Characterization of D-Mannitol by Thermal Ananlysis, FTIR, and Raman Spectroscopy

Volume 40, Number 14
by Peng Ye and Thomas Byron
Characterization of D-Mannitol by
Thermal Analysis, FTIR, and Raman
D-mannitol is a common excipient
used in the pharmaceutical formulation of tablets. It is often desirable to
process the formula into an amorphous
glassy state to improve some physical
or biological properties of the drug.
The glass property of D-mannitol, e.g.,
the glass transition temperature, Tg,
therefore plays a key role in formulation development.
Differential scanning calorimetry
(DSC) is the classical tool used to
study the thermodynamic properties of materials, including the glass
transition (Tg). The melting behavior of D-mannitol has been studied by DSC. 1,2 When D- mannitol
is cooled from its molten state, it
can be easily crystallized. Therefore, it is difficult to get a glassy
state of D-mannitol by cooling in
conventional DSC because of the
slow cooling rate. Previously, the
D-mannitol glass was achieved by
quenching the molten outside of
the DSC, for example, by contact
with a –80 to –85 °C metal block
for approximately 30 sec. Subsequent heat scanning from –30 °C
at 7 °C/min was used to detect
the glass transition. However, it
is still difficult to obtain a welldefined glass transition because
D- mannitol shows an immediate
cold crystallization right after the
glass transition, which makes the
accurate determination of glass
transition impossible. 3 Since the Tg
of D- mannitol cannot be measured
directly in conventional DSC, it
has to be inferred from other data,
for example, by estimation from
the melting point using a variety
of scaling rules, 4 or by introducing
a small amount of sorbitol as an
impurity to delay the D-mannitol
crystallization and extrapolating
the Tg of the mixture to zero sorbitol concentration to obtain the Tg
of the pure D-mannitol. 3
ferent techniques. Here, FTIR and
Raman spectroscopy were used to
identify different polymorphic forms
of D-mannitol.
One recent development of advanced
DSC technologies is the fast-scan
DSC technology pioneered by the
HyperDSC® technique (PerkinElmer
LAS, Shelton, CT). With HyperDSC,
it is possible to scan at a much faster
rate for both heating and cooling. The
fast scanning rate not only increases
the sensitivity of the measurement, but
also suppresses many kinetic events
such as cold crystallization, which may
interfere with the measurement. Since
introduction of the technique, many
new applications in the polymer and
pharmaceutical industries have been
found that were previously impossible.5–16 This article describes the use
of HyperDSC to characterize the glass
transition of D-mannitol.
D-mannitol (99+%) was obtained
from Sigma Aldrich (St. Louis, MO)
and used without further purification.
DSC measurement
The DSC experiment was performed on the PerkinElmer
Diamond DSC instrument using
the HyperDSC technique. The
instrument was equipped with
a liquid nitrogen cooling accessory with helium as the purge gas.
The instrument was calibrated
using indium at 10 °C/min. A
D- mannitol sample was prepared
in a standard aluminum pan. The
sample was melted first at 200 °C
and then cooled at several different
rates to –30 °C and subsequently
heated at several different rates up
to 500 °C/min.
D-mannitol also exhibits complex
polymorphic behaviors. Polymorphism refers to the different crystalline forms of the same molecule. Many drugs or excipients
can exist in multiple crystalline
forms. The polymorphic form
can have a profound impact on
the physicochemical properties
of the substance. D-mannitol
has three common polymorphic
forms with different thermodynamic stability. 17 Polymorphs
Figure 1
Sample temperature signal vs time at
can be identifi ed by several dif- several different cooling rates on Diamond DSC.
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Volume 40, Number 14
FTIR measurement
The FTIR experiment was performed
using a PerkinElmer Spectrum™
100 FTIR spectro meter. Samples
were measured using attenuated total
reflection (ATR) on a single bounce
diamond/ZnSe ATR crystal.
All samples were measured between
a frequency range of 4000 to 650
cm –1. Each was collected at 4 cm –1
resolution with Strong Beer-Norton
apodization. A total of 16 background
and sample scans were measured for
each sample. Data were collected with
a temperature-stabilized deuterated
tri glycine sulfate (DTGS) detector.
The three different crystalline forms of
D-mannitol were measured separately
by placing the sample in contact with
the ATR crystal and by applying force
from the pressure applicator supplied
with the ATR accessory. The application of pressure enabled the sample to
be in intimate contact with the ATR
crystal, ensuring a high-quality spectrum was achieved.
Figure 2
DSC curve of D-mannitol heating at 10 °C/min.
Figure 3
DSC heating curve at 100 °C/min after cooling from 10 °C/min to 500 °C/min.
Raman measurement
The Raman experiment was performed with a PerkinElmer
RamanStation™ 400 benchtop
Raman spectrometer, an Echellebased system that has no moving
part within the spectrograph. The
system is able to achieve 4 cm –1
resolution across a measurement
range of 95–3500 cm–1 Raman shift.
The system uses an open electrode
silicon base charged-coupled device
(CCD, 1024 × 255 pixels) detector that is thermostatically controlled to –50 °C. The system is
fitted with a 300-mW 785-nm nearinfrared laser, which delivers 100
mW of power at the sample with a
100-µm spot size. The three different D-mannitol crystalline forms
were measured directly using 100
mW of power and 100-µm spot size.
