Review

Refining stability and dissolution

rate of amorphous drug
formulations
1. Introduction
Holger Grohganz, Petra A Priemel, Korbinian Lobmann,
2. Polymer-based solid
Line Hagner Nielsen, Riikka Laitinen, Anette Mullertz,
dispersions
Guy Van den Mooter & Thomas Rades
3. Physical separation
University of Copenhagen, Department of Pharmacy, Copenhagen, Denmark
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14

4. Co-amorphous formulations
5. Recent trends
Introduction: Poor aqueous solubility of active pharmaceutical ingredients
(APIs) is one of the main challenges in the development of new small
6. Conclusion
molecular drugs. Additionally, the proportion of poorly soluble drugs among
7. Expert opinion new chemical entities is increasing. The transfer of a crystalline drug to its
amorphous counterpart is often seen as a potential solution to increase the
solubility. However, amorphous systems are physically unstable. Therefore,
pharmaceutical formulations scientists need to find ways to stabilise
amorphous forms.
Areas covered: The use of polymer-based solid dispersions is the most
established technique for the stabilisation of amorphous forms, and this
review will initially focus on new developments in this field. Additionally,
newly discovered formulation approaches will be investigated, including
For personal use only.

approaches based on the physical restriction of crystallisation and crystal

growth and on the interaction of APIs with small molecular compounds rather
than polymers. Finally, in situ formation of an amorphous form might be an
option to avoid storage problems altogether.
Expert opinion: The diversity of poorly soluble APIs formulated in an
amorphous drug delivery system will require different approaches for their
stabilisation. Thus, increased focus on emerging techniques can be expected
and a rational approach to decide the correct formulation is needed.

Keywords: amorphous, co-amorphous systems, dissolution enhancement, in situ,

microcontainers, polymers, solid dispersions, stability, surface crystallisation

Expert Opin. Drug Deliv. (2014) 11(6):977-989

1. Introduction

An increasing number of active pharmaceutical ingredients (API) suffer from one

common challenge: their low solubility in water. These drugs are classified as
class 2 and class 4 in the biopharmaceutics classification system (BCS), respectively [1].
While in the period of 2000 -- 2011, only around 20% of generics approved via the
abbreviated new drug applications system in the USA belonged to BCS class 2 [2], up
to 90% of the APIs currently under development are classified as BCS class 2 or
class 4 drugs [3]. Low aqueous solubility can seriously reduce the bioavailability of
the drug [4], and the further development of pharmacologically effective new chemi-
cal entities might be abandoned if the solubility issue cannot be resolved satisfactory.
The transformation of an API from its crystalline state to an amorphous form is gen-
erally regarded as an option to handle this challenge. Amorphous materials lack the
three dimensional long-range positional and orientational order of molecules typical
for crystalline solids and represent the highest energetic state of a solid material [5].
Amorphous drugs are expected to be advantageous in terms of solubility and dissolu-
tion rate because one of the determining steps in the dissolution process of crystalline

