Physico-chemical characterisation of three-component co-amorphous systems generated by a melt-quench method
Journal of Thermal Analysis and Calorimetry
Physico-chemical characterisation of three-component co-amorphous systems generated by a melt-quench method
A. D'Angelo 0 1 2
B. Edgar 0 1 2
A. P. Hurt 0 1 2
M. D. Antonijevic´ 0 1 2
Crystallinity 0 1 2
0 Faculty of Engineering and Science, University of Greenwich , Chatham Maritime, Kent ME4 4TB , UK
1 & M. D. Antonijevic ́
2 Abbreviations AC Acetaminophen API Active pharmaceutical ingredient ATR-FTIR Attenuated total reflectance-Fourier transform infrared spectroscopy BZD Benzamide CAF Caffeine CTMZ Clotrimazole DSC Differential scanning calorimetry HSM Hot-stage microscopy IND Indomethacin NCE New chemical entity PXC Piroxicam T
3 Crystallisation temperature T
The purpose of this work was to evaluate the possibility of creating a ternary co-amorphous system and to determine how the properties of a co-amorphous material are altered by the addition of a selected third component. Piroxicam and indomethacin form a stable co-amorphous with the Tg above room temperature. The third component added was selected based on tendency to crystallise (benzamide, caffeine) or form amorphous (acetaminophen, clotrimazole) on cooling. Generated co-amorphous systems were characterised with TGA, HSM, DSC, FTIR and XRD. Stable ternary co-amorphous systems were successfully generated, which were confirmed using XRD, DSC and FTIR analysis. In all cases, Tg of the ternary system was lower than the Tg of the binary system, although higher than that of the individual third component. Upon storage for 4 weeks, all created ternary systems showed significantly smaller variation in Tg compared to the binary system. Stable three-component co-amorphous systems can be generated via melt-quench method using either a crystalline or an amorphous third component. Addition of third component can alter the Tg of co-amorphous system and in all cases created more stable co-amorphous system upon storage. Physical parameters may not be sufficient in predicting the resulting Tg; therefore, knowledge of chemical interaction must be brought into equation as well.
Co-amorphous; Stability; Tg
Approximately 90% of new chemical entities (NCE) and
40% of drugs on the market are poorly water soluble [
Low-solubility drugs are characterised by slow dissolution
rates and slow drug adsorption which lead to inadequate
bioavailability and gastrointestinal toxicity . Therefore,
solubility improvement is a critical challenge in drug
Alteration of the solid state of a drug from crystalline to
amorphous form offers improved apparent solubility and
dissolution that lead to an increase in bioavailability [
Amorphous materials are characterised by short-range
structural order, lacking the long-range order that instead is
typical of crystalline solids. They retain an excess of
enthalpy, entropy and Gibbs free energy, which is
responsible for the improved apparent solubility and
dissolution rate. As energy is released from the system,
amorphous materials convert into their crystalline
counterpart, by doing so the properties of the materials
inevitably change [
Amorphous materials are often produced by a
quenchcooling method where samples are melted and rapidly
cooled so that molecular conformation of the liquid
material is preserved into the solid. Amorphous materials
can also be generated by introduction of energy in the
system by energetic grinding or by fast solvent removal.
Different preparation methods may induce different
molecular organisations. Therefore, properties of the
generated amorphous material might vary [
As the kinetic interactions between the polymer and the
amorphous active ingredient improve dissolution rate,
bioperformance and stability, amorphous active ingredients
are preferably delivered as polymeric solid dispersions. [
However, miscibility of the active ingredient in the
polymer is one of the major issues in amorphous solid
]. To overcome poor miscibility issues, the
amount of polymer is increased, and this causes volume
enlargement of the dosage form [
amorphous materials are more hygroscopic than crystalline
materials and the glass-transition temperature of most
amorphous drugs is lowered, even with only very small
water content [
]. Therefore, the phase change of an
amorphous active ingredient dispersed in a polymer is
facilitated by the hygroscopic nature of the polymer
adopted, which has caused the recall of many products by
the FDA [
An amorphous dispersion of low molecular weight
ingredients is defined as a co-amorphous mixture [
Coamorphous drug delivery systems have recently attracted
the interest in the pharmaceutical field to overcome
limitations of solid dispersions and improve bioavailability and
stability of the single amorphous components [
A co-amorphous is frequently composed of two low
molecular weight co-formers and primarily identified by a
single glass-transition temperature (Tg), indicating that the
components are miscible and are interacting. Low
molecular weight co-formers such as amino acids and
saccharides have shown to stabilise amorphous poorly soluble
drugs by generation of co-amorphous systems [
Active ingredients are also used as low molecular weight
co-formers with the advantage of the co-administration of
therapeutics. The first example presented in the literature
was proposed by Yamamura et al.  where a stable
coamorphous of cimetidine and indomethacin was generated
by solvent evaporation method. Since then, multiple
coamorphous systems composed of two active ingredients
have been studied.
