analysis of the FTIR spectra of amorphous drugs (simvastatin (SVS) and
glipizide (GPZ)), SVS/GPZ 2:1, 1:1 and 1:2 physical mixtures (PMs), co-amorphous
mixtures (ball milled (BM) and cryomilled (CM)) and amorphous physical mixtures
(APMs). (a) score plot showing, that all the 2:1, 1:1 and 1:2 samples (APM, BM, CM)
form their individual clusters, indicating similarity within these groups; (b) loadings
plot showing PC-1 compared to the difference between the spectra of GPZ CM and
SVS CM and PC-2 compared to the difference between the spectra of SVS-GPZ CM
and SVS-GPZ PM. Since the loading of PC-1 is identical to the subtraction spectrum
of GPZ CM and SVS CM, PC-1 explains the difference in composition. The loading of
PC-2 is identical to the subtraction spectrum of SVS-GPZ 1:1 PM and SVS-GPZ 1:1 CM
which means that PC-2 explains the difference between crystalline and amorphous
state.
Source: Reproduced from Lbmann et al. (2012a) with permission of Elsevier.
excellent reviews available for readers interested in the wider

applications of mesoporous silica- and silicon-based materials in
drug delivery (Prestidge et al., 2007; Qian and Bogner, 2012; Riikonen et al., 2012; Simovic et al., 2011).
Mesoporous silicon and silica (mesoporous silicon dioxide
(SiO2 ) and silicates) refer to porous materials exhibiting pores
with diameters between 2 and 50 nm (Prestidge et al., 2007; Sing
et al., 1985). Mesoporous silicon for pharmaceutical use is prepared by electrochemical techniques, such as anodization or stain
etching (Prestidge et al., 2007). The potential for modifying the
surface of porous silicon through chemical or thermal treatments
provides a range of possible matrices for different drug delivery
applications (Salonen et al., 2005). Silicates, such as magnesium
aluminometasilicate (Neusilin ) or calcium silicate (Florite ) are
manufactured on a commercial scale using proprietary processes
that include spray-drying (Qian and Bogner, 2012; Rowe et al.,
2011). In contrast, pharmaceutical mesoporous SiO2 is traditionally
prepared from starting materials, such as alkoxysilane or sodium
74
silicate, using a solgel process, in which nanosized particles of

Si(OH)4 are suspended in a solution (e.g. a wateralcohol cosolvent) (Qian and Bogner, 2012). Particles then aggregate and form
a porous network of solids. Terminal silanol groups covering the
surface of the SiO2 particles are critical for silicadrug interactions
and subsequent amorphization. More recently, novel production
methods which allow better control of the nal pore structure and
size distribution, such as the liquid-crystalline templating, have
been developed. With this method, mesoporous SiO2 known as
Mobil Composition of Matter (MCM-41) and Santa Barbara amorphous type material (SBA-15) are produced (Kresge et al., 1992;
Zhao et al., 1998). These materials, having a very uniform pore
structure of unidirectional channels are the most widely studied
in the eld of drug delivery (Hu et al., 2011; Kinnari et al., 2011;
Mellaerts et al., 2011; Shen et al., 2011).
Incorporation of a drug into mesoporous materials can be
achieved by solvent deposition methods (Hu et al., 2011; Kinnari
et al., 2011; Mellaerts et al., 2008b; Prestidge et al., 2007; Shen
et al., 2011), mechanical activation (co-grinding or milling) (Hailu
and Bogner, 2011; Limnell et al., 2011; Watanabe et al., 2002,
2001) or vapour-phase mediated mass transfer (Konno et al., 1986;
Qian and Bogner, 2011). Regardless of the preparation method,
the high surface free energy (due to the large surface area of the
porous material) allows the system to transfer to a lower free
energy state upon adsorption of drug molecules on the material. The adsorbed drug molecules lose their crystalline structure.
Due to the decreased Gibbs free energy, the amorphous system is
physically stable and crystallization occurs only if the thermodynamic state of the system is perturbed (Qian and Bogner, 2012). In
addition to thermodynamic factors, nucleation and crystal growth
is hindered by spatial constraints, i.e. the pores are not able to
incorporate enough molecules in order for them to reach a critical nucleation size (Jackson and McKenna, 1996; Prestidge et al.,
2007; Qian and Bogner, 2012).
The drug incorporation methods were compared in a study by
Mellaerts et al. (2008a). They used the ordered mesoporous silica
material SBA-15, the model drugs itraconazole and ibuprofen and
three different drug loading procedures (adsorption from solution,
incipient wetness impregnation, and heating of drug and SBA-15
physical mixtures). The loading procedure was found to have an
effect on the physical state of the drug in SBA-15. In the case of
itraconazole, incipient wetness impregnation and adsorption form
dichloromethane were successful methods in dispersing itraconazole molecularly into micro- and mesopores of the SBA-15 when
the theoretical loading was 20% (the actual loadings were found
to be slightly lower). When the loading was increased to 30%,
formation of an adsorbed layer in which itraconazole molecules
interact similarly as in the glassy state, was seen. Furthermore, the
incipient wetness impregnation method favored the positioning of
itraconazole molecules in the micropores of SBA-15 while the solvent method favored their positioning on the mesopore walls. In
contrast, ibuprofen was successfully incorporated inside the SBA15 micropores with all methods.
Thermally oxidized porous silicon (pSi-ox) was observed to
encapsulate indomethacin in amorphous form due to geometric connement in the nanopores, as revealed by XRPD and DSC
(Wang et al., 2010). FTIR measurements showed hydrogen bonding interactions between the acid and amide functional groups
of indomethacin and the pSi-ox surface. The pSi-ox pore calculated diameter was found to decrease from 8.8 to 6.7 m upon
indomethacin loading. The change in pore diameter was approximately equivalent to a monolayer of indomethacin molecules
adsorbed on the inner surface of the pores, according to the
indomethacin molecular size. In order to study the stability of the
amorphous indomethacin- pSi-ox systems, samples were stored
at 40 C/75% RH and analyzed using DSC and XRPD. Enhanced
solid state stability was observed under these storage conditions,

