The physico‐chemical properties of glipizide: New findings

Article abstract of DOI:10.3390/molecules26113142

The present work is a concrete example of how physico‐chemical studies, if performed in depth, are crucial to understand the behavior of pharmaceutical solids and constitute a solid basis for the control of the reproducibility of the industrial batches. In particular, a deep study of the thermal behavior of glipizide, a hypoglycemic drug, was carried out with the aim of clarifying whether the recognition of its polymorphic forms can really be done on the basis of the endothermic peak that the literature studies attribute to the melting of the compound. A number of analytical techniques were used: thermal techniques (DSC, TGA), X‐ray powder diffraction (XRPD), FT‐IR spectroscopy and scanning electron microscopy (SEM). Great attention was paid to the experimental design and to the interpretation of the combined results obtained by all these techniques. We proved that the attribution of the endothermic peak shown by glipizide to its melting was actually wrong. The DSC peak is no doubt triggered by a decomposition process that involves gas evolution (cyclohexanamine and carbon dioxide) and formation of 5‐methyl‐N‐[2‐(4‐sulphamoylphenyl) ethyl] pyrazine‐2‐carboxamide, which remains as decomposition residue. Thermal treatments properly designed and the combined use of DSC with FT‐IR and XRPD led to identifying a new polymorphic form of 5‐methyl‐N‐[2‐(4‐sulphamoylphenyl) ethyl] pyrazine‐2‐carboxamide, which is obtained by crystallization from the melt. Hence, our results put into evidence that the check of the polymorphic form of glipizide cannot be based on the temperature values of the DSC peak, since such a peak is due to a decomposition process whose Tonset value is strongly affected by the particle size. Kinetic studies of the decomposition process show the high stability of solid glipizide at room temperature.