10.1517/17425247.2014.911728 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 977
All rights reserved: reproduction in whole or in part not permitted
 H. Grohganz et al.
Article highlights.
. Poor aqueous solubility is a key challenge for
pharmaceutical development.
. Amorphous systems offer an increase in dissolution rate
and solubility but at the cost of inherent instability.
. Polymer-based solid dispersions are well-described
systems for stabilisation of an amorphous formulation.
. Physical separation may restrict crystallisation or
crystal growth.
. A promising new approach for stabilisation is
co-amorphous systems, which are based on
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
small-molecular-weight components.
. The issue of low storage stability can potentially be
avoided by in situ amorphisation.
This box summarises key points contained in the article.
solids, the disruption of the crystal lattice [6], does not have
to take place. However, the drawback of the increased free
energy of amorphous material is its inherent thermodynamic
instability leading to relaxation, nucleation and crystal growth
phenomena during storage [7]. Also, precipitation and crystal-
lisation during dissolution in the gastrointestinal fluids can
occur. Pure amorphous drugs are, therefore, usually not devel-
For personal use only.
oped as such to commercial dosage forms but in combination
with excipients that stabilise the amorphous form during
storage and prevent nucleation and crystallisation during the
dissolution process.
The stabilisation of amorphous APIs via various formula-
tion approaches is therefore a highly investigated area in
pharmaceutical research. Due to the increasing numbers and
thus increasing diversity of poorly water-soluble APIs, there
is a need for an increasing amount of different technological
approaches to stabilise amorphous formulations [8]. Solid
dispersions are the most thoroughly investigated approach so
far, and in this review, we will start with a focus on recent
developments in polymer-based solid dispersions (Section 2).
However, polymer-based systems may not be applicable
in all cases and generally require a rather large amount of
excipient. This has led to a recent increase in research aiming
to find new ways of stabilising amorphous drug formulations.
Physical separation principles have shown to be beneficial in
reducing crystallisation or restricting crystal growth and are
discussed in Section 3. Apart from polymers, also small
molecules, both API and excipients, recently showed a poten-
tial to increase the stability of amorphous formulations
(Section 4). Finally, recent trends such as stable spray-dried
salts or in situ formation of an amorphous system may prove
valuable formulation options for poorly water-soluble drugs
(Section 5).
2. Polymer-based solid dispersions
The combination of an API with excipients is known as a
solid dispersion. A classification of the different types of solid
978 Expert Opin. Drug Deliv. (2014) 11(6)
dispersions has been provided by Chiou and Riegelman [9],
but currently, the term solid dispersion is mostly linked to
(supersaturated) glass solutions of poorly soluble compounds
with amorphous or semicrystalline polymeric carriers.
A glass solution in the true sense is a one-phase system in
which all molecules of the API are intimately mixed with
the carrier molecules. The selection of the carrier is important
as it will have significant impact on the physical stability and
dissolution performance of the solid dispersions. An overview
of the polymers that are being used in marketed formulations
is provided in a recent review [10]. Polyethylene glycols,
hydroxypropyl methylcellulose (HPMC) and polyvinylpyrro-
lidone (PVP) have been most often used in the past, whereas
more recently, HPMC acetate succinate has been frequently
applied because it shows to be successful in maintaining
supersaturation of dissolved API [11,12]. Also, the amphiphilic
graft copolymer of polyethylene glycol, polyvinylcaprolactam
and polyvinylacetate (Soluplus
) is a promising carrier due to
its good flowability and excellent extrudability [13].
The ease of crystallisation of a drug from its amorphous state
depends on the driving force for crystallisation given by the free
energy difference between the amorphous and the crystalline
state and between the mobility of the amorphous state and the
crystallisation mechanism. In order to decrease pill burden,
one aims to have API loadings as high as possible in the carrier.
In many cases, API loadings up to 30 -- 40% can be obtained
without noticeable phase separation (amorphous--amorphous
phase separation or the presence of a crystalline API phase)
immediately after preparation. However, phase separation as a
function of time and/or triggered by storage conditions
(temperature and/or elevated humidity) is often reported and
contributes to the large discrepancy between the scientific and
developmental efforts and the low number of solid dispersions
that have entered the market. The solubility of crystalline drugs
in polymeric matrices is of importance for selecting the appro-
priate polymer because it will establish the limit of drug loading.
The high polymer viscosity hampers straightforward solubility
determination and is one of the reasons that there is still
no universally accepted technique to measure the solid state
drug--polymer solubility/miscibility. Vasanthavada et al. there-
fore proposed to estimate the solubility of trehalose in solid
dispersions with dextran or PVP by measuring the water-
vapour-induced crystallisation of trehalose [14]. Recently,
Mahieu et al. developed a new protocol to determine the drug
solubility in polymeric matrices, based on the idea that the
equilibrium-saturated state is reached faster by demixing of
supersaturated solid solutions compared to dissolution of
crystalline drugs, as measured by melting point depression
studies [15,16]. The equilibrium solubility was thus determined
by following the precipitation of indometacin (IMC) from a
PVP matrix when annealed above the glass transition tempera-
ture (Tg). A theoretical frame regarding the thermodynamic
basis of phase separation as a result of supersaturation in solid
dispersions has been proposed [17]. Solid dispersions of felodi-
pine and nifedipine with PVP were miscible over the whole
 Refining stability and dissolution rate of amorphous drug formulations
composition range. However, based on the Flory-Huggins
(FH) lattice theory, the predicted solid solubility value for
nifedipine was < 10% w/w. Based on these findings, the authors
hypothesised that for most miscible drug -- polymer glass solu-
tions, physical stabilisation will play a large role. Similar differ-
ences between calculated solid state solubility and practical
values were reported for naproxen-PVP and itraconazole-
eudragit E100 systems [18,19]. The increasing interest in the
FH-based model witnessed through recent literature is encour-
aging, although the focus remains on the modification of the
classical analytical expressions [20-22]. Quantitative thermody-
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
namic values of the strength of specific interactions such as
hydrogen bonding and the degree to which they influence ther-
modynamic properties still remain unaccounted in these misci-
bility models for interacting systems. The use of other modified
forms of the FH model that account for specific interactions
between mixing components might be advisable. One ubiqui-
tously used methodology in polymer chemistry for the study
of miscibility behaviour of hydrogen bonding blends is the
Painter and Coleman association model [23]. For the expression
of DGmix, this model includes a specific term of Gibbs free
energy change due to hydrogen bonding in addition to the
combinatorial entropy and enthalpy of mixing. Its magnitude
depends on the relative strength of self-associating to inter-
For personal use only.
associating hydrogen bonding and the density of specific
interacting sites. Another useful, yet unexploited, model in
pharmaceutical sciences is the Wertheim thermodynamic
perturbation theory, which accounts for directional hydrogen
bonding interactions [24].
As glass solutions are often supersaturated, kinetic stabilisa-
tion plays an important role and the manufacturing process
will significantly contribute to the degree of supersaturation.
The two most applied manufacturing methods for solid disper-
sions in pharmaceutical industry are spray drying and hot-melt
extrusion. The former process starts from a solution of API and
