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9
METTLER TOLED O UserCom 1/2007
TGA-FT IR was used to characteriz e
and distinguish between different poly-
morphs. If two polymor phic forms of
a solid are present, whereby one form
melts and the other sublimes or vapor-
izes at about the same temperature, then
evolved gas analysis can be used to ob-
tain quantitative (mass loss) and quali-
tative (spectral) data to analyze such sol-
ids. The two pharmaceutically important
compounds shown in Figure 1, the active
pharmaceutical ingredient (API) venla-
faxine hydrochloride (Structure 1) and
the well-known host material 1,1-bis(4-
hydroxyphenyl)cyclohexane (Structure
2), were analyzed by DSC, TGA, hot-stage
micro scopy (HSM) and TGA-FTIR to
study the phase transitions that occur on
heating.
A substance is said to exhibit polymor-
phism if it can exist in two or more
crystal lattice forms. These are called
polymorphs and have different physical
properties [1].
Venlafaxine hydrochloride
(VenHCl)
VenHCl is a widely sold anti-depressant.
The hydrochloride salt of venlafaxine,
(±)-1-[2(dimethylamino)-1-(4-meth-
oxy-phenyl)ethyl]cyclohexanol, exists in
several different polymorphic modifica-
tions.
The polymorphs of VenHCl are classified
according to their main melting temper-
atures in the DSC: Form 1 (210-212 °C),
Form 2 (208-210 °C), Form 3 (202-
204 °C, phase from the melt) and Form 4
(219-220 °C, hydrate/alcoholate). A new
amorphous, transient, glassy (semisolid)
phase (Form 5) was isolated by sublima-
tion under vacuum during the course of
our thermal studies on this API [2].
TGA, TGA-FTIR and DSC measure-
ments
The TGA curves of the marketed drug
Forms 1 and 2 showed complete loss
of mass between 220 and 260 °C (Fig-
ure 2a). We interpreted the mass loss as
being due to decomposition or vaporiza-
tion of the sample after melting.
The vaporization products were analyzed
by simultaneous FTIR spectroscopy. The
gaseous products formed in the TGA were
passed through a heated transfer line to
the FTIR spectrometer and FTIR spectra
continuously recorded. The TGA-FTIR
spectra of the vaporized VenHCl Forms 1
and 2 were identical and the main peaks
matched the peaks in the solid state FTIR
spectrum of Ven HCl. This meant that
VenHCl vapor is evolved from both forms
after the phase change between 214 and
Figure 1.
Venlafaxine ((±)-1-[2(dimethylamino)-1-
(4-methoxyphenyl)ethyl]cyclohexanol
hydrochloride (Structure 1)) and
1,1-bis(4-hydroxyphenyl)cyclohexane
(Structure 2).
Figure 2 (a).
TGA (above) and
DSC (below) of
VenHCl Form 1 and
Form 2.
Note the mass loss
that accompanies
sublimation.
Figure 2 (b).
FTIR spectra of the
vapor from Forms 1
(black) and 2 (red).
Figure 2 (c and d).
FTIR spectra as a
function of tempera-
ture (220–260 °C)
in (c) Form 1 and
(d) Form 2.
The characterization of polymorphs by thermal
analysis
Saikat Roy, Bipul Sarma und Ashwini Nangia, School of Chemistry, University of Hyderabad, India
Dr. Matthias Wagner, Dr. Rudolf Riesen
Tempera-
ture °C
Absorb ance
Units
Wavenumbe r cm-1
Tempera-
ture °C
Absorb ance
Units
Wavenumbe r cm-1
10 METTLER TOLEDO User Com 1/2007
216 °C, a phenomenon that accompa-
nies sublimation of the solid during the
broad endothermic effect between 220
and 260 °C.
The TGA cur ves show that Form 2 sub-
limes more rapidly than Form 1.