Full text of DOI:10.3390/molecules26113142

molecules
Article
The Physico-Chemical Properties of Glipizide: New Findings
1
,
1
1
2
1
Giovanna Bruni * , Ines Ghione , Vittorio Berbenni , Andrea Cardini , Doretta Capsoni
,
1
1
and Amedeo Marini 1
Alessandro Girella , Chiara Milanese
1
C.S.G.I.—Department of Chemistry, Physical-Chemistry Section, University of Pavia, Via Taramelli 16,
7100 Pavia, Italy; ines.ghione01@universitadipavia.it (I.G.); vittorio.berbenni@unipv.it (V.B.);
2
doretta.capsoni@unipv.it (D.C.); alessandro.girella@unipv.it (A.G.); chiara.milanese@unipv.it (C.M.);
amedeo.marini@unipv.it (A.M.)
A.M.S.A. Anonima Materie Sintetiche Affini S.p.A., Viale Giuseppe Di Vittorio 6, 2100 Como, Italy;
a.cardini@amsacomo.it
2
*
Correspondence: giovanna.bruni@unipv.it; Tel.: +39-0382-987667
Abstract: The present work is a concrete example of how physico-chemical studies, if performed
in depth, are crucial to understand the behavior of pharmaceutical solids and constitute a solid
basis for the control of the reproducibility of the industrial batches. In particular, a deep study of
the thermal behavior of glipizide, a hypoglycemic drug, was carried out with the aim of clarifying
whether the recognition of its polymorphic forms can really be done on the basis of the endothermic
peak that the literature studies attribute to the melting of the compound. A number of analytical
techniques were used: thermal techniques (DSC, TGA), X-ray powder diffraction (XRPD), FT-IR
spectroscopy and scanning electron microscopy (SEM). Great attention was paid to the experimental
design and to the interpretation of the combined results obtained by all these techniques. We
proved that the attribution of the endothermic peak shown by glipizide to its melting was actually
wrong. The DSC peak is no doubt triggered by a decomposition process that involves gas evolution
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Citation: Bruni, G.; Ghione, I.;
Berbenni, V.; Cardini, A.; Capsoni, D.;
Girella, A.; Milanese, C.; Marini, A.
The Physico-Chemical Properties of
Glipizide: New Findings. Molecules
(
cyclohexanamine and carbon dioxide) and formation of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl]
pyrazine-2-carboxamide, which remains as decomposition residue. Thermal treatments properly
designed and the combined use of DSC with FT-IR and XRPD led to identifying a new polymorphic
form of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide, which is obtained by
crystallization from the melt. Hence, our results put into evidence that the check of the polymorphic
form of glipizide cannot be based on the temperature values of the DSC peak, since such a peak is
due to a decomposition process whose Tonset value is strongly affected by the particle size. Kinetic
studies of the decomposition process show the high stability of solid glipizide at room temperature.
2
021, 26, 3142. https://doi.org/
1
0.3390/molecules26113142
Academic Editors: Anan Yaghmur
and Adriana Violeta Ledet,i
Keywords: glipizide; differential scanning calorimetry; thermogravimetric analysis; decomposi-
tion; polymorph; 5-methyl-N-[2-(4-sulphamoylphenyl)ethyl]pyrazine-2-carboxyamide; kinetic study;
shelf-life
Received: 29 April 2021
Accepted: 21 May 2021
Published: 24 May 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
Glipizide (Figure 1), N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl] phenethyl)-5-
methylpyrazine-2-carboxyamide (GPZ), a second-generation sulfonylurea derivative, is
an oral hypoglycemic drug used to treat type II diabetes. Its therapeutic use is due to
the stimulation of the release of insulin through interaction with the SUR1 receptor on
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
K/ATP-sensitive channels in
sensitivity and decrease hepatic glucose production by an indirect extra pancreatic mecha-
nism [ ]. It is completely absorbed when administered orally but, having a short half-life,
is rapidly metabolized in the liver, and its inactive metabolites are excreted in urine [5,6].
β cells membrane [1–3]. Furthermore, it can increase insulin
4
4
.0/).
Molecules 2021, 26, 3142. https://doi.org/10.3390/molecules26113142
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 3142
2 of 20
Figure 1. Glipizide molecular structure.
GPZ is very slightly soluble in water and in an acidic environment. R. Matsuda et al.
−
1
reported a solubility of 20 mg L in water at room temperature [
under the same conditions, were obtained by N. Seedher and M. Kanojia, whose study also
revealed a higher solubility in basic rather than acidic conditions [ ]. Due to its very low
7] and similar results,
8
solubility in water, glipizide is classified as class II by BCS (biopharmaceutical classification
system); therefore, its bioavailability is limited by the dissolution rate [9].
According to the studies published in the scientific literature, GPZ melts at a tempera-
◦
ture higher than 200 C, and different melting temperatures have been reported [10
–
12]. The
crystal structure of glipizide has been recently addressed by single-crystal X-ray diffraction
data [13]. It crystallizes in the triclinic P-1 Space Group, Z = 2, a = 5.1578(3) Å, b = 8.9760(5) Å,
◦
◦
◦
3
c = 23.9704(13) Å, a = 83.247(2) , b = 85.543(2) , g = 78.987(2) , V = 1080.01(11) Å at 100 K.
The crystal structure data are deposited in the Cambridge Crystallographic Data Centre
(
CCDC N. 1516974). In the last few years studies have been performed with the aim to
identify new polymorphs of this compound [14 16]. This interest arises from the need to
improve its dissolution profile in order to achieve a higher bioavailability [17 18]. Renuka
–
,
et al. [14] claimed the identification of six different crystalline forms (forms I, II, III, IV,
V, and VI; all obtained by different crystallization methods) on the basis of a different
thermal behavior. However, both the experimental design of their measurements and
the conclusions drawn from these raised some doubts. Our main criticisms are related to
the following issues: (1) the differential scanning calorimetry (DSC) measurements were
performed at a single heating rate; (2) the DSC peaks were integrated with non-uniform
criteria; (3) an inappropriate comparison was made between XRPD (X-ray powder diffrac-
tion) patterns; (4) no TGA (thermogravimetric analysis) measurements were performed,
which can provide important information about thermal stability; (5) the deduction of the
monotropic relationship between the polymorph forms was based on weak considerations.
Another way to improve the pharmaceutical behavior of poorly soluble drugs is
to use them in the amorphous form, which, by virtue of its higher free energy, shows
higher solubility and dissolution rate [19
grinding, but to avoid its intrinsic tendency to recrystallize, a proper selection of the
process parameters is necessary [19 23]. K. Xu et al. [15 16] defined the process parameters
,20]. The amorphous form can be obtained by
–
,
to ball-mill glipizide form I, identified by Renuka et al. [14], that allow its transition to
form II (amorphous form) and form III. However, also in this work, the experimental set
up seems to be inappropriate, and the conclusions drawn from the experimental evidence
are not convincing. Indeed, more attention and a deeper analysis should be paid to the
mass changes measured in TGA.
In the present work the physico-chemical process underlying the endothermic peak
present in the DSC curve of glipizide, generally attributed to the melting of the active
principle, was deeply investigated. Since its temperature could be used to evaluate the
polymorphic purity of industrial batches of glipizide, it is important to verify the reliability
of this control method.
A wide range of analytical techniques was used: DSC, TGA, simultaneous DSC–
TGA (SDT), XRPD, Fourier-transform infrared spectroscopy (FT-IR), and scanning electron
microscopy (SEM). In addition, great attention was paid to the experimental set up and to
the complementary interpretation of the results obtained by all the techniques.