carrier in a common organic solvent or mixture of solvents,
which is subsequently atomised using a nozzle and quickly
evaporated to obtain a powder. The very fast solvent evapora-
tion contributes to the amorphous state of the formed solid
dispersion. Janssens et al. reported the importance of fast
solvent evaporation for miscibility. Solid dispersions made up
of itraconazole and Eudragit E100
were better mixed follow-
ing spray drying compared to a film-casting process with a low
rate of solvent evaporation [18]. Recent findings also indicate
the importance of solvent characteristics in determining the
properties of the resulting solid dispersions [25,26]. Alternatively,
solid dispersions can be prepared by spraying a drug--polymer
solution onto inert beads. A layer of solid dispersion is thus
formed following evaporation of the organic solvent [27]. The
commercial form of itraconazole (Sporanox
) is an example
of this process. Spray congealing where a melt is transformed
into solid spherical particles by spraying the melt into a cooling
chamber is a solvent-free variant of spray drying [28]. Hot-melt
extrusion is a scalable and industrially applicable technology
originating from the polymer industry [29]. In the most
Expert Opin. Drug Deliv. (2014) 11(6)
common setup, a powder blend is introduced via a hopper
into a heated barrel with a rotating screw, where the powder
blend is intensively mixed in the liquid state and moved
towards a die that shapes the melt as strands, films, pellets or
tablets. The amount of heat and shear forces applied, as well
as the rate of cooling when the extrudate leaves the die,
contributes to the physical structure of the solid dispersion.
A relatively new pharmaceutical processing technology is the
KinetiSol Dispersing technology, which is a high-energy mix-
ing process for the production of amorphous pharmaceutical
solids [30]. This technology utilises a series of rapidly rotating
blades to process the drug and polymeric carrier through a
combination of kinetic and thermal energy without external
heating sources. The mild conditions at which carbon dioxide
can exist as a supercritical fluid (31.06 C at 73.8 bar)
prompted researchers to exploit this material as processing
aid during manufacturing. Solid dispersions of furosemide
and carbamazepine (CBZ) were prepared using supercritical
carbon dioxide as antisolvent [31,32]. Verreck et al. studied the
possibility to apply supercritical and subcritical carbon dioxide
as a temporary plasticiser during hot-melt extrusion [33,34].
3. Physical separation
Another strategy to improve the physical stability of the amor-
phous form of a drug is to separate the amorphous drug in
microcontainers and thereby restrict the crystal growth of
the drug to the diameter of the microcontainer. Microcon-
tainers are small polymeric devices consisting of a flat base
surrounded by a walled reservoir and were fabricated in three
different sizes of 73, 174 and 223 m in inner diameter [35,36].
Amorphous IMC was prepared in the three different sizes of
microcontainers by melting g-IMC in an oven, followed by
quench-cooling. The samples were stored at 30 C and 23%
RH for up to 30 days. Raman microscopy was used to observe
if each microcontainer contained amorphous or crystalline
IMC over time, and numeric crystallisation was obtained
and compared with the crystallisation rate of amorphous
bulk IMC [35].
The onset of crystallisation for the amorphous bulk IMC to
the crystalline form occurred rapidly, and around 51%
converted within 30 days of storage (Figure 1). Improvement
in stability was seen when confining amorphous IMC in the
microcontainers, but different levels of crystallinity between
the two larger sized microcontainers were observed. After
day 30, the numeric crystallisation was found to be 29 and
38% in the 174 m and 223 m microcontainers, respec-
tively. In the 73 m microcontainers, no stability improve-
ment was observed as no remaining amorphous IMC was
found after 15 days of storage. This unexpected behaviour
may be due to the material used to fabricate the microcon-
tainers (SU-8), as it is known to absorb moisture or capillary
condensation in the small microcontainers [35].
The confined amorphous IMC contains cracks in the
surface, and these cracks were proposed to be nucleation sites
979
 H. Grohganz et al.
60
Crystalline indomethacin (%)
40
20
0
Preparation conditions
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
Figure 1. Numeric crystallisation for amorphous bulk IMC and amorphous IMC confined in 223 mm microcontainers prepared
either by melting the IMC in an oven and cooling with liquid nitrogen or melting on a heating plate and cooling either at a
rate of 36, 23 or 14 K/min. The samples were stored at 22 C and 33% RH for 30 days and are an average of three replicates.
for crystal growth. Therefore, it was investigated if the prepa-
ration conditions of the amorphous IMC could have an effect
on the physical stability. The largest microcontainers were
filled with g-IMC, melted on a heating plate and cooled
with either liquid nitrogen (36 K/min), ice (23 K/min) or at
room temperature (14 K/min). Quench-cooling led to a
significant risk of surface cracking, while cooling the melt of
For personal use only.
IMC at 14 K/min resulted in a smooth surface without any
cracks. The physical stability of the microcontainer-confined
amorphous IMC was again investigated using Raman micros-
copy. The fastest cooled IMC (36 K/min) had a crystallisation
number of about 31% after 30 days of storage, whereas the
melt of IMC cooled at 23 K/min and 14 K/min had numeric
crystallisation of around 21 and 10% after 30 days of storage,
respectively (Figure 1), indicating that the more gentle cooling
conditions reduced the likelihood of crystallisation [36]. It was
concluded that microcontainers can be utilised for stabilising
amorphous IMC and that the preparation conditions affect
the physical stability of amorphous IMC.
Besides restricting the surface by confinement in physical
containers, also the surface of a particle in itself has to be
considered. The particle surface separates the particle from
its environment and has considerably different properties
compared with the bulk material. Surface properties have
often been neglected as their contribution to the overall prop-
erties of a material is relatively small [37]. However, molecules
situated at the surface have a higher molecular mobility than
the bulk molecules [38,39] and surface crystallisation of amor-
phous material is thought to be a consequence thereof. Ana-
lytically, surface crystallisation may result in different
quantitative crystallinity values, depending on the analytical
technique used (i.e., if the analytical method has a surface
bias or not). Most importantly, surface crystallisation was
found to reduce the dissolution behaviour of amorphous
IMC in such a way that the amount of dissolved drug was
the same as the crystalline form [40]. However, a change in
dissolution behaviour is not always observed. Hot-melt
extrudates of guaifenesin with either Eudragit L100-55
or
980
Amorphous bulk indomethacin
Oven/N2
Heating plate/N2 (cooling rate: 36 K/min)
Heating plate/ice (cooling rate: 23 K/min)
Heating plate/room temperature (cooling rate: 14 K/min)
Acryl-EZE
started to recrystallise at the surface shortly after
preparation [41]. Nevertheless, as the crystalline and the amor-
phous form of the drug are highly soluble, the dissolution
behaviour of the extrudates was not affected by the solid state
change.
Due to the importance of surface crystallisation, approaches
were undertaken to prevent or inhibit surface crystallisation.
Amorphous IMC, griseofulvin and nifedipine were coated
with a thin gold layer, and all drugs exhibited reduced surface
crystallisation [42-44]. A pharmaceutically more relevant formu-
lation was investigated using physical mixtures of amorphous
IMC and either Eudragit
E or Soluplus particles [45]. IMC
crystallisation was slowed down by the addition of Eudragit
E but not by Soluplus particles. Scanning electron microscopy
revealed surface coverage of IMC by Eudragit E particles
(Figure 2). In contrast, a simple mixture formed when combin-
ing amorphous IMC particles with Soluplus particles. Reduced
molecular mobility through surface coverage and mechanical
hindrance of outwards growing crystallites are thought to
slow down surface crystallisation [46]. The surface crystallisation
of the above-mentioned hot-melt extrudates of guaifenesin
could be slowed down after they were coated with Aquacoat