This work aimed to investigate whether a
three-component co-amorphous system can be created reliably using
a melt-quench method as way to stabilise amorphous
materials by the improvement of their singular glass
transitions and stability upon storage. The delivery of
threecomponent co-amorphous systems would have the
advantage of allowing the simultaneous administration of
APIs, to reduce the number of medications consumed by
the patient and therefore improve patient compliance.
Multicomponent co-amorphous systems could be used to
combine the administration of two APIs that act in synergy
and a chemical ingredient that facilitates their absorbance,
as for example the caffeine.
Among the selected active crystalline ingredients
majority were characterised by poor solubility in water
(Table 1). The generation of multiple component
coamorphous system aimed to improve the apparent
solubility and dissolution rate of the co-amorphous
constituents. In the pharmaceutical field, there is a great
interest in the systematic knowledge of the influence of the
third component as it is not yet defined.
Materials and methods
Materials were chosen from initial preliminary test where
different APIs were analysed using differential scanning
calorimetry (DSC) to determine their propensity to form
amorphous or crystalline materials upon cooling from a
melt with different cooling rates.
Piroxicam (PXC) (Sigma-Aldrich, Lot: SLBG9097 V)
and indomethacin (IND) (Tokyo Chemical Industry, Lot:
JU2BN-AB) were selected due to the formation of
stable amorphous state with glass-transition temperatures
above room temperature.
The third components added to the binary combination
of PXC and IND were chosen from the API screening
previously described. Benzamide (BZD) (Sigma-Aldrich,
Lot: STBF1753 V) and caffeine (CAF) (Sigma-Aldrich,
Lot: S21606-124) were selected due to their strong
tendency to crystallise on even when melted material was
subjected to Newtonian cooling. Acetaminophen
(SigmaAldrich, Lot: SLBH0185 V) and clotrimazole (Tokyo
Chemical Industry, Lot: PCZNB-QA) were chosen as they
showed a propensity towards forming an amorphous on
cooling. Physical mixtures were prepared in 1:1:1 molar
The production of amorphous samples was conducted
by melting and rapidly cooling within the differential
scanning calorimetry (DSC) instrument as rapid cooling of
the melted sample is one of the many validated techniques
used to generate an amorphous from a crystalline material
]. Before analysis, all samples were finely ground using
an agate mortar and pestle to ensure a homogenous
distribution of components and to reduce the possibility of
thermal lag within larger particles.
Physical mixtures and melt-cooled products were
characterised with thermogravimetric analysis (TGA),
hotstage microscopy (HSM), DSC, X-ray diffraction (XRD)
and attenuated total reflection-Fourier transform infrared
spectroscopy (ATR-FTIR). Physical mixtures were
analysed to verify that grinding did not alter the solid state of
the sample, while the analysis of the products assured that
the adopted preparation method induced complete
amorphisation of the mixture components.
TGA was conducted using the Q5000 IR TGA (TA
Instruments, UK) in aluminium pans with sample size
2.0 ± 0.5 mg. Samples were heated from ambient
temperature (20 C) to 300 C at 10 C min-1, under nitrogen
(25 mL min-1). HSM was conducted using a Mettler
Toledo FP90 Central Processor with a FP82HT hot stage.
The heating programme used was 10 C min-1 from
30 to 300 C. This allowed the visual identification of
thermal events (melting, crystallisation, evaporation and
degradation). These data were combined with that gathered
from TGA to determine the maximum temperature for the
DSC experiments. DSC was carried out using a Q2000
DSC (TA Instruments, UK) in hermetically sealed Tzero
aluminium pans with 2.0 ± 0.5 mg of sample. Heating
rates were kept consistent throughout experiments to
ensure comparable data; however, the end temperature of
experiments was different for each mixture. Three heating
and cooling cycles were conducted for the samples to
assure the homogeneity of the products and to evaluate
possible differences in Tg measured in each heating cycle.