Molecules 2021, 26, 3142
3 of 20
2. Materials and Methods
2.1. Materials
Four production batches and two standard USP batches (USP R09020, USP H1H396)
of GPZ, together with a batch of one of its synthesis intermediates, 5-methyl-N-[2-(4-
sulphamoylphenyl) ethyl] pyrazine-2-carboxyamide (GS in the following), were kindly
provided by AMSA S.p.A. (Como, Italy).
2.2. Ground Samples
One of the production batches was ground by a planetary mill (Planetary Micro
MillPulverisette 7, Fritsch) in an agate ball-milling jar containing 50 balls of 5 mm in
diameter of the same material, with a 500-rpm rotation speed. Grinding periods of 10 min
were alternated with intervals of 5 min to avoid an overheating of the powder. The powder
was ground for 120 (GPZ2h), 180 (GPZ3h), 300 (GPZ5h), and 480 min (GPZ8h).
2.3. Analytical Techniques
2.3.1. Thermal Measurements
Simultaneous DSC–TGA measurements were performed by a SDT Q600 interfaced
with a TA5000 data station (TA Instruments, New Castle, DE, USA). The measurements
were performed in open standard aluminum pans under two different atmospheres, ni-
−
1
trogen flow (50 mL min ) or static air, at several heating rates (β): 0.5, 1, 2, 5, 10, and
·
−
1
20·K·min
.
Conventional DSC and TGA measurements were carried out by a DSC Q2000 ap-
paratus and a TGA Q5000 apparatus, both interfaced with a TA 5000 data station (TA
Instruments, New Castle, DE, USA). The DSC instrument was calibrated using ultrapure
◦
−1
(
99.999%) indium (m.p. = 156.6 C; ∆H = 28.54·J·g ) as standard. The heating rates used
−
1
were: 0.3, 0.5, 1, 2, 5, 10, 20, and 30 K
sample amounts of about 3–4 mg in open pans under nitrogen flow (25 mL min ) or in
air. Furthermore, both cyclic measurements with different final temperatures in the first
heating and measurements with an isothermal step were performed.
·
min . The measurements were performed on
−
1
·
2.3.2. FT-IR Measurements
For the FT-IR analysis a Nicolet FT-IR iS10 spectrometer (Nicolet, Madison, WI, USA)
equipped with ATR (attenuated total reflectance) sampling accessory (Smart iTR with
−
1
−1
diamond plate) was used. Thirty-two scans in the 4000–600 cm range at 4 cm resolution
were coadded.
2
.3.3. XRPD
XRPD measurements were performed by using a Bruker D5005 diffractometer (Bruker
BioSpin, Fällanden, Switzerland) using CuK radiation ( = 1.54056 Å), graphite monochro-
α
λ
mator, and scintillation detector. The patterns were collected in air at room temperature in
◦
step scan mode with a step size of 0.02 and counting time of 2 s per step in the angular
◦
range 2θ of 5–35 (voltage = 40 kV, current intensity = 40 mA).
2.3.4. SEM
SEM images were collected with a Zeiss microscope Evo MA10 (Carl Zeiss, Oberkochen,
Germany). Before the analysis, the samples were sputtered with carbon to make them
conductive.
3. Results and Discussion
3
.1. Preliminary Studies
−
1
Figure S1, Supplementary Materials, shows the DSC curves, all collected at 10 K min
·
from different batches. The shape of the endothermic peak (asymmetrical) is common to all
batches, but its onset temperature (Tonset) can be appreciably different. In particular, all the
production batches by AMSA S.p.A. (trace a of Figure S1 is representative of all production

Molecules 2021, 26, 3142
4 of 20
batches) and the USP H1H396 batch (trace b of Figure S1) provided identical results (within
◦
the experimental error). The Tonset was 214.5
±
0.8 C and the enthalpy change (
∆
H) was
−
1
290.8 ± 0.3 J·g
.
The thermal behavior of the USP R09020 batch was instead somewhat different (trace
c). While the enthalpy change was the same obtained for the USP H1H396 batch, the Tonset
◦
of the peak (204.9 ± 0.8 C) was significantly lower.
Additionally, for the GPZ3h sample (trace d) the enthalpy change was identical (within
◦
◦
the experimental error) to those already discussed, while the peak Tonset (206.3 C
±
0.8 C)
was lower than that of the original production batches (and then of USP H1H396), but
similar to that of USP R09020.
To summarize, except for the USP R09020 batch, all the batches analyzed as received
gave identical calorimetric results (Tonset and
∆H) within the experimental error. The
milling process (sample GPZ3h) lowered the Tonset of the peak without modifying the
enthalpy change.
USP R09020 differed from the other batches only for the appreciably lower Tonset of
the peak.
The fact that the measured enthalpy was identical for all the batches examined suggests
that they all have the same chemical/phase composition. This is confirmed by the perfect
superimposition of the XRPD patterns and of the FT-IR spectra collected on the samples of
the different batches (Figures S2 and S3A,B). The XRPD pattern well is comparable to the
simulated one, obtained by the crystal structure reported in literature [13]: the investigated
samples display the triclinic crystal structure. The reason why we observe different Tonset
for the USP R09020 batch will be discussed further below once additional knowledge has
been gained about the process behind the DSC peak.
In the following, the study of the thermal behavior of glipizide will be deepened.
Unless otherwise specified, the measurements were performed on just one of the production
batches.
3.2. Simultaneous DSC–TGA Measurements
3.2.1. Simultaneous DSC–TGA Measurements under Nitrogen Flow
As can be seen in Figure 2, the DSC endothermic peak is associated with a significant
mass loss measured on the TG curve. Furthermore, the measurements carried out at
−
1
−1
heating rates ranging from 1 K
·
min to 20 K
·
min show that the endothermic peak
. The shift concerns
shifts towards gradually increasing temperatures with increasing
β
both Tonset and T (see Table 1; T is the final temperature of the peak), but if the strong
f
f
dependency of T on
β
is expected, it is, on the contrary, a significant variation of Tonset,
f
which should be substantially independent of the heating rate in a melting process, is
unexpected.
Table 1. Mass change, Tonset, and T of the DSC peak measured by SDT on a GPZ production batch
f
under nitrogen flow at different heating rates.
β, K·min−
1
∆m%
Tonset, C
◦
T , C
◦
f
2
1
5
2
1
0
0
28.3
28.0
26.8
28.3
27.3
212.1
208.9
205.6
200.1
195.3
298.8
272.5
250.9
236.9
213.8
Mean value ± s.d.
2
7.7% ± 0.7%