ECD but not when Opadry
was used as coating agent [47].
The latter polymer has a lower solubilisation potential for the
drug and additionally requires a higher curing temperature,
hence molecular mobility of drug molecules increased and
led to crystallisation.
Recently, different stabilisation approaches for amorphous
spin-coated films were compared to each other, namely a glass
solution film, a drug film coated with a polymer film and a
drug film on top of a polymer film [48]. The study was
performed using CBZ, felodipine, fenofibrate and celecoxib
as model drugs and PVP K30, Eudragit E PO and Soluplus
as polymers. In glass solutions, drug molecules are immobi-
lised by the polymer chains, the Tg is raised and molecular
interactions between drug and polymer may be established.
Surface coverage reduces surface molecular mobility, and the
drug film or particle is separated from its environment. Under
Expert Opin. Drug Deliv. (2014) 11(6)
 Refining stability and dissolution rate of amorphous drug formulations
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
Figure 2. Scanning electron microscopy picture of indome-
tacin with surface coverage by Eudragit E
.
high humidity conditions, the polymer-coated drug films
were physically more stable than the glass solution films and
the drug film on polymer-coated substrate. Hence the reduced
surface crystallisation and the protection from humidity were
For personal use only.
more effective in stabilising the amorphous nature of the drug
at high humidity. However, this order might change if the
study was performed at lower humidity, where plasticisation
of the glass solution and potential phase separation are less
prominent, as previously reported for some glass solutions [49].
The use of mesoporous inorganic materials (porous silicon,
silica, Al2O3, TiO2, carbon and hydroxycarbonate apatite) is
another relatively new approach to overcome poor drug solu-
bility via amorphisation and physical separation [50-52]. Incor-
poration of a drug into mesoporous materials for example, by
solvent deposition [52,53], mechanical activation (co-grinding
or milling) [54] or vapour-phase-mediated mass transfer [55]
may lead to loss of the crystalline structure of the adsorbed
drug molecules. Nucleation and crystal growth of the drug in
the pores are hindered by spatial constraints as long as the
pores are smaller than the critical nucleus of the drug, which
makes the nucleus growth energetically unfavourable [50-52].
In small pores (< 10 nm wide), drugs have been observed to
be in the amorphous state [53,56]. In case the pore and the
drug cluster in the pore are larger than the critical nucleus,
crystallisation may occur but it can still be prevented by kinetic
factors if the rate of nucleation is low [50]. However, if the drug
clusters within the material are physically separated from each
other (i.e., in non-interconnected pores), nucleation takes place
independently within each pore. Thus, in order to a significant
amount of loaded drug to crystallise, a high nucleation rate is
required. Due to this stabilising mechanism, several drug-
loaded mesoporous systems have been observed to be
physically stable under accelerated storage conditions [54,57,58].
For example, amorphous IMC-pSi-ox (thermally oxidised
porous silicon) systems (pSi-ox) were observed to be stable
Expert Opin. Drug Deliv. (2014) 11(6)
for more than 6 months when stored at 40 C/75% RH,
whereas amorphous IMC alone recrystallised after 1 month [57].
In addition, the pSi carrier facilitated immediate release of IMC
and enhanced oral delivery performance in in vivo absorption
study. A 200% Cmax was reached four times faster (i.e., shorter
Tmax), and a significant increase in bioavailability were observed
compared to crystalline IMC and a commercially available
formulation.
4. Co-amorphous formulations
The increasing need to improve the dissolution properties of
poorly water-soluble drugs and the interest in combining drugs
for more efficient medication have led to the development of
co-amorphous drug--drug formulations. This novel formula-
tion approach offers the opportunity not only to enhance
bioavailability of BCS class 2 drugs but also to prepare formu-
lations intended for combination therapy. Moreover, reduc-
tion in the size of the dosage form compared to the
traditional drug--polymer glass solutions, where generally large
polymer amounts are used, can be regarded as an additional
advantage.
The concept of co-amorphous formulations was intro-
duced by Chieng et al. [59] to differentiate amorphous mixtures
of two low-molecular-weight components from amorphous
solid dispersions of a drug and a polymer. In the initial study,
the two drugs IMC and ranitidine HCl were combined with
the aim to enhance their complimentary pharmacological
effect. More specifically, by administering the histamine
H2-receptor antagonist ranitidine HCl in an amorphous com-
bination with NSAID IMC, the gastrointestinal side effects
associated with NSAIDs may be reduced. Since then, a similar
combination of a poorly soluble NSAID and an antihistaminic
drug (naproxen-cimetidine) [60] in addition to combinations of
two NSAIDs (naproxen-IMC) [61] and two drugs intended for
the treatment of metabolic disorders (simvastatin-glipizide) [62]
have been investigated.
The drug--drug combinations, generally processed by
melt-quenching or mechanical activation in molar ratios of
2:1, 1:1 and 1:2, formed single-phase amorphous systems, as
indicated by single, composition-dependent Tg. However,
in co-amorphous drug--drug systems the formulation with
the highest Tg did not usually turn out to be the most stable
mixture. Thus, an increase in Tg alone cannot explain the
principal stabilisation mechanism. Applying spectroscopic
methods, specific hydrogen-bonding or p--p interactions
between the two molecules were shown to lead to superior
stability of the 1:1 combinations. For example, the 1:1
co-amorphous mixtures of IMC-ranitidine HCl, naproxen-
cimetidine and naproxen-IMC remained physically stable,
whereas the two other blends (1:2 and 2:1) showed recrystal-
lisation of the excess component in the stability studies [59-61].
The intermolecular interactions were also shown to be an
important dissolution-enhancing factor in co-amorphous
mixtures. Not only was the dissolution rate increased above
981
 H. Grohganz et al.
the individual crystalline and amorphous drugs, but it was
also synchronised for the two components [60,61]. In the case
of naproxen-IMC, intermolecular hydrogen bonding was
observed to result in the formation of an energetically stable
heterodimer between naproxen and IMC [63]. In order for
recrystallisation to occur, the hydrogen bonds within the het-
erodimer first need to be broken. Subsequently, the molecules
need to rearrange themselves and establish interactions
between like molecules in order to recrystallise as homo-
dimers. This cascade is assumed to reduce the likelihood of
re-crystallisation.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
The formation of intermolecular hydrogen bonds is, how-
ever, not a strict prerequisite for an increase in stability. It
has been shown that molecular-level mixing may be sufficient
to obtain an enhanced stability of co-amorphous mixtures [62].
Single-phase mixtures of simvastatin and glipizide showed
increased physical stability compared with physical mixtures
of the corresponding amorphous drugs, even though no inter-
molecular interactions were observed in the co-amorphous
mixtures. However, the lack of specific interactions was
reflected in the fact that the dissolution rate did not improve
compared with the individual amorphous drugs.
It can be concluded that the strength of the co-amorphous
drug--drug systems lies in their ability to offer stabilisation of
For personal use only.
the amorphous forms at a lower bulk volume compared to
amorphous polymer dispersions and a potential for synchron-
ised release of the two APIs. However, this approach should
not be limited to combinations of two APIs, as this would
be limited by pharmacologically meaningful combinations.
Accordingly, inactive low-molecular-weight excipients were
combined with a poorly soluble drug, thus expanding the
co-amorphous concept. From the studies above, it became
apparent that the investigated excipients should ideally result
in directed molecular interactions, molecular level mixing
and if possible, an increase of the drug Tg. Considering the
interaction of APIs with the active receptor site in the human
body, amino acids were chosen as a rational starting point.
In two studies by Lobmann et al. [64,65], the amino acids
arginine, phenylalanine (PHE), tryptophan and tyrosine
were investigated towards their suitability as co-amorphous
formation agent, stabiliser and dissolution enhancer in combi-
nation with APIs CBZ and IMC. The authors were able to
prepare several different co-amorphous mixtures with one or
two amino acids at the molar ratios 1:1 or 1:1:1. From the
preparative ball milling studies, 8 of 16 investigated mixtures
formed a single, co-amorphous phase. It became apparent that
the four investigated amino acids were not equally suitable to
induce the formation of co-amorphous mixtures with the
drugs. In this context, tryptophan showed very good amorph-
isation properties, arginine and PHE showed intermediate
amorphisation properties for co-amorphous systems, whereas
tyrosine was unable to form any co-amorphous phase in any
of the investigated mixtures with the drugs.
During further investigations, most of the successfully
prepared co-amorphous drug amino-acids mixtures fulfilled
982 Expert Opin. Drug Deliv. (2014) 11(6)
the initially requested demands. First, the prepared blends
were homogeneous, molecular-level mixtures. Second, specific
molecular interactions between the drug and the amino acids
could be identified, both hydrogen bonds and p--p interactions.
Third, all co-amorphous blends had an increased Tg compared
to the pure drugs Tg. In addition, several drug--amino acid
combinations had Tg values in the range of 70 -- 80 C, which
is in the generally desired range for Tg in amorphous formula-
tions, assuming storage conditions at room temperature (Tg
minus 50 K rule) [66]. Because of these findings, it was not
surprising that seven out of the eight co-amorphous mixtures
remained physically stable over at least 1 year at room tempera-
ture and at 40 C, under dry storage conditions (Figure 3) [67]. By
contrast, the pure amorphous drugs, CBZ and IMC, showed
recrystallisation within 1 week at both storage conditions. The
only co-amorphous blend that did not remain amorphous
over a period of 1 year at both storage conditions was IMC-
PHE. This blend showed recrystallisation of both IMC and
PHE after a period of 6 months at 40 C. This mixture had
the lowest Tg of all investigated blends and in addition, did
not show any signs of molecular interactions. This supports
the idea of a stabilising interplay of molecular level mixing,
molecular interactions and increased Tg. Finally, the co-
amorphous drug amino-acid mixtures were tested towards their
intrinsic dissolution rate (IDR) in phosphate buffer (pH 7.2).