When VenHCl was sublimed/vaporized
at reduced pressure (0.2 Torr, ~160 °C),
amorphous, semi-solid droplets formed
on the cold finger (Figure 3a). The glassy
mass was immediately transferred to a
glass plate as liquid-like droplets (Fig-
ure 3b). The DSC curve of the sublimed
semi-solid material showed crystalliza-
tion between 95 and 100 °C (exother-
mic) followed by melting between 216
and 218 °C (endothermic), and finally a
broad endothermic effect between 220
and 260 °C due to sublimation/vapori-
zation (Figure 3d, left). The exothermic
effect at 100 °C is due to the solidifica-
tion of the glassy mass, the endothermic
effect between 217 and 218 °C from melt-
ing. Vapor loss occurs between 220 an
260 °C.
Figure 3d, right, shows the DSC of Ven-
HCl hydrate obtained from Form 5 after
one day exposure in open air (above) and
the hydrate Form 4 prepared by crystalli-
zation from methanol (below). The endo-
thermic effect at 80 °C is due to the loss
of solvent/water.
DSC heating-cooling-heating
experiments
The presence of two endotherms between
210 and 220 °C in the DSC curve s of
Forms 1 and 2 (Figure 2 effects marked 1
and 2) raised the following questions.
Is the first endothermic effect due to
a phase transition and the second due
to melting, or vice versa?
Is the endo-exo peak in Form 2 a
melting crystallization phenomenon?
Which polymorph is more stable? Do
they interconvert or transform to a
new, different phase?
To clarify this, a number of DSC heat-
ing-cooling-heating experiments were
performed.
Form 1 was heated at 2 K/min to
212 °C, a temperature that is just
after the larger endothermic peak
marked 1 (in Figure 2) but before the
small peak marked 2. The sample was
then cooled to room temperature at
5 K/min in the DSC cell (Figure 4a).
Reheating at 2 K/min showed a broad
endothermic peak at 212 °C. This
meant that the solid is still in Form 1
and not a transformed product. The
exothermic behavior at 195 °C in the
cooling segment is due to solidifi-
cation/crystallization of the melted
Form 1. We believe that the peak
between 210 and 212 °C in Figure 4a
is due to melting and is not a phase
transition.
When the same procedure was re-
peated but heating was continued to
219 °C, just past the second small
peak, the DSC curve of the reheated
Form 1 is very different. There is now
1)
2)
3)
A)
B)
Applications
Figure 4 (a).
Heating-cooling-
heating experiments
performed on Form 1
with dif ferent maxi-
mum temperatures
resulting in the for-
mation of different
end products.
Figure 3 (a, b and c).
The transient semi-solid, glassy phase on the cold finger of the sublimation apparatus
(a) and droplets immediately placed on a glass plate (b). The sublimed material, Form 5,
transforms to the hydrate, Form 4, after exposure to the Hyderabad climate (25-30 °C,
RH 40–50%) for one day.
Figure 3 (d).
DSC curves of the
freshly formed
Forms 4 and 5.
11
METTLER TOLED O UserCom 1/2007
a broad exothermic effect at 110 °C
and an endothermic effect at 200 °C.
The exothermic effect corresponds to
the crystallization of the transformed
Form 3, which melts at 200 °C. Thus
Form 1 undergoes a phase change to
Form 3 on heating to 218−219 °C and
cooling.
In a similar procedure, Form 2 was
heated in the DSC at 2 K/min to the
endo-exo peak at 213 °C and then
cooled at 5 K/min to room tempera-
ture (Figure 4b). The cooling curve
is flat and shows no crystallization,
which means that the crystalliza-
tion of Form 2 (exothermic effect
at 213 °C) was correctly assigned.
Reheating at 2 K/min shows a sharp
endothermic peak between 218 and
220 °C corresponding to the melting
of Form 5, the phase obtained by
sublimation.
On heating Form 2 to beyond the se-
cond endothermic effect up to 220 °C,
cooling to room temperature and
then reheating, different peaks occur.
Now the DSC cooling curve shows
crystallization at 150 °C and endo-
thermic peaks that resemble Form 3.
The heating-cooling-heati ng curves
show that Forms 1 and 2 first melt and
then phase transform to different solid-
state forms (3 and 5) in the range 210 to
220 °C.
Hot-stage microscopy (HSM)
Morphological and phase transitions in
Forms 1 and 2 and the thermal events
leading to sublimation of Form 5 were
studied by HSM.