Experiments were conducted in triplicate under nitrogen
atmosphere (flow rate 50 mL min-1). Data were analysed
using TA Advantage Universal Analysis V5.5.22 software.
Co-amorphous systems were produced in situ using the
capability of the DSC to control heating and cooling rates
and then used to characterise the thermal transitions of the
Samples were equilibrated at - 80 C and then heated
to 180 C with 10 C min-1 heating rate to erase the solid
history of the samples and ensure mixing of the component
molecules to form a homogeneous dispersion. After
melting, the samples were cooled. To analyse the propensity of
the materials to convert into amorphous, crystalline or a
mixture of the phases, two different cooling rates were
selected as follows: a fast cooling rate of 20 C min-1 and
a slow cooling rate of 5 C min-1 were chosen. All
physical mixtures were heated to analyse the generated
coamorphous. Experiments were conducted using multiple
heating and cooling cycles to determine the reproducibility
of the thermal events over repeated cycles. During the final
cooling ramp, the samples were brought to 20 C and
subsequently stored in a temperature-controlled room at
20 C. Experiments were conducted in triplicate to verify
the reproducibility of the obtained results.
XRD was conducted using a D8 Advance X-ray
Diffractometer (Bruker, Germany) with theta–theta
geometry in reflection mode. Cu Ka radiation at 40 kV and
40 mA was used to irradiate samples from a 0.2-mm exit
slit. Data collection was between 2 and 40 2h, step size of
0.02 and a counting time of 0.3 s per step. Data collection
was carried out using DIFFRAC plus XRD Commander
Version 2.6.1 software (Bruker-AXS), qualitative
assessment with the aid of EVA version 16.0 (Bruker-AXS). The
Spectrum TwoTM FTIR spectrometer (PerkinElmer, UK)
fitted with the diamond/ZnSe ATR (single reflection)
accessory was used. Sixteen scans were collected over the
range of 4000–650 cm-1. Data were analysed using the
Spectrum 10TM software suite.
The initial stability study was conducted under
laboratory conditions over period of 1 month to assess whether
generated co-amorphous system will remain intact, without
exposure to any exaggerated conditions. Samples were
stored in sealed glass containers at 20 C away from
excessive vibration and sunlight. They were tested every
7 days using DSC to analyse changes in transitions and
therefore the solid state of the systems.
Results and discussion
Differential scanning calorimetry
DSC traces (Fig. 1) showed that indomethacin converts
into an amorphous upon rapid cooling (20 C min-1) with
a Tg of 47.9 C, which is stable upon heating. The PXC
subjected to the same conditions formed an amorphous
with a Tg of 64.6 C which recrystallises on reheating at the
temperature of 138.1 C and then melts at 181.4 C. This
also shows the polymorphism exhibited by piroxicam [
Thermal transitions of other starting materials are shown in
The physical mixture composed of PXC and IND at a
1:1 molar ratio was analysed in the DSC, the sample was
heated above the melting point of both constituents, cooled
at 20 C min-1 and reheated to characterise the generated
The DSC trace of the heating cycle after subsequent
cooling revealed a single Tg at 57.6 C which was
stable upon cooling, as no recrystallisation occurred, and
no recrystallisation was present on heating. This was an
indication of the generation of a co-amorphous system
comprising PXC and IND characterised by a Tg
intermediate between the Tgs of the single components. Hence, the
amorphous IND was stabilised by the interaction with the
amorphous PXC as obtained Tg is greater than Tg of IND.
The IND is in turn stabilising the amorphous PXC and
preventing it from crystallising on reheating.
Third components were added to the binary mixture of
IND and PXC, these were characterised in DSC as in
Table 1, physical mixtures were in 1:1:1 molar ratios.
Coamorphous systems were produced in situ using the
capability of the DSC to control heating and cooling rates and
Tg, glass transition; Tc, crystallisation; Tm, melting
203.1 ± 0.1
161.1 ± 0.1
126.2 ± 0.3
236.7 ± 0.1
169.8 ± 0.2
145.5 ± 0.1
then used to characterise the thermal transitions of the
The physical mixture of PXC-IND-BZD cooled at
20 C min-1 had only a single Tg in the second heating
cycle at 31.0 C; therefore, these characteristics were
associated with a co-amorphous system, which was further
analysed. The BZD as pure compound showed a strong
propensity to form crystalline material upon quench
cooling giving such an exothermic response that the signal
became a loop instead of a peak as the temperature of the
cell was increased. Because of the strong propensity of the
BZD to recrystallise, the generated ternary mixture had a
Tg lower than the glass transitions of the other components.