All formulations had an increased IDR compared with the
pure crystalline and amorphous drugs.
In addition to amino acids as low-molecular-weight stabil-
isers for the amorphous drug, there is a growing interest of
using other low-molecular excipients to stabilise drugs in the
amorphous form. These include weak carboxylic acids, such
as citric acid [68] and tartaric acid [69], weak bases, such as
meglumine [70], saccharin [71], phospholipids [72], sugars,
urea and nicotinamide [73]. The stabilisation mechanism of
these co-amorphous formulations was again attributed mainly
to molecular or ionic interactions (salt formation) between the
drug and excipient in the blend, but also an increase in drug
Tg in some cases. In a particular co-amorphous mixture, a
co-precipitated blend of acyclovir and citric acid at a molar
ratio of 1:2 offered in addition to the amorphous stabilisation
also an increased improvement of skin permeation flux com-
pared with crystalline acyclovir [74]. In another study, even
at storage conditions above the Tg, the co-amorphous blend
containing paracetamol and citric acid showed high physical
stability for at least 2 years due to the strong intermolecular
interactions [75].
Overall, co-amorphous formulations proved to be a
promising new approach and alternative to polymer solid dis-
persion and the future will show if this new and promising
approach can live up to its expectations.
5. Recent trends
In the previous section, it was shown that molecular interac-
tions by for example, hydrogen bonds or p--p interactions
 Refining stability and dissolution rate of amorphous drug formulations
CBZqc
CBZ-TRP
CBZ-PHE-TRP
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
Intensity
CBZ-ARG-TRP
IMC-PHE-TRP
IMC-ARG-PHE
IMC-ARG
IMC-TRP
5.7 PHE
IMC-PHE
IMC
For personal use only.
5 10 15 20 25 30 35
Angle/2q ()
Figure 3. XRPD diffractograms of co-amorphous drug
amino-acid mixtures and the respective pure drugs carba-
mazepine (CBZ) and IMC stored over a period of 1 year at
40 C/dry conditions. The diffractogram shown for co-
amorphous IMC-phenylalanine (PHE) was collected after a
storage period of 6 months and indicates recrystallisation of
both, IMC and PHE. The diffractograms of the pure
amorphous drugs, IMC and CBZqc (quench-cooled), were
collected after a storage time of 7 days and indicate the fast
recrystallisation of the individual drugs.
Adapted with permission from [67].
IMC: Indometacin.
contribute to an enhanced stability of an amorphous mixture.
If achievable, the formation of amorphous salts is another
option for molecular interaction. Spray drying is a well-
known method for converting drugs to their amorphous
form in a reproducible manner [76,77] and is a suitable method
for producing amorphous salts, which often show a higher
stability than their respective non-salts [78,79]. The selection
of solvent and spray-drying conditions (pressure, drying gas
and temperature) influences the stability of the formed
amorphous drug [79].
Amorphous sodium and potassium salts of the poorly
soluble drug chlorothiazide were prepared by spray drying
from both aqueous and organic solvent [77]. All chlorothiazide
salts were physically stable for at least 6 months when stored
at dry conditions at 25 C -- significantly longer than the
Expert Opin. Drug Deliv. (2014) 11(6)
non-salt amorphous form [80]. Poorly water-soluble sulfathia-
zole turned out to be amorphous after spray drying from an
ethanol/water solution, whereas pure ethanol resulted in crys-
talline sulfathiazole, showing the influence of the solvent [79].
Furthermore, sulfathiazole sodium salts were produced using
various solvents (both aqueous and organic) and no crystalli-
sation was observed over a period of 12 months when stored
at dry conditions at 4 C. The salts were not stable at ambient
conditions (18 -- 22 C and 40 -- 80% RH), and the non-salt
forms of amorphous sulfathiazole started to crystallise already
after 1 h regardless of the storage conditions [79]. The stability
was improved significantly by co-spray drying solutions of
sulfathiazole and sulfathiazole sodium. The optimal ratio
between the acid and salt was found to be 1:1, which led to
at least 6 months stability at ambient conditions, but even
small amounts of salt increased the stability significantly [81].
The varying oral bioavailability of the BCS class 4 drug furo-
semide is closely related to its dissolution rate [82,83]. It was
possible to produce amorphous furosemide sodium salt and
amorphous furosemide acid by spray drying [84]. The amor-
phous salt had a Tg 39 C higher than the amorphous
acid [84]. The amorphous salt showed promising in vitro
characteristics in terms of higher solubility and dissolution
rate in physiologically relevant media and a significantly faster
Tmax (oral dosing to rats) compared with amorphous and
crystalline furosemide acid. Importantly, the amorphous salt
was stable for 291 days at 22 C and 33% RH, whereas the
amorphous furosemide acid was only stable for 4 days at the
same conditions (Figure 4) [84]. At high humidity and during
dissolution, the amorphous furosemide salt converted quickly
to a trihydrate [85]. Spray drying furosemide together with
HPMC stabilised the amorphous furosemide sodium salt
during dissolution at pH 6.5 [86].
A very recent approach to address low storage stability of
amorphous formulations is the formation of an amorphous
form in situ. This was realised during intrinsic dissolution
testing for crystalline g-IMC in the presence of Eudragit
E [87]. In situ amorphisation was observed when drug polymer
compacts were immersed in a buffer of a pH value at which
the drug, but not the polymer, can dissolve, in this case at
pH 6.8. Compacts changed colour from white to yellow,
indicating amorphisation of IMC. DSC thermograms showed
a single Tg comparable to the glass solution of the same com-
position. In the scores plot of a principal component analysis
of FT-ATR-IR spectra, in situ amorphised samples clustered
together with a quench-cooled glass solution of the same
drug--polymer composition. In XRPD measurements, the
intensity of the reflections decreased considerably. Neverthe-
less, reflections did not disappear completely and scanning
electron microscopy was able to depict a few remaining
crystallites in the cross-section of compacts after in situ
amorphisation.
The mechanism of in situ amorphisation is assumed to be
due to pH-dependent dissolution and ionisation behaviour.
The drug can partially dissolve, whereas the polymer is
983
 H. Grohganz et al.
Amorphous salt,
291 days storage
Amorphous salt,
4 days storage
Intensity (a.u.)
Amorphous acid,
4 days storage
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
Crystallline acid
10
Figure 4. XRPD diffractogram of amorphous furosemide salt and acid after storage at 22 C and 33% RH. For comparison the
diffractogram for crystalline furosemide is also shown.
plasticised by the water and swells, enabling molecular mixing
to some extent. At a drug--polymer ratio of 3:1 and 1:1, the
For personal use only.
compacts swelled and were yellow throughout the whole
cross-section. However, the 1:3 ratio compact did not swell
to the same extent and amorphisation took place only on
the surface, probably due to restricted penetration depth of
buffer into the compact once the polymer has swollen. At
pH 6.8, amorphisation did not improve dissolution behaviour
compared to a physical mixture. Dissolution advantages
became obvious at pH values at which the polymer dissolves.
The 3:1 and 1:1 in situ samples out-performed the physical
drug--polymer mixtures as well as a quench-cooled glass solu-
tion. By contrast, at the 1:3 ratio, where only the surface was
converted in situ, the glass solution was superior.
The dissolution behaviour of amorphous formulations has
been extensively studied. The preparation technique used for
conversion into the amorphous form has been found to influ-
ence the dissolution rate of amorphous drugs such as IMC [88]
as well as glass solutions [89,90]. Due to their high-energy form
and increased dissolution rate, amorphous formulations will
create supersaturation upon dissolution.
However, supersaturation is thermodynamically unstable
and will usually lead to precipitation. Therefore, different
approaches to maintain supersaturation and inhibit precipita-
tion have been investigated. By creating supersaturation in a
slow manner, the maximum concentration of drug was lower
and was reached later. Nevertheless, the AUC in a concentra-
tion versus time profile was larger compared with fast creation
of supersaturation. This finding held true for drugs and for
drug polymer glass solutions [91]. As already mentioned in
Section 2, the polymer used for glass solution systems affects
the dissolution rate and may inhibit precipitation. In order
to find the most potent precipitation inhibitor for a drug,
984
20 30
Angle/2q ()
different materials were screened for their precipitation
inhibition of nine drugs in a model fasted duodenal fluid [12].
Other groups used principal component analysis to gain
understanding about the effect of molecular properties of
the polymers on drug precipitation behaviour [92] or screening
combined with dissolution, interaction and imaging assays
with a strong focus on development of successful glass
solution formulations [93]. All these studies are important to
understand and optimise amorphous formulations with
regard to their supersaturation and precipitation behaviour.
However, in a study where absorption was studied using
CaCo cells, the effect of the precipitation inhibitor HPMC
was found to be lower than estimated from studies in a non-
absorptive environment [94]. Similarly, studies performed in
dogs [95] and humans [96] that precipitation in vivo might be
overestimated from in vitro studies.
6. Conclusion
The transformation of drugs to an amorphous form is one of
the key techniques to address the problem of low solubility of
APIs. Several techniques are available to pharmaceutical scien-
tists, with polymer-based solid dispersions being the most
investigated system. Here, the miscibility of the API with
the polymer is of importance and theoretical approaches can
assist in the choice of the right polymer. New developments
are the application of physical separation by micro-containers
and surface coverage, which have been shown to reduce
crystallisation or crystal growth. Exchanging polymers by
small-molecular-weight substances led to the development of
co-amorphous systems. Initially intended for combination
therapy with two drug molecules, the concept has now been
generalised by using amino acids as excipients. Finally, the
Expert Opin. Drug Deliv. (2014) 11(6)
 Refining stability and dissolution rate of amorphous drug formulations
use of a crystalline system that undergoes in situ amorphisa-
tion close to application may circumvent the low stability of
amorphous formulations. It can be summarised that prepara-
tion and stabilisation approaches for amorphous systems
will play a major role in pharmaceutical sciences also in the
future, in order to address the growing challenge of poorly
water-soluble APIs.
7. Expert opinion