The photomicrographs in Figure 5 show
snapshots of the transformation of both
solids to Form 5.
Whereas the extent of vaporization was
almost complete when the starting form
was Form 2, it was only partial in the
case of Form 1.
HSM measurements confirm the inter-
pretation of the DSC curves in Figure 4
and the existence of the new transient,
glassy phase Form 5.
C)
D)
Figure 5 (a and b).
HSM of Form 1 and
HSM of Form 2.
Figure 4 (b).
Heating-cooling-
heating experiments
performed on Form
2 to two different
end temperatures
again yield different
results.
Figure 6. BHPC
(Structure 2) p 12.
DSC of 2m and 2s
polymorphs. The
metastable phase
2m has a lower
melting temperature
and shows phase
transition to the
higher melting
thermodynamically
stable Form 2s.
Form 1
30 °C 150-190 °C
209-210 °C 210-215 °C
215-216 °C Microcrystals under
polarized light after
cooling
Form 2
30 °C 150-195 °C
208-209 °C 210-217 °C
217-218 °C Microcrystals under
polarized light after
cooling
12 METTLER TO LEDO UserCom 1/2007
1,1-Bis(4-hydroxyphenyl)cyclo-
hexane (BHPC)
1,1-bis(4-hydroxyphenyl)cyclohexane
molecules are highly prone to forming
inclusion complexes in over 30 host-guest
crystal structures.
We employed two solvent-free condi-
tions, melt crystallization and sublima-
tion under vacuum, to crystallize guest-
free forms. Single crystals of BHPC were
solved and refined in triclinic space
group P1 (2s, Z′ = 1, sublimation phase)
and in orthorhombic space group Pbca
(2m, Z′ = 2, phase from the melt). Z′ is
the number of symmetr y-independent
molecules in the crystallographic unit
cell.
TGA, TGA-FTIR and DSC measure-
ments
Phase relationships of 2s and 2m and
possible mechanisms for their intercon-
version were studied by DSC and HSM
[3].
The DSC cur ve of 2s showed a single
broad endothermic peak at ~184 ºC
(Tpe ak , peak 1), while 2m shows two
sharp endothermic peaks at 183 ºC and
188 ºC (Figure 6, peaks 2 and 3). These
two peaks were assigned to the melting of
2m (peak 2), then crystallization (exo-
thermic, peak 4) to 2s and finally fusion
of the sublimed form (peak 3). On heat-
ing a second time in the DSC, both forms
showed a single endothermic peak (peaks
5 and 6), implying transformation to the
stable 2s polymorph. Polymorph 2m is a
metastable phase, which shows a phase
transition to the thermodynamic, sub-
limation polymorph 2s on heating to
200 °C. Under the same conditions, poly-
morph 2s does not show phase changes
except the vaporization endotherm. In
general, the endothermic peak obtained
on reheating is shifted by about 5 K to
lower temperature compared to the first
heating run due to better thermal con-
tact of the sample with the crucible after
melting.
TGA-FTIR measurements of the evolved
vapor were performed in order to con-
firm the sublimation process in BHPC.
This was done by heating 8−12 mg of
substance at 10 K/min in a dry nitrogen
gas flow of 50 mL/min. The FTIR spectra
showed that vaporization of both forms
occurs after the phase change between
183 and 185 ºC (Figure 7). Sublimation
below melting is two to three times more
pronounced with polymorph 2s com-
pared to the melt phase 2m, even though
only a marginal loss of mass is observed
on the TGA curve (Figure 7a).
Hot-stage microscopy (HSM)
Hot-stage microscopy shows blocks of
melt crystals beginning to melt between
178 and 182 ºC with complete melting be-
tween 183 and 185 ºC. With both forms,
cooling resulted in sublimed crystals
with fine needle morphology (Figure 8).
On the other hand, sublimed crystals 2s
did not show any apparent crystal form
change in a similar heating-cooling cy-
cle on the hot stage.