where no evidence of crystalline indomethacin was observed in
the XRPD diffraction pattern obtained for the indomethacin loaded
pSi-ox over 6 months. In contrast, amorphous indomethacin alone
recrystallized after 1 month. In addition, the pSi carrier facilitated
immediate release of indomethacin and enhanced oral delivery
performance in comparison with crystalline indomethacin and
a commercially available formulation, i.e. a 200% increase on
peak concentration (Cmax ), a four-times reduction in the time to
reach Cmax (Tmax ) and a signicant increase in bioavailability were
observed.
In a recent study, surface-modied mesoporous silicon (thermally carbonized PSi (TCPSi), thermally oxidized PSi (TOPSi)) and
non-ordered mesoporous silica (Syloid AL-1 and 244) materials
were investigated as drug carriers for the poorly soluble drug itraconazole (Fig. 5a; Kinnari et al., 2011). Loading of the mesoporous
particles was performed by the immersion method, in which the
particles were immersed into a concentrated itraconazole solution in dichloromethane. The drug loading was performed with
two different drug concentrations for the silica particles (high/low).
Silicon particles were loaded only with the low concentration.
Despite their signicant differences in pore size, surface area
and pore volume, the two Syloids (silica particles) showed similar loading capacities when the low loading concentration was
used (21.0 w-% for SylAL-1 and 21.9 w-% for Syl244). These however, were higher than those obtained with mesoporous silicon
microparticles (about 11% for both TOPSi and TCPSi) using the
same loading procedure. As expected, at high-loading concentrations of itraconazole, the loading capacities for Syloid AL-1 and
244 were increased to 25.1 and 32.8 w-%, respectively. It was suggested that the higher loads observed for the mesoporous silica
particles might be attributable to different pore geometry and to
the fact that the mesoporous surfaces of silica particles contain
large amounts of silanol groups that are favorable for interactions
with itraconazole through hydrogen bonds. XPRD and DSC measurements showed that the loaded itraconazole was present in an
amorphous form and SEM and FTIR investigations suggested that
the loading process did not change the chemical structure or morphology of the particles surface. Drug amorphization resulted in
a signicant improvement in dissolution rate as compared to the
crystalline itraconazole. The release of itraconazole at pH 1.2 from
TCPSi and Syloid AL-1 microparticles was found to be faster than
from TOPSi and Syloid 244 particles. This was suggested to result
from the smaller pore size of Syloid AL-1 compared to Syloid 244,
and from the more favorable surface chemistry of TCPSi compared
to TOPSi. The amorphous state of the drug was retained in the mesoporous silica particles even after 3 months storage at 40 C and
70% RH, but this was not the case with the silicon particles due to
the almost complete chemical degradation of itraconazole during
storage (Fig. 5b).
The stability of indomethacin formulations based on ordered
mesoporous silica MCM-41 and SBA-15 materials has been studied by Limnell et al. (2011). Only small amounts of crystalline
indomethacin (<3.0 wt.-%) were detected by DSC in the samples
directly after loading. However, the physico-chemical stability of
the samples during prolonged storage under stressed conditions
was found to be variable. The physical stability of the samples
was found satisfactory. The dissolution studies demonstrated the
ability of both MCM-41 and SBA-15 microparticles to improve
the dissolution of indomethacin by stabilizing it in a disordered
state inside the mesopores and by further maintaining this state
even during storage in stressed conditions. However, the chemical
stability analyses revealed a decrease in the degree of loading
and possible indomethacin degradation products formation,
especially in MCM-41-based samples. In contrast, in a study by
Van Speybroeck et al., 2009, the SBA-15 formulations were found
75
Fig. 5. Surface-modied mesoporous silicon and non-ordered mesoporous silica materials as drug carriers for the poorly soluble drug itraconazole (ITZ). (a) Scanning electron
microscopy (SEM) pictures of the mesoporous silica and silicon microparticles: TOPSi (a), TCPSi (b), Syloid 244 (c), and Syloid AL-1 (d), showing that the PSi particles are
larger and have more angular structures than the more spherical-like mesoporous silica particles; (b) Release proles of ITZ from ITZlow + TCPSi and ITZlow + Syl244 particles
at pH 1.2 and 37 C before and after the three months storage under stress conditions (40 C and 70% RH) (lines n 4, mean SD), demonstrating the physical stability of the
Syl244 formulations.
Source: Reproduced from Kinnari et al. (2011) with permission of Elsevier.
to be physically stable. Ten physicochemically diverse model