Over the last decades, formulation of poorly water-soluble
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
drugs as amorphous systems, especially by using polymers as
excipients, has made tremendous progress and several amor-
phous drug formulations have successfully entered the market.
This progress was based on a better understanding of the
nature of the amorphous form and the development of pre-
parative techniques that are scalable in the pharmaceutical
industrial context. However, still the number of amorphous
drug formulations on the market is small, especially when
considering the large number of poorly water-soluble drugs
coming out of the drug discovery process and many challenges
still remain to be addressed before amorphous drug formula-
tions can be routinely used in the development of medicines.
This review has shown that alternative or additional
For personal use only.
approaches to using drug polymer glass solutions merit fur-
ther investigation. Coating of amorphous forms, including
coating of glass solutions, may increase the stability of the
drug against crystallisation, by reducing surface mobility and
preventing or reducing water absorption into the amorphous
formulation during storage. But just how to coat amorphous
formulations in a reliable and scalable process requires further
research. Also, the segmentation of amorphous formulations
into small, independent units can further stabilise the formu-
lation, or at least slow down the crystallisation rate and extent.
In this context, the question of how much crystalline drug in
an overall amorphous dosage form can be tolerated without
compromising the bioavailability of the formulation needs
to be further investigated. This can be facilitated by the use
of physiologically relevant in vitro dissolution studies and ani-
mal studies of amorphous dosage forms. Furthermore, the use
of analytical techniques that can clearly separate the total
amount of crystallinity from the spatial distribution of the
crystalline and amorphous material is highly desirable and
requires the use of several orthogonal analytical techniques,
including the use of imaging techniques.
Salt formation is usually the initial step in improving the
dissolution properties of a drug and thus, rarely investigated
for amorphous systems. However, the formation of an amor-
phous salt, for example between a basic amino acid and a
poorly soluble acidic drug, might even further improve the
dissolution rate in comparison to a crystalline salt. Prelimi-
nary studies in our group indicate that such co-amorphous
salts can remain amorphous, even in a slow evaporation
process, and thus might be unable to crystallise.
Expert Opin. Drug Deliv. (2014) 11(6)
Another area of great practical importance in the develop-
ment of amorphous formulations is the lack of reliable and
reproducible stress tests with respect to their physical and
chemical stability. With the amorphous form being inherently
non-Arrhenius in its behaviour, the prediction of physical
stability remains a challenge. In this context, the fast and
reliable determination of the thermodynamic solubility of a
drug in a polymer remains challenging, despite recent
advancements in this field. Also, the influence of small
amounts of moisture on the solubility of the drug in a given
polymer needs to be determined in a more predictable way.
An intriguing development is the use of drug formulations
that only convert to an amorphous form immediately before
administration or even in the gastrointestinal tract. This
work is only at its very beginning, but recently it has been
found that precipitation of the drug during lipolysis of
lipid-based drug delivery systems may occur in an amorphous
form during biorelevant in vitro dissolution tests [97]. In this
form, precipitation of the drug may not constitute a formula-
tion problem, but may still lead to a high bioavailability due
to the amorphous nature of the precipitate and thus a fast
re-dissolution that could be expected at the absorptive sites
in the small intestine. In fact, initial in vivo investigations
appear to support this conclusion [98,99].
Several options were shown to be available for the solubility
improvement of poorly water-soluble drugs and for the stabi-
lisation of amorphous systems. It can be expected that the
trend of developing new approaches will continue and that
several new techniques will emerge in the not too distant
future. Considering the increasing diversity of poorly soluble
APIs, these different approaches will also be necessary for
optimal performance of the formulation. What still remains
to be achieved is the establishment of a rational choice for
the optimal amorphous system. The miscibility of the drug
with a polymer, the solubility in various solvents, the possibil-
ity for molecular interactions with various excipients, the ten-
dency for surface crystallisation, the melting temperature and
thus the available production processes are just some examples
for variables that all influence the applicable processes and the
final quality of the amorphous formulation. However, so far a
comprehensive understanding of the interactions between all
these variables is far from being achieved but this will be
necessary in order to establish a rational basis for the optimal
choice of an amorphous formulation.
Declaration of interest
The authors have no relevant affiliations or financial involve-
ment with any organisation or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
985
 H. Grohganz et al.
Bibliography
Papers of special note have been highlighted as
either of interest () or of considerable interest
() to readers.
1. Amidon GL, Lennernas H, Shah VP,
et al. A theoretical basis for a
biopharmaceutic drug classification - the
correlation of in-vitro drug product
dissolution and in-vivo bioavailability.
Pharm Res 1995;12(3):413-20
2. Nair AK, Anand O, Chun N, et al.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
Statistics on BCS classification of generic
drug products approved between
2000 and 2011 in the USA. AAPS J
2012;14(4):664-6
3. Babu NJ, Nangia A. Solubility advantage
of amorphous drugs and pharmaceutical
cocrystals. Cryst Growth Des
2011;11(7):2662-79
4. Martinez MN, Amidon GL.
A mechanistic approach to understanding
the factors affecting drug absorption:
a review of fundamentals.
J Clin Pharmacol 2002;42(6):620-43
5. Hancock BC, Zografi G. Characteristics
For personal use only.
and significance of the amorphous state
in pharmaceutical systems. J Pharm Sci
1997;86(1):1-12
6. Hancock B, Parks M. What is the true
solubility advantage for amorphous
pharmaceuticals? Pharm Res
2000;17(4):397-404
7. Aaltonen J, Rades T. Commentary:
towards physicorelevant dissolution
testing: the importance of solid-state
analysis in dissolution.
Dissolution Technol 2009;16:47-54
8. Grohganz H, Lobmann K, Priemel PA,
et al. Amorphous drugs and dosage
forms. J Drug Deliv Sci Tec
2013;23(4):403-8
9. Chiou WL, Riegelman S. Pharmaceutical
applications of solid dispersion systems.
J Pharm Sci 1971;60(9):1281-302
10. Alam MA, Ali R, Al-Jenoobi FI, et al.
Solid dispersions: a strategy for poorly
aqueous soluble drugs and technology
updates. Expert Opin Drug Deliv
2012;9(11):1419-40
.. Recent review with relevant
information, concerning materials,
methods of preparation and many
examples. A good review to start
learning this topic.
11. Curatolo W, Nightingale JA,
Herbig SM. Utility of
986
hydroxypropylmethylcellulose acetate
succinate (HPMCAS) for initiation and
maintenance of drug supersaturation in
the GI milieu. Pharm Res
2009;26(6):1419-31
12. Janssens S, Van den Mooter G. Review:
physical chemistry of solid dispersions.
J Pharm Pharmacol
2009;61(12):1571-86
13. Linn M, Collnot EM, Djuric D, et al.
Soluplus (R) as an effective absorption
enhancer of poorly soluble drugs in vitro
and in vivo. Eur J Pharm Sci
2012;45(3):336-43
14. Vasanthavada M, Tong WQ, Joshi Y,
et al. Phase behavior of amorphous
molecular dispersions I: determination of
the degree and mechanism of solid
solubility. Pharm Res
2004;21(9):1598-606
15. Mahieu A, Willart JF, Dudognon E,
et al. A new protocol to determine the
solubility of drugs into polymer matrices.
Mol Pharm 2013;10(2):560-6
16. Sun Y, Tao J, Zhang GGZ, et al.
Solubilities of crystalline drugs in
polymers: an improved analytical method
and comparison of solubilities of
indomethacin and nifedipine in PVP,
PVP/VA, and PVAc. J Pharm Sci
2010;99(9):4023-31
17. Marsac PJ, Shamblin SL, Taylor LS.
Theoretical and practical approaches for
prediction of drug-polymer miscibility
and solubility. Pharm Res
2006;23(10):2417-26
18. Janssens S, De Zeure A, Paudel A, et al.
Influence of preparation methods on
solid state supersaturation of amorphous
solid dispersions: a case study with
itraconazole and eudragit E100.
Pharm Res 2010;27(5):775-85
19. Paudel A, Van Humbeeck J,
Van den Mooter G. Theoretical and
experimental investigation on the solid
solubility and miscibility of naproxen in
poly(vinylpyrrolidone). Mol Pharm
2010;7(4):1133-48
. Different methods of calculation of the
drug--polymer solubility are compared
and discussed.
20. Bellantone RA, Patel P, Sandhu H, et al.
A method to predict the equilibrium
solubility of drugs in solid polymers near
room temperature using thermal analysis.
J Pharm Sci 2012;101(12):4549-58
Expert Opin. Drug Deliv. (2014) 11(6)
21. Huang JJ, Li Y, Wigent RJ, et al.
Interplay of formulation and process
methodology on the extent of nifedipine
molecular dispersion in polymers.
Int J Pharm 2011;420(1):59-67
22. Tian YW, Booth J, Meehan E, et al.
Construction of drug-polymer
thermodynamic phase diagrams using
Flory-Huggins interaction theory:
identifying the relevance of temperature
and drug weight fraction to phase
separation within solid dispersions.
Mol Pharm 2013;10(1):236-48
23. Painter PC, Graf JF, Coleman MM.
Effect of hydrogen-bonding on the
enthalpy of mixing and the composition
dependence of the glass-transition
temperature in polymer blends.
Macromolecules 1991;24(20):5630-8
24. Wertheim MS. Fluids with highly
directional attractive forces. 1. Statistical
thermodynamics. J Stat Phys
1984;35(1-2):19-34
25. Al-Obaidi H, Brocchini S, Buckton G.
Anomalous properties of spray dried
solid dispersions. J Pharm Sci
2009;98(12):4724-37
26. Paudel A, Van den Mooter G. Influence
of solvent composition on the miscibility
and physical stability of naproxen/PVP K
25 solid dispersions prepared by
cosolvent spray-drying. Pharm Res
2012;29(1):251-70
27. Kolasinac N, Kachrimanis K, Djuris J,
et al. Spray coating as a powerful
technique in preparation of solid
dispersions with enhanced desloratadine
dissolution rate. Drug Dev Ind Pharm
2013;39(7):1020-7
28. Passerini N, Perissutti B, Moneghini M,
et al. Characterization of carbamazepine-
gelucire 50/13 microparticles prepared by
a spray-congealing process using
ultrasounds. J Pharm Sci
2002;91(3):699-707
29. Breitenbach J. Melt extrusion: from
process to drug delivery technology.
Eur J Pharm Biopharm
2002;54(2):107-17
30. DiNunzio JC, Brough C, Miller DA,
et al. Fusion processing of itraconazole
solid dispersions by kinetisol (R)
dispersing: a comparative study to hot
melt extrusion. J Pharm Sci
2010;99(3):1239-53