A combination of thermoanalytical meth-
ods such as TGA, DSC and HSM indicate
that 2m is the metastable polymorph and
2s the thermodynamically stable phase
(T2m = 183 ± 1 ºC; T2s = 188 ± 1 ºC).
The single endothermic peak after re-
heating is the thermodynamically stable,
Figure 8 (a to f).
HSM images.
2m: (a) at 25 ºC, (b) 181−182 ºC,
(c) after cooling to room temperature
2s: (d) at 25 ºC, (e) 183−184 ºC,
(f) after cooling to room temperature.
Phase transition of a block crystal of 2m
to needle fibers of 2s (a−c).
Applications
Figure 7 (a, b
and c).
TGA (a) and FTIR
spectra of the
evolved vapor of
polymorphs 2s (b)
and 2m (c).
The measured FTIR
peaks match with
those expected for
BHPC.
Form m Form s
(a) (d)
(b) (e)
(c) (f)
Time
in min
Trans-
mitance
in %
Wavenumbe r cm-1
Time
in min
Trans-
mitance
in %
Wavenumbe r cm-1
(b) (c)
13
METTLER TOLED O UserCom 1/2007
Introduction
The measurement and interpretation
of melting processes using temperature
modulated DSC (TMDSC) is one of the
more demanding tasks in thermal analy-
sis.
This is possibly the reason why a number
of ideas and proposals can be found in
the scientific literature that do not stand
up to a critical analysis. Despite this,
TMDSC can provide interesting and im-
portant information about melting be-
havior that would otherwise be difficult
to obtain.
Starting out from the basic principles of
melting behavior discussed in reference
[1], we want to show with the aid of suit-
able examples how melting behavior can
be investigated using TOPEM®.
Basic principles of temperature
modulated DSC
Measurement principles and
requirements
In TMDSC, a conventional temperature
program (heating or cooling at a con-
stant rate, or isothermal conditions) is
overlaid with a small temperature pertur-
bation (modulation). In the evaluation
algorithm, it is assumed that the reaction
of the sample to the conventional tem-
perature program and the modulation do
This article discusses the conditions required for analyzing melting proc-
esses using TOPEM®. If these conditions are fulfilled, the reversing
heat flow measures processes that occur under equilibrium conditions
and the non-reversing heat flow processes that involve supercooling or
superheating. This separation allows a classification of melting proc-
esses and the differention of crystal structures of different stability.
higher melting crystallized phase. TGA-
FTIR confirms the vaporization/subli-
mation of BHPC.
Conclusions
The phase relationships between VenHCl
polymorphs are summarized in Figure 9.
In addition to recording quantitative
and reproducible data on four previously
reported Forms 1 to 4 of VenHCl, a new
form, Form 5, was obtained by sublima-
tion. Form 5 is short-lived under inert
conditions (stable for a few hours up to
one day). It transforms to the hydrate,
Form 4, in the open air and to Form 1
under dry conditions.
TGA, DSC and hot-stage microscopy show
that the 5 K lower melting solid 2m form
of BHPC is the metastable modification
and 2s is the thermodynamically stable
phase. The single endothermic peak after
reheating both forms is ascribed to the
thermodynamically stable, higher melt-
ing phase, which can also be obtained by
vaporization/sublimation.
In addition to the above application, we
have also used TGA-FTIR to differentiate
between aniline and phenol inclusion in
a guest-selective host lattice [4].
Literature
[1]
W. C. McCrone, in Physics and Chem-
istry of the Organic Solid State, Vol. 2,
D. Fox, M. M. Labes and A. Weiss-
berger (Eds.), Wiley Interscience:
New York, 1965, pp. 725–767.
[2] S. Roy, S. Aitipamula and A. Nangia,
Cryst. Growth Des. 2005, 5, 2268–
2276.
[3] B. Sarma, S. Roy, and A. Nangia,
Chem. Commun. 2006, 4918–4920.
[4] S. Aitipamula and A. Nangia, Chem.
Eur. J. 2005, 11, 6727–6742.
Figure 9.
Phase transforma-
tions in VenHCl
polymorphs 1 to 5.
Analysis of melting processes using TOPEM®
Dr. Jürgen Schawe