Molecules 2021, 26, 3142
5 of 20
Figure 2. Simultaneous DSC–TGA curves recorded on one of the production batches at 10 K·min−1
under nitrogen flow.
Another noteworthy aspect is that the mass loss associated with the peak (also reported
in Table 1) was constant at any heating rate. A mass loss suggests that a decomposition
process takes place, and this could also explain the observed Tonset dependency on β. How-
ever, the fact that the mass loss remained constant while occurring in different temperature
ranges suggests that the underlying process is not a simple evaporation/sublimation of
a chemical substance but a real transformation that leads to a chemical entity of definite
composition, different from the initial one. The mass change was
−
27.7%
±
0.7%, and it
was measured by analyzing in each case the derivative thermogravimetric curve (DTG
curve). As it is well known, the determination of the enthalpy change requires the exact
integration of the peak, which is difficult in this case because of the quite different levels of
the baseline before and after the peak. Furthermore, the ∆H values measured with the SDT
instrument are less quantitatively reliable than those measured with a DSC instrument.
These are the reasons why the curves obtained with the simultaneous instrument were not
used for the measurement of enthalpy changes.
3.2.2. Simultaneous DSC–TGA Measurements in Air Atmosphere
The thermal behavior of glipizide in an air atmosphere was completely similar to that
observed under nitrogen flow. The DSC peak and the associated mass change were, indeed,
in the identical temperature range previously observed. Moreover, the mass change in
air—also independent of the heating rate—was
−
27.8%
±
0.5%, i.e., identical, within the
experimental error, to that obtained in nitrogen atmosphere. These findings indicate that
the decomposition underlying the DSC peak is not an oxidative process, since it proceeds
to an identical extent in air and in nitrogen atmosphere.
3.3. DSC and TGA Measurements
In order to confirm the framework deduced by SDT measurements and to perform
an accurate quantitative analysis, the thermal measurements were also performed by
−
1
−1
−1
independent DSC and TGA apparatuses. Heating rates from 30 K
were used. The Tonset of the endothermic peak ranged from 217.7
·
min to 0.5 K
±
·
min
min
◦
0.4 C at 30 K
·

Molecules 2021, 26, 3142
6 of 20
◦
−1
to 196.1
±
0.1 C at 0.5 K min (Table 2 and Figure S4, Supplementary Materials). The
·
−
1
peak enthalpy change remained constant at 291.0 ± 0.6 J·g
.
Table 2. Tonset, T , and enthalpy change measured by DSC on a GPZ production batch under nitrogen
f
flow at different heating rates.
β, K·min−
1
Tonset, C
◦
T , C
◦
∆H, J·g−1
f
3
2
1
5
2
1
0
0
0
217.7 ± 0.4
216.2 ± 0.4
214.5 ± 0.8
210.3 ± 0.3
205.2 ± 0.2
201.3 ± 0.4
196.1 ± 0.1
293.3 ± 4.6
285.1 ± 12.7
271.2 ± 3.5
257.3 ± 2.4
238.4 ± 1.4
229.2 ± 3.8
212.8 ± 5.1
291.2 ± 0.6
290.1 ± 0.5
290.8 ± 0.3
290.0 ± 0.3
290.2 ± 0.1
286.8 ± 3.7
0
.5
292.2 ± 2.2
Mean value ± s.d.
2
91.0 ± 0.6
TGA measurements confirmed that the mass loss associated with the calorimetric peak
was independent of and agreed, within the experimental error, with that measured by the
β
simultaneous apparatus. In addition, the TG curves obtained in air perfectly superimposed
to those under nitrogen flow (Figure S5, Supplementary Materials), and the effect of
increasing
β
was merely to shift the entire TG curve to higher temperatures (Figure S6,
27.9% 0.2%)
0.2%), which confirmed the non-oxidative nature of the
Supplementary Materials). Finally, the mass loss was the same in nitrogen (
da ne dc o imn pa io rs ai t ti mo no sp pr ho ec er es s(.−27.8%
−
±
±
3.3.1. Comments on SDT, DSC, and TGA Measurements
Our deductions from thermal measurements can be summarized as follows:
1.
What underlies the DSC peak is not a melting process but a decomposition process.
This is proven by two experimental findings: (a) its Tonset significantly increases with
increasing β, and this behavior is not compatible with a melting process; (b) the DSC
peak is associated with a consistent mass loss.
2.
The decomposition is non-oxidative, as proven by the fact that the mass loss is the
same both in air and nitrogen atmospheres.
Therefore, the attribution of the glipizide DSC peak to a simple melting process is not
correct [10
which involves a gaseous product evolution and then a mass loss under the peak. The
fact that such a mass loss is constant with changing (and then the temperature range in
–12]. The calorimetric peak is undoubtedly triggered by a decomposition process,
β
which the decomposition takes place) suggests that, in all cases, the same gaseous product
is released by the sample and the same decomposition product is obtained. It is worth
analyzing this aspect, verifying if, starting from the amount of the mass loss, the nature of
the gaseous phase released by the sample and then the nature of the decomposition residue
can be deduced.
Furthermore, it is worth noting that the experimental evidence described so far does
not require—but neither does it exclude—the co-presence of a melting process under
the DSC peak. This aspect also deserves clarification by further measurements able to
determine whether the decomposition is accompanied or followed by the melting of the
solid residue.
3.3.2. The Nature of the Decomposition Reaction
Assuming that the solid compound obtained by decomposition is in 1:1 stoichio-
m(g)
45.54(g·mol )
metric ratio with GPZ, from m grams of glipizide, corresponding to 4
=
−
1
−
3
m·2.244
×
10 moles, we should obtain an identical number of moles of decomposition
residue. Since the decomposition involves a mass loss of 27.9% (mean value obtained