31. De Zordi N, Moneghini M, Kikic I,
et al. Applications of supercritical fluids
to enhance the dissolution behaviors of
Furosemide by generation of
microparticles and solid dispersions.
Eur J Pharm Biopharm
2012;81(1):131-41
32. Moneghini M, Kikic I, Voinovich D,
et al. Processing of carbamazepine PEG
4000 solid dispersions with supercritical
carbon dioxide: preparation,
characterisation, and in vitro dissolution.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
Int J Pharm 2001;222(1):129-38
33. Verreck G, Decorte A, Heymans K, et al.
The effect of pressurized carbon dioxide
as a temporary plasticizer and foaming
agent on the hot stage extrusion process
and extrudate properties of solid
dispersions of itraconazole with PVP-VA
64. Eur J Pharm Sci
2005;26(3-4):349-58
34. Verreck G, Decorte A, Heymans K, et al.
Hot stage extrusion of p-amino salicylic
acid with EC using CO2 as a temporary
plasticizer. Int J Pharm
2006;327(1-2):45-50
For personal use only.
35. Nielsen LH, Keller SS, Gordon KC,
et al. Spatial confinement can lead to
increased stability of amorphous
indomethacin. Eur J Pharm Biopharm
2012;81(2):418-25
36. Nielsen LH, Keller SS, Boisen A, et al.
A slow cooling rate of indomethacin melt
spatially confined in microcontainers
increases the physical stability of the
amorphous drug without influencing its
biorelevant dissolution behaviour.
Drug Deliv Transl Res
2013;published online 14 August 2013;
doi: 10.1007/s13346-013-0166-7
37. Luth H. Solid surfaces, interfaces and
thin films. 5th edition. Heidelberg
Springer; New York: 2010
38. Sun Y, Zhu L, Wu T, et al. Stability of
amorphous pharmaceutical solids: crystal
growth mechanisms and effect of
polymer additives. AAPS J
2012;14(3):380-8
39. Weber R, Grotkopp I, Stettner J, et al.
Embedding of gold nanoclusters on
polystyrene surfaces: influence of the
surface modification on the glass
transition. Macromolecules
2003;36(24):9100-6
40. Priemel PA, Grohganz H, Gordon KC,
et al. The impact of surface- and nano-
crystallisation on the detected amorphous
content and the dissolution behaviour of
Refining stability and dissolution rate of amorphous drug formulations
amorphous indomethacin. Eur J
Pharm Biopharm 2012;82(1):187-93
41. Bruce C, Fegely KA,
Rajabi-Siahboomi AR, et al. Crystal
growth formation in melt extrudates.
Int J Pharm 2007;341(1-2):162-72
42. Wu T, Sun Y, Li N, et al. Inhibiting
surface crystallization of amorphous
indomethacin by nanocoating. Langmuir
2007;23(9):5148-53
. Article highlighting the importance of
coating on increasing stability of
amorphous particles.
43. Zhu L, Jona J, Nagapudi K, et al. Fast
surface crystallization of amorphous
griseofulvin below T g. Pharm Res
2010;27(8):1558-67
44. Zhu L, Wong L, Yu L. Surface-enhanced
crystallization of amorphous nifedipine.
Mol Pharm 2008;5(6):921-6
45. Priemel PA, Laitinen R, Barthold S,
et al. Inhibition of surface crystallisation
of amorphous indomethacin particles in
physical drug-polymer mixtures.
Int J Pharm 2013;456(2):301-6
46. Sun Y, Zhu L, Kearns KL, et al. Glasses
crystallize rapidly at free surfaces by
growing crystals upward. Proc Natl Acad
Sci USA 2011;108(15):5990-5
47. Bruce CD, Fegely KA,
Rajabi-Siahboomi AR, et al. Aqueous
film coating to reduce recrystallization of
guaifenesin from hot-melt extruded
acrylic matrices. Film coating improves
physical stability of melt extruded tablets.
Drug Dev Ind Pharm 2010;36(2):218-26
48. Ng YC, Yang Z, McAuley WJ, et al.
Stabilisation of amorphous drugs under
high humidity using pharmaceutical thin
films. Eur J Pharm Biopharm
2013;84(3):555-65
49. Rumondor ACF, Marsac PJ,
Stanford LA, et al. Phase behavior of
poly(vinylpyrrolidone) containing
amorphous solid dispersions in the
presence of moisture. Mol Pharm
2009;6(5):1492-505
50. Xu W, Riikonen J, Lehto V-P.
Mesoporous systems for poorly soluble
drugs. Int J Pharm 2013;453(1):181-97
51. Qian KK, Bogner RH. Application of
mesoporous silicon dioxide and silicate in
oral amorphous drug delivery systems.
J Pharm Sci 2012;101(2):444-63
52. Prestidge CA, Barnes TJ, Lau C-H, et al.
Mesoporous silicon: a platform for the
Expert Opin. Drug Deliv. (2014) 11(6)
delivery of therapeutics. Expert Opin
Drug Deliv 2007;4(2):101-10
53. Shen S-C, Ng WK, Chia L, et al.
Physical state and dissolution of
ibuprofen formulated by co-spray drying
with mesoporous silica: effect of pore
and particle size. Int J Pharm
2011;410(1 -- 2):188-95
54. Limnell T, Heikkila T, Santos HA, et al.
Physicochemical stability of high
indomethacin payload ordered
mesoporous silica MCM-41 and SBA-15
microparticles. Int J Pharm
2011;416(1):242-51
55. Qian KK, Suib SL, Bogner RH.
Spontaneous crystalline-to-amorphous
phase transformation of organic or
medicinal compounds in the presence of
porous media, part 2: amorphization
capacity and mechanisms of interaction.
J Pharm Sci 2011;100(11):4674-86
56. Mellaerts R, Jammaer JAG,
Van Speybroeck M, et al. Physical state
of poorly water soluble therapeutic
molecules loaded into SBA-15 ordered
mesoporous silica carriers: a case study
with itraconazole and ibuprofen.
Langmuir 2008;24(16):8651-9
57. Wang F, Hui H, Barnes TJ, et al.
Oxidized mesoporous silicon
microparticles for improved oral delivery
of poorly soluble drugs. Mol Pharm
2009;7(1):227-36
58. Ambrogi V, Perioli L, Pagano C, et al.
Use of SBA-15 for furosemide oral
delivery enhancement. Eur J Pharm Sci
2012;46(1 -- 2):43-8
59. Chieng N, Aaltonen J, Saville D, et al.
Physical characterization and stability of
amorphous indomethacin and ranitidine
hydrochloride binary systems prepared by
mechanical activation. Eur J
Pharm Biopharm 2009;71(1):47-54
60. Alleso M, Chieng N, Rehder S, et al.
Enhanced dissolution rate and
synchronized release of drugs in binary
systems through formulation: amorphous
naproxen-cimetidine mixtures prepared
by mechanical activation.
J Control Release 2009;136(1):45-53
.
Highlights possibilities of co-
amorphpous drug--drug combinations
to increase and synchronise the release.
61. Lobmann K, Laitinen R, Grohganz H,
et al. Coamorphous drug systems:
enhanced physical stability and
dissolution rate of indomethacin and
987
 H. Grohganz et al.
naproxen. Mol Pharm
2011;8(5):1919-28
62. Lobmann K, Strachan C, Grohganz H,
et al. Co-amorphous simvastatin and
glipizide combinations show improved
physical stability without evidence of
intermolecular interactions. Eur J
Pharm Biopharm 2012;81(1):159-69
63. Lobmann K, Laitinen R, Grohganz H,
et al. A theoretical and spectroscopic
study of co-amorphous naproxen and
indomethacin. Int J Pharm
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
2013;453(1):80-7
64. Lobmann K, Grohganz H, Laitinen R,
et al. Amino acids as co-amorphous
stabilizers for poorly water soluble drugs
-- Part 1: preparation, stability and
dissolution enhancement. Eur J
Pharm Biopharm 2013;85(3B):873-81
. First example of co-amorphous
drug--amino acid combinations.
65. Lobmann K, Laitinen R, Strachan C,
et al. Amino acids as co-amorphous
stabilizers for poorly water-soluble drugs
-- Part 2: molecular interactions. Eur J
Pharm Biopharm 2013;85(3B):882-8
For personal use only.
66. Yu L. Amorphous pharmaceutical solids:
preparation, characterization and
stabilization. Adv Drug Deliv Rev
2001;48(1):27-42
67. Lobmann K, Jensen K, Laitinen R, et al.
Formulating poorly water soluble drugs
into co-amorphous drug-amino acid
mixtures. In: Qu H, Rantanen J,
Malwade C, editors, BIWIC 2013: 20th
international workshop on industrial
crystallization. University of Southern
Denmark; Odense, Denmark:
2013. p. 31-7
68. Lu Q, Zografi G. Phase behavior of
binary and ternary amorphous mixtures
containing indomethacin, citric acid, and
PVP. Pharm Res 15(8):1202-6
69. Hu Y, Gniado K, Erxleben A, et al.
Mechanochemical reaction of
sulfathiazole with carboxylic acids:
formation of a cocrystal, a salt, and
coamorphous solids. Cryst Growth Des
2013;14(2):803-13
70. Telang C, Mujumdar S, Mathew M.
Improved physical stability of amorphous
state through acid base interactions.
J Pharm Sci 2009;98(6):2149-59
71. Gao Y, Liao J, Qi X, Zhang J.
Coamorphous repaglinide--saccharin with
enhanced dissolution. Int J Pharm
2013;450(1 -- 2):290-5
988
72. Hussain MD, Saxena V, Brausch JF,
et al. Ibuprofen--phospholipid solid
dispersions: improved dissolution and
gastric tolerance. Int J Pharm
2012;422(1 -- 2):290-4
73. Ahuja N, Katare OP, Singh B. Studies
on dissolution enhancement and
mathematical modeling of drug release of
a poorly water-soluble drug using water-
soluble carriers. Eur J Pharm Biopharm
2007;65(1):26-38
74. Masuda T, Yoshihashi Y, Yonemochi E,
et al. Cocrystallization and amorphization
induced by drug--excipient interaction
improves the physical properties of
acyclovir. Int J Pharm
2012;422(1 -- 2):160-9
75. Hoppu P, Jouppila K, Rantanen J, et al.
Characterisation of blends of paracetamol
and citric acid. J Pharm Pharmacol
2007;59(3):373-81
76. Corrigan OI, Holohan EM, Sabra K.
Amorphous forms of thiazide diuretics
prepared by spray-drying. Int J Pharm
1984;18:6
77. Paluch KJ, Tajber L, Corrigan OI, et al.
Impact of process variables on the
micromeritic and physicochemical
properties of spray-dried porous
microparticles, part I: introduction of a
new morphology classification system.
J Pharm Pharmacol
2012;64(11):1570-82
78. Sonje VM, Kumar L, Puri V, et al.
Effect of counterions on the properties of
amorphous atorvastatin salts. Eur J
Pharm Sci 2011;44(4):462-70
79. Bianco S, Caron V, Tajber L, et al.
Modification of the solid-state nature of
sulfathiazole and sulfathiazole sodium by
spray drying. AAPS PharmSciTech
2012;13(2):647-60
80. Paluch KJ, Tajber L, Amaro MI, et al.
Impact of process variables on the
micromeritic and physicochemical
properties of spray-dried microparticles --
Part II. Physicochemical characterisation
of spray-dried materials.
J Pharm Pharmacol
2012;64(11):1583-91
81. Bianco S, Tewes F, Tajber L, et al. Bulk,
surface properties and water uptake
mechanisms of salt/acid amorphous
composite systems. Int J Pharm
2013;456(1):143-52
82. McNamara PJ, Foster TS, Digenis GA,
et al. Influence of tablet dissolution on
Expert Opin. Drug Deliv. (2014) 11(6)
furosemide bioavailability:
a bioequivalence study. Pharm Res
1987;4(2):150-3
83. Matsuda Y, Tatsumi E. Physiochemical
characterization of furosemide
modifications. Int J Pharm 1990;60:16
84. Nielsen LH, Gordon S, Holm R, et al.
Preparation of an amorphous sodium
furosemide salt improves solubility and
dissolution rate and leads to a faster T
after oral dosing to rats. Eur J
Pharm Biopharm 2013;85(3B):942-51
85. Nielsen LH, Gordon S, Pajander JP,
et al. Biorelevant characterisation of
amorphous furosemide salt exhibits
conversion to a furosemide hydrate
during dissolution. Int J Pharm
2013;457(1):14-24
86. Nielsen LH, Rades T, Mullertz A.
Characterisation during storage and
dissolution of solid dispersions
containing furosemide and
hydroxypropyl methylcellulose. J Drug
Deliv Sci Tech 2013;23(4):409-15
87. Priemel PA, Laitinen R, Grohganz H,
et al. In situ amorphisation of
indomethacin with Eudragit E during
dissolution. Eur J Pharm Biopharm
2013;85(3B):1259-65
. Article highlighting the potential of in
situ amorphisation prior
to administration.
88. Karmwar P, Graeser K, Gordon KC,
et al. Effect of different preparation
methods on the dissolution behaviour of
amorphous indomethacin. Eur J
Pharm Biopharm 2012;80(2):459-64
89. Mahmah O, Tabbakh R, Kelly A, et al.
A comparative study of the effect of
spray drying and hot-melt extrusion on
the properties of amorphous solid
dispersions containing felodipine.
J Pharm Pharmacol 2014;66(2):275-84
90. Patterson JE, James MB, Forster AH,
et al. Preparation of glass solutions of
three poorly water soluble drugs by spray
drying, melt extrusion and ball milling.
Int J Pharm 2007;336(1):22-34
91. Ozaki S, Kushida I, Yamashita T, et al.
Evaluation of drug supersaturation by
thermodynamic and kinetic approaches
for the prediction of oral absorbability in
amorphous pharmaceuticals. J Pharm Sci
2012;101(11):4220-30
92. Warren DB, Bergstrom CAS,
Benameur H, et al. Evaluation of the
structural determinants of polymeric