compounds were successfully loaded onto SBA-15 using a generic
solvent impregnation method, and in all cases, the adsorbed drug
fraction was found to be non-crystalline. This resulted in signicant
improvement of the dissolution rate compared to the crystalline
drugs. The formulations were stored at 25 C/75% RH and no drug
crystallization was observed during storage for six months. The
authors concluded that this demonstrated the potential of SBA-15
to yield physically stable, dissolution enhancing formulations,
irrespective of the drugs physicochemical prole.
Miura et al. (2011) prepared carrier systems for a poorly soluble drug (K-832) by adsorbing it onto porous silica Sylysia 740
(2.5-nm-diameter pores) and Sylysia 350 (21-nm-diameter pores).
Formulations, in which K-832 was found to be present in an amorphous form, were stored at 60 C/80%RH (under open and closed
conditions). It was observed by XRPD that the K-832Sylysia 740
and K-832Sylysia 350 formulations stored at 60 C/80% RH for up
to 1 month in closed glass vials did not show diffraction peaks
suggesting that it was difcult to crystallize amorphous K-832 in
the mesopores of silica. However, under high-humidity conditions
76
(80% RH, open vials), the formulations showed small peaks after
storage for 2 weeks. DSC measurements revealed that the heat of
fusion of the K-832Sylysia 740 formulation, which increased with
the storage period, was smaller than that of the K-832Sylysia 350
formulation. This result suggested that the adsorption of K-832
onto Sylysia 740, which has much smaller mesopores (2.5 nm), was
responsible for the higher physical stability of amorphous K-832.
Furthermore, the spinlattice relaxation times in the rotating frame
(T1, as a measure of molecular mobility) measured using solidstate 13 C NMR, revealed that the molecular mobility of K-832 was
lower for the 2.5 nm pores (larger T1) than for the 21 nm pores,
making the crystallization rate of amorphous K-832 in the 2.5-nm
pores much slower.
6. Conclusions and future perspectives