Molecules 2021, 26, 3142
7 of 20
from TG measurements under nitrogen flow), the mass (grams) of the decomposition
1
00−27.9
. Given that both moles and mass values of the
100
residue must correspond to m·
decomposition residue are known, it is easy to calculate the molar mass of the solid residue:
ꢀ
ꢁ
1
00−27.9
(g)
100
m·
=
321.2 g·mol−1 . This value is very similar to the molar mass of 5-
methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide (320.4 g
represents the compound that could remain as residue, assuming that the decomposition
takes place with the breaking of the amide bond colored in red in the molecular structure
reported in Figure 3, according to the A reactive scheme in Figure 4. In this case the mass
change would be caused by the loss of cyclohexanamine (since its boiling temperature
m·2.244 × 10 3(mol)
−
−
·
mol 1), which
◦
is 134 C, it should be in vapor phase at the DSC peak temperature values) and carbon
dioxide.
Figure 3. Molecular structure of GPZ. The two chemical bonds that could be subjected to breaking
are colored in red and green.
Figure 4. Decomposition reaction schemes hypothesized for the GPZ molecule. (
sulphamoylphenyl) ethyl] pyrazine-2-carboxamide; ( ) Formation of 1-cyclohexyl-3-[[4-(2aminoethyl) phenyl] sulfonyl]
urea.
A) Formation of 5-methyl-N-[2-(4-
B

Molecules 2021, 26, 3142
8 of 20
Then, the quantitative data support the hypothesis that the DSC peak corresponds to
the decomposition of glipizide with the formation of 5-methyl-N-[2-(4-sulphamoylphenyl)
ethyl] pyrazine-2-carboxamide, which remains as solid residue.
It is worth noting that the glipizide decomposition could also take place with the break-
ing of the amidic bond colored in green in Figure 3, which would lead to the formation of
1-cyclohexyl-3-[[4-(2aminoethyl) phenyl] sulfonyl] urea and 5-methyl-2-pyrazinecarboxylic
acid, according to the B reactive scheme reported in Figure 4. However, we consider that
this second pathway is unlikely since 5-methyl-2-pyrazinecarboxylic acid has a boiling
◦
temperature of 316 C.
With the aim to confirm the hypothesized decomposition scheme, thermal measure-
ments with isothermal steps were performed to obtain GPZ samples that had undergone
a controlled decomposition in order to compare them with the GS samples, precisely
constituted by 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide. The
comparison was carried out by DSC, FT-IR and XRPD measurements.
3.3.3. Measurements with Isothermal Steps
The TGA measurements with isothermal steps at different temperatures and for
different time ranges were performed according to Table 3. The selected temperature
values were significantly lower than Tonset and even more than T , which define the
f
thermal range in which the decomposition takes place in dynamic conditions: the extent
of the decomposition reaction depends on both temperature and time so that the use of
isothermal temperatures lower than those of the dynamic measurements is compensated by
the longer time available to complete the reactive process in the isothermal measurements.
At each temperature the isothermal steps were allowed to proceed for at least the time
necessary to reach a constant mass. Relatively low values of isothermal temperatures have
the advantage of avoiding the melting process of the hypothesized decomposition residue
◦
(
whose melting point is 235 C). At the end of the isothermal steps, the samples, named as
reported in Table 3, were analyzed by both FT-IR and XRPD.
Table 3. Temperature and time of the isothermal steps performed on one of the production batches
of glipizide in TG furnace and codes of the recovered solid samples.
Temperature
of Isothermal Step, C
Time
Sample Code
◦
of Isothermal Step, min
2
10 min
1
1
1
1
70
75
80
85
210
150
135
125
GPZ1
◦
70
C
1
50 min
GPZ1
◦
75
C
GPZ11
GPZ11
35 min
◦
80
C
25 min
◦
85
C
FT-IR spectra of GPZ2
10 min
,
GPZ
150 min
,
GPZ
135 min
and GPZ185
125 min
samples were
C
◦
◦
◦
◦
1
70
C
175
C
180
C
almost indistinguishable from each other and from the spectrum of the GS sample, but they
2
10 min
definitely differed from that of GPZ. As an example, in Figure 5 the spectra of GPZ1
◦
70
C
and GPZ11
25 min
are reported, representing the two samples treated at the two ends of the
◦
85
C
isothermal step temperatures.
The XRPD patterns of these samples are also very similar to that of the GS sample,
as can be observed in Figure 6, where the results obtained for GPZ12
10 min
and GPZ185
125 min
◦
◦
70
C
C
samples are reported.

Molecules 2021, 26, 3142
9 of 20
Figure 5. FT-IR spectra of a GPZ production batch (a), GPZ12
10 min
(b), GPZ
125 min
(c), and GS (d) samples.
C
◦
◦
70
C
185