DSC traces of the mixture with CAF presented no
crystallisation upon cooling, indicating the generation of an
amorphous material and a single Tg at 45.8 C, which
recrystallised at 106.6 C and then melted at 131.3 C.
These two events can be shown to be of very close
enthalpies, which indicate it is a single crystal phase (one
polymorph) crystallising from the mixture and then melting
again. This also shows that the initially created material
was entirely amorphous. The melting point of the
recrystallised material was compared with the melting
temperatures of the single pure components of the system and of
their polymorphic forms. However, this comparison was
not sufficient to identify the entity that undergoes
Both CAF and BZD, although as pure compounds
presented the propensity to generate crystalline materials upon
heating after cooling of the melted compound, are shown to
generate stable co-amorphous ternary systems in
association with PXC and IND. The Tg of the co-amorphous
system containing CAF was significantly higher than the Tg
of the co-amorphous incorporating BZD. This is likely
related to the elevated Mp of the CAF, in comparison with
BZD, and therefore to the strong interactions existing
between the molecules of CAF.
The amorphous form of pure AC has the lowest glass
transition of all the examined compounds; however, the
64.6 ± 1.0
47.9 ± 0.7
24.9 ± 0.6
30.1 ± 0.3
glass transition of this co-amorphous is dramatically higher
than the glass transition of the pure AC, showing the
potential of this approach to stabilising low Tg materials.
The CTMZ was characterised by a low Tg at 30.1 C,
significantly lower than the glass transitions of the pure
IND and PXC; however, the co-amorphous generated by
the melting of this three-component mixture had a Tg at
53.3 C, very similar with the glass transition of the binary
system. The ternary system has therefore stabilised the
amorphous CTMZ without altering the stability of the
PXC-IND co-amorphous system.
The formulations described above were also analysed
with a cooling rate of 5 C min-1 cooling. From Table 3, it
is possible to observe the difference in glass transition
measured for ternary co-amorphous from the heating cycle
after cooling rate of 20 and 5 C min-1 is smaller than the
difference in Tg values encountered for the binary system.
It is important to notice that the cooling rate has not
influenced the PXC-IND-CAF system, which crystallises
upon heating and then melts at the same temperature
obtained from DSC traces of the heating following the fast
cooling (Fig. 2).
Repeatability was tested by exposing every sample to
consecutive heating and cooling cycles. In these
experiments, heating and cooling rates were not modified but
were cycled multiple times. The standard deviation
between the glass-transition temperatures of the PXC-IND
was 0.4 C when evaluated in heating cycles after fast
cooling and 0.2 C in slow cooling experiments, whereas
ternary mixtures revealed higher variations in Tg measured
in fast and slow cooling experiments (Table 3). This points
out to the importance of careful selection of appropriate
cooling rate in order to obtain reproducible quality of
Each physical mixture was subjected to repeated heating
and cooling cycles with the same ramp rate and
temperature limits as used in the DSC analysis. HSM video
revealed the same thermal transitions identified in the DSC
traces confirming those results. Additional information was
gathered from the HSM video of the PXC-IND-BZD
system (Fig. 3). The video collected from the heating of the
co-amorphous system confirmed a glass transition, which
started at 47.3 C (Fig. 3b) and finished at 92.4 C
(Fig. 3c). However, unlike the DSC data, HSM showed
evidence of the generation of crystalline material at
100.0 C, with defined needle-like shape, emerging from
the rubbery material (Fig. 3d). These crystals were not
homogenously distributed in the melted sample and grew
reaching maximum dimensions at 148.3 C (Fig. 3e), and
melting temperature was observed in a range from 152.6 to
160.8 C (Fig. 3f, g).
The melting temperature of the newly generated crystals
was compared with the melting temperature of the pure
Tg, glass transition; Tc, crystallisation; Tm, melting
components of the system and possible polymorphic forms,
but it was not possible to identify the component that
recrystallised. PXC-IND-BZD was the only generated
coamorphous that presented this peculiar recrystallisation
behaviour where the DSC did not show the thermal event.
This suggests the possibility of concurrently processes
producing a net zero heat flow or that the energy released
during recrystallisation is low causing the DSC to show no
signal for the event. However, the recrystallisation
observed in the HSM might be initiated by the energy
introduced in the sample when scrapped from the DSC pan.