The solubility and dissolution of poorly water-soluble drugs can
be increased by transformation into an amorphous form, but this
high-energy state of the material also is prone to recrystallization
and thus the loss of these benets. Crystallization of the amorphous
state is a complex phenomenon with many contributing factors
whose relative importance to the amorphous stability still remains
unclear. There are only limited approaches to ensure stability for
an amorphous drug alone but with addition of certain excipients
stability can be increased. Drug formulation in solid dispersions
(most often as glass solutions) is one of the rst and most commonly
used techniques for the dissolution rate enhancement of poorly
water-soluble drugs and stabilization of the amorphous state.
However, with an increasing need for strategies to improve poor
solubility, additional effective amorphization methods are needed.
In this review, approaches such as binary co-amorphous mixtures
and mesoporous materials were discussed. Special attention has
been given to co-amorphous mixtures, consisting of two active drug
substances. In these systems, stabilization of the amorphous state
and improved drug dissolution is generally achieved through intermolecular interactions, such as hydrogen bonding, and/or mixing
on the molecular level. This approach offers interesting opportunities for new formulations intended for combination therapy. In
these types of formulation a synchronized release of the two drugs
is often achieved without relying on an excipient, such as a polymer.
Co-amorphous systems are often prepared by co-milling or quench
cooling from the melt. In milling the processing temperature is
relatively low which is particularly important for pharmaceutical
compounds which are unstable at high temperature. It has been
also shown, that the co-amorphous approach is not limited to combination of two drug molecules, but other small molecules can be
employed, thus avoiding the need to match e.g. the pharmacological effect and dose of the two active substances.
When processing mixtures of two small molecules (e.g. two drug
molecules) by solvent evaporation, melting methods or mechanical
activation, formation of co-crystals might occur when attempting
to prepare a co-amorphous system and vice versa (Bladgen et al.,
2007; Lu and Rohani, 2009). Co-crystals are multi-component crystals based on hydrogen bonding interactions without the transfer
of hydrogen ions to form salts (Lu and Rohani, 2009). Furthermore,
pharmaceutical co-crystals can be dened as crystalline materials comprised of an active pharmaceutical ingredient (API) and
one or more unique co-crystal formers, which are solid at room
temperature (Vishweshwar et al., 2006). There is a stoichiometric
ratio between the API and the co-crystal former. Currently, little is known about the relation between co-amorphous systems
and co-crystals. Both result from formation of interactions, such
as hydrogen bonds, between the components. If these interactions are energetically more favorable than those between the like
molecules of either component, then either a co-amorphous system
or a co-crystal is formed. Co-crystal formation may be rationalized

to some extent, for example by understanding the supramolecular
chemistry of the functional groups present in the given molecules
and selection of appropriate co-crystal formers (Etter, 1990; Vishweshwar et al., 2006). However, whether co-crystal formation is
favored over co-amorphous systems cannot currently be predicted,
but must be answered experimentally. For example, acyclovir has
been reported to form an amorphous mixture with anhydrous
citric acid through hydrogen bond interactions, as previously mentioned, but with l-tartaric acid, a co-crystal is formed (Masuda
et al., 2012). In addition, spontaneous co-crystal formation might
occur when storing physical mixtures or co-amorphous systems
under extreme conditions e.g. during stability studies. Moisture
is known to generate co-crystals (Arora et al., 2011; Jayasankar
et al., 2007; Maheshwari et al., 2009), such as the carbamazepinenicotinamide co-crystal as a consequence of storage (Maheshwari
et al., 2009). To our knowledge co-crystal formation has never been
reported as a consequence of the storage of co-amorphous systems, but this possibility should be kept in mind and investigated.
Usually, co-amorphous systems have been observed to recrystallize to pure components, with the excess component crystallizing
out rst (Alles et al., 2009; Chieng et al., 2009; Lbmann et al.,
2011). However, the amorphous state has been reported to act as an
intermediate state before formation of co-crystals (Seefeldt et al.,
2007). Depending on the conditions (heating rate in DSC), amorphous mixtures of carbamazepine and nicotinamide were found
to generate either co-crystals through a metastable cocrystalline
phase (low heating rate) or co-crystals after initial recrystallization as individual components (high heating rate). Pajula et al.
(2010) have suggested a pathway to describe the crystallization
of an amorphous, molecularly mixed, binary system. In their theory, an excipient that forms a thermodynamically miscible mixture
and a stable binary system with a drug compound enables the formation of a stable amorphous structure. It is assumed that such
thermodynamically miscible binary systems require phase separation to occur before the individual components can crystallize.
After the phase separation has occurred, the system might proceed
to nucleation and crystal growth. These transformational stages are
governed by both thermodynamic and kinetic factors that must
be taken into account for the successful development of a stable
amorphous binary system. However, it was also suggested that it is
possible that crystallization initiates the formation of co-crystals,
which might be desirable if the physicochemical properties of the
co-crystals are advantageous compared to those of the pure components.
The stabilizing effect of loading drug molecules into mesoporous
silica- and silicon-based materials is different to co-amorphous
systems. In mesoporous systems, amorphization of the drug
occurs through spatial constraints, i.e. the critical nucleation
size of the drug is larger than the pore diameter of the mesoporous material. The molecular mobility of a drug in mesopores
is different in pores of different sizes and it also depends
on the interaction between the drug and the mesopore wall.
Decreased molecular mobility leads to the stabilization of drugs
in amorphous forms. A decrease in the Gibbs free energy occurs
upon adsorption of drug molecules, which makes the system
physically stable. The amorphization of the drug is the main
factor for the observed dissolution rate enhancement of poorly
soluble drugs in these systems. However, more work is still required
needed to understand the detailed mechanisms of interaction in
these systems.
Clearly, more mechanistic insight is required to fully understand amorphous systems in general. What is currently known,
is that molecular interactions play an important role in both
co-amorphous and mesoporous silica-based systems. However,
proving and even more so, predicting the existence of these
interactions in multi-component amorphous systems, can be challenging. Little is known about the molecular arrangement of these
systems and vibrational spectroscopy is usually used to gain information on molecular interactions such as hydrogen bonding or
interactions. However, the experimental spectra of even single
amorphous substances can be difcult to analyze because changes
in the vibrational modes due to solid state changes or molecular
interactions might only be minor or get lost in the complexity of the
spectra. This becomes even more complicated in amorphous mixtures. In this regard, computational methods could provide a clearer
insight, helping to support and interpret experimentally obtained
vibrational spectra. Using quantum mechanical calculations to predict vibrational spectra for various possible molecular interactions
could be used and may provide insight into changes in experimental
spectra. Similar changes in the calculated and experimental spectra
therefore give information on the short-range order in these amorphous systems. Such an approach is currently under investigation in
our group in order to analyze the formation of a heterodimer in coamorphous naproxenindometacin (Lbmann et al., 2012b). These
kinds of calculations might even serve as a rational way of knowing
if a co-amorphous system can be formed between two molecules.
Both of the stabilization methods discussed in this review are
expected to gain increased interest in the future. The strength of
the co-amorphous systems lies in their ability to offer synchronized
release of two active molecules and stabilization of the amorphous
forms with lower bulk volumes of the material compared to solid
polymer dispersions. However, their processability into pharmaceutical products has not yet been shown. In contrast, mesoporous
systems have proven their efcacy in formulations of poorly soluble/low bioavailability drugs. This is due to the fact that the drug
is dispersed on a very large surface area, often as an amorphous
dispersion. Functionalization of the surface of the mesoporous
materials offers possibilities to gain a better control over drug loading and release properties. However, more data on mesoporous
materials is required in order to comprehensively assess their performance as drug delivery vehicles for specic applications. In
addition, the use of solvents for drug loading remains a drawback
of this method.
Acknowledgments
The Academy of Finland (grant no. 136699), Magnus Ehrnrooth
Foundation (grant no. KE2010n14) and Saastamoinen Foundation
are acknowledged for nancial support for RL.
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International Journal of Pharmaceutics 453 (2013) 6579

Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics

Emerging trends in the stabilization of amorphous drugs

their amorphous counterparts is one of the most promising tools,

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

presented as potential means to increase the stability of amorphous

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

The amorphous state is characterized by the absence of

than TK . Thus, this approach has only limited practical meaning, as

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

Observed impact on stability

Stability increases with increasing Tg . Polymers with high

Bansal et al. (2010);

Short relaxation times in the region of Tg correlate with a

Andronis and Zogra

-relaxation is generally associated with faster motion on

Bhugra and Pikal (2008);

Entropic barrier for

Often found to be the best thermodynamic parameter to

Graeser et al. (2009b);

Enthalpic driving force

The increased nucleation rate of nifedipine compared to

Marsac et al. (2006)

Gibbs free energy

Often poorer predictor for crystallization than

Graeser et al. (2009b);

Amorphous materials with similar Tg values might show

Ambike et al. (2005);

The presence of moisture in storage conditions increases

Bhugra et al. (2008);

Factors on the molecular level

Factors independent of the molecule

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

Observed impact on stability

All preparation methods result in different thermal

Bhugra and Pikal (2008);

Structural differences between amorphous indomethacin

Bhugra et al. (2008);

at temperatures lower than Tg -50 K, is less stable due to the larger

samples clustered in the scores plot according to the cooling rate,

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

under such conditions of rapid solidication, crystallization was

4. Binary co-amorphous mixtures

interactions (Lu and Zogra, 1998; Masuda et al., 2012). Formation

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

1:1 mixture was

Alles et al. (2009)

1:1 mixture was

Ball milling (BM)

Chieng et al. (2008,

Lbmann et al. (2011)

Lbmann et al. (2012a)

NA, not analyzed.

4.1. Co-amorphous indomethacin/ranitidine hydrochloride

to be stable for up to 30 days at 4 C and 25 C despite the fact

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

highest Tg . Again, crystallization of the excess component of the

Fig. 2. Glass transition temperatures of co-amorphous binary drugdrug mixtures

manner (with every naproxen molecule also one indomethacin

Fig. 3. Intrinsic dissolution rate (nmol mL1 min1 ) of the co-amorphous

R. Laitinen et al. / International Journal of Pharmaceutics 453 (2013) 6579

4.4. Co-amorphous simvastatin/glipizide systems