Samples were measured between
200 and 3200 cm –1 Raman shift at 4
cm –1 resolution. A total of 16 sec of
collection time was used.
Results and discussion
HyperDSC is a premier fast-scan
DSC technology performed only on
power compensation DSC. With
HyperDSC, valid DSC measurements
can be made with a scanning rate up
to 500 °C/min covering a broad temperature range, as seen in Figure 1.
The figure shows measured sensor
temperature (blue curve) and program temperature (red) as functions
of time. Conventional DSC is incapable of heating at rates approaching
500 °C/min or realizing a constant
cooling rate higher than 20 °C/min
over a broad temperature range. Of
course, both of these capabilities are
important for accurate fast-scan measurements. In Figure 1, all heating
ramps were performed at a rate of 500
°C/min. In every case, the sample
temperature coincided with the programmed temperature very well. For
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Volume 40, Number 14
D-MANNITOL continued
amorphous state, and the Tg can be
detected during subsequent heating.
The higher the quenching rate, the
more amorphous material was generated. The heat capacity change during the glass transition after cooling at 500 °C/min was 0.76 J/g* °C
compared with the reported value
of 1.27 J/g* °C.3 It is clear that only
part of the sample was quenched
into glass even at a cooling rate of
500 °C/min.
Figure 4
DSC heating curve from 10 °C/min to 500 °C/min after quenching at 500 °C/min.
Figure 5
a) FTIR spectroscopy of D-mannitol. b) Raman spectroscopy of D-mannitol.
the cooling experiment, several different cooling rates were used from
100 °C/min to 500 °C/min. The
results obtained in the cooling scans
demonstrate the exceptional cooling
capability of HyperDSC. Only toward
the end of the cooling scan did the
sample temperature start to deviate
from the program temperature.
The D-mannitol sample was first
heated to 200 °C at 10 °C/min. It
had a big melting peak with onset at
166 °C. The sample was then cooled
down to –30 °C at 10 °C/min and
heated again to check for glass transition around 10 °C. Clearly, there
was no detectable Tg (Figure 2). The
sample was crystallized fully during cooling at 10 °C/min, which is
expected due to its strong tendency
to crystallize.
Since quench cooling increases the
chance of glass formation and HyperDSC offers the flexibility of cooling
at a much higher rate than conventional DSC, quench cooling experiments were performed on the sample
to study its effect on the glass formation. The sample was first melted at
200 °C and cooled down to –30 °C
at several different rates up to 500
°C/min. It was then heated at 100
°C/min to check for the glass transition. The results are shown in Figure
3. There is no glass formation at a
cooling rate up to 200 °C/min. Only
at a quenching rate of ≥300 °C/min
can the sample be quenched into an
Figure 4 shows the heating curves at
several different heating rates after the
sample was quenched at 500 °C/min.
The cold crystallization right after Tg
prevented accurate Tg determination
at a conventional scanning rate of 10
°C/min (inset, Figure 4). However,
HyperDSC is able to suppress kinetic
events such as cold crystallization.
The cold crystallization was pushed
to a higher temperature so that the Tg
measurement became possible as evidenced at 500 °C/min. Another obvious advantage of HyperDSC is the
increased signal associated with the
high scanning rate. Thus, low-energy
transition can be detected more easily
with HyperDSC.
D-mannitol has three common polymorphic forms. The D-mannitol
received has a β polymorph. δ and
α forms were made by cooling down
after melt at slow (0.5 °C/min) and
fast (10 °C/min) rates, respectively.
The selection rules that govern
Raman and FTIR spectroscopy are
different. Raman spectra feature
the symmetrical bonds within the
molecule, while FTIR spectra feature bonds that have strong dipole
moments. The two techniques
together provide unique and complementary insight into the structure of molecules.
Figure 5 shows the FTIR and
Raman spectra of three polymorphic forms of D-mannitol. Both
FTIR and Raman spectra show the
difference among these three polymorphs of D- mannitol due to the
varied arrangement of molecules in
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Volume 40, Number 14
the crystals. FTIR demonstrates the
obvious difference between 1200
and 1400 cm–1 in the C–H deformation vibrations region. In Raman,
the difference shows up in the region
between 1000 and 1200 cm–1.
15. Giannellini, V.; Bambagiotti-Alberti,
M.; Bartolucci, G.; Bruni, B.; Coran,
S.A.; Costantino, F.; Di Vaira, M. J.
Pharm. Biomed. Anal. 2005, 39, 444–54.
16. McGregor, C.; Saunders, M.H.; Buckton, G.; Saklatvala, R.D. Thermochim.
Acta 2004, 417, 231–7.
17. Burger, A.; Henck, J.; Hetz, S.;
Rollinger, J.M.; Weissnight, A.A.;
Stottner, H. J. Pharm. Sci. 2000,
89(4), 457–68.
Dr. Ye is Applications Scientist, and Mr. Byron is
Senior Product Specialist, PerkinElmer LAS, 710
Bridgeport Ave., Shelton, CT 06484, U.S.A.;
tel.: 203-402-1708; fax: 203-944-4928; e-mail:
[email protected]
Fast-scan DSC technology offers new
opportunities for materials characterization. The direct measurement
of Tg of D-mannitol is now possible
with the efficient cooling and heating capability of HyperDSC. Different
polymorphic forms can be identified
by FTIR and Raman spectroscopy.
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