To further characterise the PXC-IND-BZD
co-amorphous, a fresh sample was heated up the temperature where
the initial traces of the crystals were visible (100 C) and
left isothermal for 1 h. A similar process was carried out
for the PXC-IND-CAF co-amorphous, which has shown
recrystallisation of a material upon heating of the created
co-amorphous. This sample showed homogeneous
recrystallisation upon heating at 83 C; therefore, the sample was
heated at 10 C min-1 up to 83 C and then left isothermal
for 1 h (Figs. 4, 5).
Both samples showed a clear increase in crystal
dimensions over the isothermal period. In the
PXC-INDBZD, co-amorphous, crystals were formed initially in the
borders of the rubbery material and in localised nucleation
amorphous (92.4 C); d appearance of the first crystals from the
rubbery amorphous (100 C); e crystal growth (148.3 C); f melting
of crystals generated (152.6 C); g final stage of melting (160.8 C)
centres. Crystal growth was quantified from the video
measuring length of the selected crystals with the HSM
software at specified time intervals. The growth of the
crystals was analysed up to the moment where the crystal
encountered others making difficult to quantify the length.
Results showed an initial elevated length increase starting
at 0.07 lm s-1 after only 30 s and decreasing to
0.03 lm s-1 after 90 s of isothermal. Interestingly, the
growth was stable at 0.04 lm s-1 from 180 s onwards until
the end of the experiment.
In the PXC-IND-CAF, co-amorphous crystals appear to
generate homogeneously throughout the entire structure
and to grow progressively, promoting the generation of
new crystals from the rubbery sample. Because of the
elevated density of the crystals, it was not possible to
accurately measure the length of the crystals and therefore
the kinetics of crystal growth.
XRD was used to characterise the solid state of the initial
materials, physical mixtures and co-amorphous systems by
comparing the diffractograms to PDF-2 database entries
(ICDD, 2008). Diffractograms of the physical mixtures
presented peaks belonging to each component of the
mixture. This indicates that the grinding adopted to
generate the physical mixtures did not alter the solid state of
the components. Data were processed with the EVA
analysis software for the quantification of the crystallinity of
the systems, which revealed no traces of amorphous
Analysis of the co-amorphous system has confirmed that
the generated materials were amorphous confirming what
observed in the DSC curves, characterised by a single glass
transition and no melting points. The analysis with EVA
confirmed that for each sample 100% of the material was in
the amorphous state. The co-amorphous system of
PXCIND and AC revealed a diffraction peak at 38 (2h);
therefore, the sample was retested up to 60 (2h) to
evaluate the possible presence of crystalline materials of
inorganic origin. Analysis revealed that the sample presented
diffraction peaks typical of aluminium, material from
the vessel used to generate the co-amorphous systems
(Figs. 6, 7).
Co-amorphous systems containing BZD and CAF kept
isothermal for 1 h at the starting temperature of the
crystallisation were analysed with the same XRD methods used
for the samples described above. Results for the
PXC-INDBZD allowed for the identification of the recrystallised
material as PXC. The diffractogram of the sample of
coamorphous PXC-IND-CAF after being held isothermal at
the crystallisation temperature showed diffraction peaks
that were not identified as belonging to the pure
components or any of their known polymorphic forms. This
suggests a number of possibilities including a polymorphic
form of a single component or a co-crystal comprised of an
unknown combination of at least two of the three starting
materials. This is shown in Fig. 8 where the crystalline
material present in the mixture of PXC-IND-BZD clearly
matches that of PXC whereas the diffractogram for
PXCIND-CAF does not.
Fourier transform infrared spectroscopy
Infrared spectroscopy provides information on both the
chemical and physical states, and it was used to further
characterise the solid state of pure compounds, physical
mixtures and products. Molecular bonding vibrational
frequencies are affected the molecular environment. When
attempting to change the environment, such as changing
the material from crystalline to amorphous, these
frequencies will shift which can confirm successful
modification of the environment.
Physical mixtures were characterised by bands relative
to the crystalline components. The spectra of all tested
physical mixtures were characterised by sharp bands
typical of the crystalline state. Therefore, data indicate that in
the physical mixtures, the components were not interacting
and that the grinding used to generate the dispersion did not
influence the solid state of the adopted materials. The
generated co-amorphous systems were characterised by
broad bands, with absorbance at the same wavelengths as
the physical mixtures. This shows that no chemical
interaction has occurred during the heating process and that the
differences in peak shape are due to the change from
crystalline to amorphous.