precipitation inhibitors using solvent shift
methods and principle component
analysis. Mol Pharm 2013;10(8):2823-48
93. Wyttenbach N, Janas C, Siam M, et al.
Miniaturized screening of polymers for
amorphous drug stabilization (SPADS):
rapid assessment of solid dispersion
systems. Eur J Pharm Biopharm
2013;84(3):583-98
94. Bevernage J, Brouwers J, Annaert P,
et al. Drug precipitation--permeation
interplay: supersaturation in an
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nanyang Technological University on 06/04/14
absorptive environment. Eur J
Pharm Biopharm 2012;82(2):424-8
95. Carlert S, Akesson P, Jerndal G, et al. In
vivo dog intestinal precipitation of
mebendazole: a basic BCS class II drug.
Mol Pharm 2012;9(10):2903-11
96. Psachoulias D, Vertzoni M, Goumas K,
et al. Precipitation in and supersaturation
of contents of the upper small intestine
For personal use only.
Refining stability and dissolution rate of amorphous drug formulations
after administration of two weak bases to
fasted adults. Pharm Res
2011;28(12):3145-58
97. Sassene PJ, Knopp MM, Hesselkilde JZ,
et al. Precipitation of a poorly soluble
model drug during in vitro lipolysis:
characterization and dissolution of the
precipitate. J Pharm Sci
2010;99(12):4982-91
. Article highlighting the potential of in
situ amorphisation during in
vitro lipolysis.
98. Thomas N, Holm R, Mullertz A, et al.
In vitro and in vivo performance of
novel supersaturated self-nanoemulsifying
drug delivery systems (super-SNEDDS).
J Control Release 2012;160(1):25-32
99. Thomas N, Rades T, Mullertz A. Recent
developments in oral lipid-based drug
delivery. J Drug Deliv Sci Tech
2013;23(4):375-82
Expert Opin. Drug Deliv. (2014) 11(6)
Affiliation
Holger Grohganz1, Petra A Priemel1,2,
Korbinian Lobmann1, Line Hagner Nielsen1,
Riikka Laitinen3, Anette Mullertz1,
Guy Van den Mooter4 & Thomas Rades1
Author for correspondence
1
University of Copenhagen, Department of
Pharmacy, Universitetsparken 2,
2100 Copenhagen, Denmark
Tel: +45 3533 6032;
E-mail: Thomas.rades@sund.ku.dk
2
University of Otago, School of Pharmacy,
Dunedin, New Zealand
3
University of Eastern Finland, School of
Pharmacy, Kuopio, Finland
4
University of Leuven, Department of
Pharmaceutical and Pharmacological Sciences,
Leuven, Belgium
989