Molecules 2021, 26, 3142
10 of 20
), GPZ12
10 min
(
b), GPZ
125 min
(
c), and GS
Figure 6. XRPD patterns of a GPZ production batch (
d) samples.
a
◦
◦
70
C
185
C
(
Then, the FT-IR and XRPD characterization of the samples obtained after the isother-
mal steps confirms the reaction scheme according to which glipizide, after heating, un-
dergoes decomposition with formation of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl]
pyrazine-2-carboxamide.
At this point, our scheme of what happens when heating glipizide is quite clear.
Glipizide, when heated, decomposes. The decomposition produces a solid residue and a
gas phase, which evolves from the sample and is responsible for the mass loss observed.
The gas phase is cyclohexanamine, the solid phase is 5-methyl-N-[2-(4-sulphamoylphenyl)
ethyl] pyrazine-2-carboxamide (GS as defined in Section 2.1), which is an intermediate of
the glipizide synthesis and was provided by AMSA S.p.A., together with GPZ batches.
The study of the thermal behavior of GS will allow us to deepen our knowledge about the
decomposition of glipizide.
3
.3.4. Cyclic DSC Measurements on GS
◦
Cyclic DSC measurements with heating up to 250 C were performed on GS (Figure 7)
In the first heating, a melting endothermic peak at Tonset = 237.9 C with ∆H = 161.2 J·g
.
◦
−1
−
1
was present. In the following cooling (2 K
cess was present at a temperature significantly lower than that of the melting process
·
min ), an exothermic crystallization pro-
◦
−1
(
T
onset = 174.4 C and
∆
H =
−
120.6 J
·
g
). During the second heating, an endothermic
◦
−1
peak with Tonset = 214.3 C and ∆H = 134.4 J·g appeared.
Reiterating the cycle several times, i.e., heating and cooling the sample repeatedly,
the exothermic peak of the first cooling and the endothermic one of the second heating
were reproduced both in temperature and in enthalpy change values. This suggests that,
once melted, GS crystallizes in a polymorphic form GS*, whose melting temperature and
enthalpy are different from those of the original form and that, unlike this, is stable to
melting since it can be melted and obtained again by crystallization of the melt. We noted
that the shape of the crystallization peak of GS* (i.e., of the polymorph that invariably forms
from the melt) was rather strange (see the insert of Figure 7). The crystallization process was
so fast that the heat released caused an increase in the temperature of the sample, despite
the fact that the temperature of the calorimetric cell in which the sample was contained was
−
1
decreasing at a rate of 2 K
·
min . This happens because the crystallization is considerably
◦
◦
undercooled (174.4 C vs. 214.3 C of the subsequent melting) and, consequently, occurs
as a substantially instantaneous process; it is then foreseeable that the significant self-

Molecules 2021, 26, 3142
11 of 20
heating of the sample during crystallization leads to an underestimation of the enthalpy
of crystallization, whose absolute value is in fact lower than that of the melting enthalpy
120.6 J·g− vs. 134.4 J·g ).
1
−1
(
−
1
−1
min
Figure 7. DSC curves recorded on a GS sample: first heating at 10 K
(
·
min
(a
), cooling at 2 K
·
(b) and insert), and second heating at 10 K·min− (c).
1
The evidence from DSC measurements was confirmed by FT-IR and XRPD techniques.
◦
The measurements were performed on the GS sample, which was melted up to 250 C and
−
1
then cooled at 2 K
·
min to room temperature in DSC. The sample was coded GS* because,
according to our speculations, it should have been transformed, following the cooling after
the melting, into the polymorph GS*. The XRPD patterns and FT-IR spectra of GS* are
compared with those of GS in Figures 8 and 9 respectively.
It is immediately apparent at first glance that the XRPD patterns of the two samples
are quite dissimilar and reflect different crystallographic structures.
On the contrary, as expected, the differences between the FT-IR spectra of the two
samples are less evident: this happens because the technique shows the absorption of func-
tional groups characteristic of the molecules, and the functional groups remain unchanged
in the different polymorphic forms of the compound. The different crystallographic struc-
ture of the two polymorphic modifications reflects a different relative arrangement of the
molecules of the compound, against which more or less evident shifts of the absorption
bands of the functional groups can only be expected. Indeed, Table 4 shows that the absorp-
tion peaks/bands of GS are all present and shifted to a lower or higher wavenumber in the
GS* sample, confirming that the two samples correspond to polymorphic modifications of
the same compound.
To our best knowledge, in literature, the existence of polymorphs of GS (5-methyl-N-
[
2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide) is unknown.

Molecules 2021, 26, 3142
12 of 20
Figure 8. XRPD patterns of GS (a) and GS* (b) samples.
Table 4. Main peaks/bands of FT-IR spectra of GS and GS* (b) samples.
−
1
−1
GS* cm
GS cm
3
3
3
3
1
1
1
1
1
1
1
1
358
3392
3294
3170
3075
1639
1578
1532
1331
1300
1268
1153
1091
915
264
160
049
651
582
537
328
306
273
156
095
9
11
829
821

Molecules 2021, 26, 3142
13 of 20
Figure 9. FT-IR spectra of GS (a) and GS* (b) samples.
.3.5. Cyclic DSC Measurements on Glipizide
Now that the thermal behavior of GS (5-methyl-N-[2-(4-sulphamoylphenyl) ethyl]
3
pyrazine-2-carboxamide) has been studied in some detail, there is a key question: why is
the GS melting not observed in the DSC traces (Figure S4), if, according to our evidence, it
represents the decomposition residue of glipizide? At all heating rates, the Tmax values
of the decomposition peak, in correspondence to which a large portion of the sample had
decomposed, were lower than the melting temperature of GS, but the return of the peak to
the baseline (i.e., the part following Tmax) did not show any discontinuity due to melting
of the obtained GS. However, the return of the peak to the baseline was very slow, which