Broadening is typical of amorphous materials. Due to
the lack of long-range order a specific bond present, the
amorphous material has numerous slightly different
arrangements with neighbouring molecules, which shifts
the vibrational frequency. Therefore, FTIR results were in
agreement with DSC and XRD data that indicate that the
products of quench cooling were amorphous.
Band broadening has reduced significantly the band at
3338 cm-1 relative to the pyridin-2-yl-amino stretching of
the piroxicam [
]. This band was present in all physical
mixtures, but not visible in the co-amorphous systems. Two
strong and resolute peaks at 1715 and 1690 cm-1 relative
to the C=O stretching of indomethacin and piroxicam were
present in all physical mixtures. However, due to peak
broadening of amorphous materials, these were merged in a
single peak and shifted at 1680 cm-1.
Another band shift recognised between crystalline and
amorphous samples was relative to the C-H stretching
which was measured at 2970 cm-1 in the crystalline
samples and in the co-amorphous samples at 2980 cm-1.
Band shifting indicates that components of the studied
coamorphous systems were not only solid dispersions in
amorphous phase, but also interacting. In PXC-IND,
PXCPXC AC CAF
PXC AC BZD
Fig. 8 Overlay of diffraction traces of pure piroxicam (bottom),
PXCIND-BZD co-amorphous left isothermal for an hour at 100 C
(middle) and XC-IND-CAF co-amorphous left isothermal for an hour
at 183 C (top)
PXC IND physical mix
PXC IND coamorphous
PXC IND AC physical mix
PXC IND AC coamorphous
% PXC IND CTMZ physical mix
sa PXC IND CTMZ coamorphous
PXC IND BZD physical mix
PXC IND BZD coamorphous
PXC IND CAFF physical mix
PXC IND CAFF coamorphous
3000 2500 2000
IND-CAFF and PXC-IND-BZD systems, the intensity of
this band was higher in the co-amorphous systems than in
their crystalline counterparts (Fig. 9).
Over the 4 weeks’ storage, the binary co-amorphous
system of PCX-IND has shown a decrease in Tg (DTg) of
13.2 C, which is significantly higher than the DTg of all
the ternary co-amorphous under analysis. The decrease in
Tg that occurred between the 3rd and the 4th week was
significant for the binary system, whereas the ternary
coamorphous appears to have a smaler DTg.
The PXC-IND-CTMZ was characterised by final DTg of
8.6 C which was second only to that of the binary
coamorphous (Table 4). The systems that when freshly
generated had the highest Tg, with respect to the other
coamorphous, were characterised by the highest depression in
Tg of all the stored samples. The other co-amorphous
system where all components, as pure compounds, had the
tendency to form amorphous, PXC-IND-AC, showed a DTg
of 5.0 C. Results have shown that the addition of a third
component with tendency to form crystalline
material (BZD, CAF) stabilises the system, causing a reduction
of the DTg as shown in Table 4.
Three-component co-amorphous systems were reliably
generated via a melt-quench method. Components that
have tendency to crystallise on cooling, i.e., are not easily
converted into amorphous phase, demonstrated not only the
ability to form a co-amorphous system when combined into
a co-amorphous mixture, but also showed greater stability
of created co-amorphous system, with respect to the Tg
values compared to compounds with tendency to create an
amorphous material on rapid cooling. Short-term stability,
over 4 weeks, demonstrated that the ternary system is more
stable when compared to the binary system. Unexpectedly
it was found that the pure materials, which have a
propensity to form crystalline materials on cooling, created
more stable three-component systems with a much lower
deviation in glass-transition temperature across 4 weeks of
storage. Based on this study, it is evident that the Tg of
coamorphous system can be altered using appropriate
components of ternary mixture. The most commonly used
physical parameters, i.e. Tm and Tg, may not be sufficient to
predict the resulting Tg of the multicomponent
co-amorphous systems. Therefore, knowledge of chemical
interactions must be taken into account when manipulating Tg
and selecting components for a ternary co-amorphous
Rapid cooling after melting is confirmed to be a
valuable method for the amorphisation of single chemicals and
in the generation of complex co-amorphous systems.
Improvement in stability of the ternary co-amorphous
systems with respect to binary co-amorphous is valuable
for the development of complex co-amorphous, especially
in the pharmaceutical field where co-amorphous are used to
improve apparent solubility and dissolution rate of active
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