Molecules 2021, 26, 3142
14 of 20
could be justified by an endothermic process extended over a temperature range rather
than by the melting of a crystalline phase. To deepen this point, two Glipizide samples were
◦
prepared. One, coded GPZ2 , was obtained by heating a GPZ sample up to 250 C and
50
−
1
180
then cooling it (at 2 K
·
min ) down to room temperature. The other one, coded GPZ2
,
50
◦
−1
was a glipizide sample heated to 250 C, then cooled (at 2 K·min ) to room temperature,
◦
heated again up to 180 C, and then cooled back to room temperature. The XRPD patterns
of the two samples are reported in Figure 10, together with that of GS* (which is the same
pattern shown in Figure 8).
Figure 10. XRPD patterns of GS* (a), GPZ 21 (b), and GPZ250 (c) samples.
80
50
It seems clear that: (a) GPZ2 is mainly amorphous; (b) heating this sample up to
80 C (GPZ250) causes an at least partial crystallization; (c) the diffraction peaks of GPZ
50
◦
180
180
250
1
show a lower intensity but they have the same angular positions of those of the GS* sample.
Therefore, these results show that: (a) the residue obtained from glipizide decom-
position is a mainly amorphous form of GS; (b) this amorphous form crystallizes to the
polymorphic modification GS*.
We can explain the shape of the DSC peaks, especially the very slow return to the
baseline, considering that, in the experimental conditions used for the DSC measurements,
the glipizide decomposition produced amorphous GS: an amorphous phase does not
melt at a defined temperature, but it softens in a wide temperature range by a prolonged
endothermic process, exactly as it happened in our DSC curves.
3
.3.6. Obtaining Crystalline GS (5-methyl-N-[2-(4-sulphamoylphenyl) ethyl]
pyrazine-2-carboxamide)
To complete the picture, we still must verify if it is possible to identify the experimental
conditions of the DSC measurements that allow us to obtain GS in the crystalline form in-
stead of the amorphous phase from the glipizide decomposition. Obviously, if a crystalline
form of GS could be obtained, we could see its melting peak during the DSC scan. With this
aim, it is necessary: (1) to lower the initial temperature of the glipizide decomposition as
much as possible; (2) to restrict the thermal range necessary to complete the decomposition
process so that its final temperature is below the melting point of the crystalline form of
GS as much as possible; (3) to provide the amorphous phase, originated from the decom-
position, enough time for the transition in the crystalline phase. The operating mode to
pursue, at the same time, all the requirements described, is to further lower the heating rate,

Molecules 2021, 26, 3142
15 of 20
compared to the DSC measurements previously discussed. In Figure 11, the DSC curve
−
1
recorded on GPZ at 0.3 K
·
min is shown. The Tonset and T values of the decomposition
f
◦
◦
peak were 193.8
±
0.1 C and 205.6
±
0.2 C, respectively. The decomposition peak was
◦
followed by an endothermic peak with Tonset = 238 C, corresponding to the melting of
the polymorphic modification GS. As expected, in this experiment GS* was not obtained,
because, as noted above, this polymorph can form only from the GS melt.
Figure 11. DSC curve registered on glipizide under nitrogen flow at a heating rate of 0.3 K·min−1
.
3.3.7. Batches of Glipizide with Different DSC Peak Tonset: Explanation
Before closing the discussion about the interpretation of the thermal measurements,
it is important to return to the preliminary DSC measurements described in Section 3.1.
It was seen that, except for the USP R09020 batch, all the numerous analyzed batches
of glipizide provided identical results, within the experimental error, both for the Tonset
and the
∆
H values of the DSC peak. The USP R09020 batch distinguished itself from the
H value. However, as we observed in
others because of the lower Tonset, but not for the
∆
paragraph 3.1, the chemical composition of this batch was identical to that of all the other
batches analyzed.
Figure 12 shows the SEM images of three batches of glipizide: a production batch, USP
H1H396, and USP R09020. It was well evident that the mean size of the particles of the USP
R09020 batch were significantly lower than those of the production batch and of the USP
H1H396 batch. The lower Tonset of the DSC peak of USP R09020, the only characteristic
that distinguished it from the other batches, was due to the lower particle size.

Molecules 2021, 26, 3142
16 of 20
1
Figure 12. SEM images of a glipizide production batch, USP H1H396, and USP R09020 batches,
000× magnification.
5

Molecules 2021, 26, 3142
17 of 20
3.4. Kinetic Study of the Thermal Decomposition
The shift of the maximum temperature of the DSC peak (Tmax) when changing the
heating rate can be considered for the determination of the kinetic parameters of the
decomposition process. For this determination we adopted two methods frequently used
for the kinetic study in solid phase by dynamic thermal measurements: Kissinger and
Ozawa–Flynn–Wall methods [24–27].
3.4.1. Kissinger Method
The data used to verify the linear relationship predicted by the Kissinger equation are
reported in Supplementary Materials Table S1, while in Figure S7, the experimental data
points and their linear regression are reported. The equation obtained is:
ꢂ
ꢃ
β
43, 805
Tmax
2
ln
= 79.812 −
R = 0.9928
2
T
max
2
The good correlation coefficient (R ) confirms the existence of a linear relationship
between the variables.
−
1
From the slope of the straight line, the apparent activation energy of 364.2 kJ
obtained.
·
mol is
3
.4.2. Ozawa–Flynn–Wall Method
The data used to verify the linear relationship predicted by the Ozawa–Flynn–Wall
equation [24 27] are reported in Table S2, while in Figure S8, the data points and their
linear regression are reported. The equation obtained is:
–
log β = −1
9, 442
Tmax
+ 40.894 R = 0.9931
2
In this case as well, a good correlation coefficient between variables is obtained.
−
1
From the slope of the straight line, the apparent activation energy of 353.9 kJ
obtained, which is close to the value obtained by the Kissinger method.
·
mol is
The pre-exponential factor A was determined by Equation (1) under the E698-16
standard method stated by the ASTM International American regulatory body [28].
ꢂ
ꢃ
ꢂ
ꢃ
Ea
2
Ea
R Tmax
A = β
exp
(1)
R T
max
This method suggests replacing
β with an intermediate value between those used for
−
1
β (and using the value measured at that β as Tmax). Here, 5 K·min was used as β.
mol 1), A =
−
Using the E
a
value deducted from the Kissinger method (364.2 kJ
·
39
−1
1
.8
×
10 min is obtained, while using the E
method (353.9 kJ·mol ), A = 1.3 × 10 min is calculated.
a
deducted from the Ozawa–Flynn–Wall
−
1
38
−1
Substituting these values of activation energy and pre-exponential factor in the Arrhe-
◦
nius equation (Equation (2)), the kinetic constants of the decomposition at 25 C (298.15 K)
were obtained (Table 5). Assuming that the fractional lifetime is independent of the ini-
tial concentration of the reagent, as it happens in first-order kinetic, Equations (3) and
◦
(
4) were applied to determine half-life (
t
) and shelf-life (t ) values at 25 C. The kinetic
90
data obtained by the two methods (Kissinger and Ozawa–Flynn–Wall) are reported in
Table 5. The results indicate that glipizide is extremely stable at room temperature and
has a particularly long shelf-life, which is certainly longer than the conservation period
required for pharmaceuticals.

Molecules 2021, 26, 3142
18 of 20
ꢂ
ꢃ
Ea
R T
K = A·exp
−
(2)
0
.693
K
.105
K
t =
(3)
(4)
0
t90
=
Table 5. Kinetic parameters, half-life and shelf-life obtained with Kissinger and Ozawa–Flynn–Wall methods.
◦
◦
◦
Ea
kJ·mol
364.2
353.9
A
min
K at 25 C
min
t
1
2
at 25 C
t90 a 25 C
Years
Method
−
1
−1
−1
Years
3
9
8
−25
−24
18
17
Kissinger
Ozawa–Flynn–Wall
1.8 × 10
1.3 × 10
2.8 × 10
4.7 × 10
9.9 × 10
7.2 × 10
3
17
17
1.3 × 10
1.5 × 10
4. Conclusions
This work allowed us to obtain new information about the thermal behavior of
glipizide, which can be of interest both from a scientific point of view and from a practical
point of view, (i.e., for the pharmaceutical industry).
First, we shed light on the process responsible for the endothermic peak present in
the DSC curves of glipizide, and the reason why different batches of this compound can
show the above peak at a different temperature was revealed, correcting the literature data
attributing the peak to a melting process whose temperature can be used to differentiate
the polymorphic forms of the compound.
Thanks to a proper experimental design, we obtained strong evidence that the
DSC peak corresponds to a decomposition process. It was proven that 5-methyl-N-[2-
(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide is obtained from the decomposition
reaction, and several well-designed thermal treatments, in addition to the combined use
of thermal techniques, FT-IR and XRPD, allowed us to find a new polymorph of this
compound, unknown until now.
The kinetic studies of the decomposition process, performed with two different non-
isothermal methods based on the shift of the maximum temperature of the DSC peak with
the heating rate, show the high stability of the solid glipizide at room temperature.
Supplementary Materials: The following are available online. Figure S1: DSC traces of a production
−
1
batch (a), USP H1H396 (b), USP R09020 (c) and GPZ3h (d) samples at 10 K min heating rate,
Figure S2: XRPD patterns of a glipizide production batch (a), USP H1H396 (b), USP R09020 (c) and
GPZ3h (d) samples. XRPD simulated pattern of GPZ [13] (e), Figure S3: FT-IR spectra of a glipizide
production batch (a), USP H1H396 (b), USP R09020 (c) and GPZ3h (d) samples, Figure S4: DSC curves
−
1
−1
recorded on a glipizide production batch under nitrogen flow at 30 K min (a), 10 K min (b), 2 K
−
1
−1
min (c) and 0.5 K min (d), Figure S5: TG curves registered on a glipizide production batch at 10
K min under nitrogen flow (red) and in air (blue), Figure S6: TG curves registered on a glipizide
−
1
−
1
production batch under nitrogen flow at different heating rates. From right to left: 30 K min (blue),
− −1 −1 −1 −1
1
2
0
0 K min (red), 10 K min (violet), 5 K min (yellow), 2 K min (pink), 1 K min (black) and
−
1
.5 K min (green), Figure S7: Experimental data points plotted according to the Kissinger method,
Figure 8: Experimental data points plotted according to the Ozawa-Flynn-Wall method and their
linear regression. Table S1: Data used to determine the Kissinger equation, Figure S2: Data used to
determine the Ozawa-Flynn-Wall equation.
Author Contributions: Conceptualization, G.B. and A.M.; methodology, G.B. and A.M.; inves-
tigation, I.G., V.B., D.C. and C.M.; resources, A.C.; data curation, A.G.; writing—original draft
preparation, G.B. and I.G.; writing—review and editing, G.B. and A.M.; visualization, I.G..; supervi-
sion, G.B.; project administration, G.B. All authors have read and agreed to the published version of
the manuscript.

Molecules 2021, 26, 3142
19 of 20
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data available on request.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Not available.
References
1
.
Ämmälä, C.; Moorhouse, A.; Gribble, F.; Ashfleld, R.; Proks, P.; Smith, P.A.; Sakura, H.; Coles, B.; Ashcroft, S.J.H.; Ashcroft, F.M.;
et al. Promiscuous coupling between the sulphonylurea receptor and inwardly rectifying potassium channels. Nat. Cell Biol. 1996
79, 545–548. [CrossRef] [PubMed]
,
3
2
.
Oh, C.; Kohanim, S.; Kong, F.; Song, H.; Huynh, N.; Mendez, R.; Chanda, M.; Kim, E.E.; Yang, D.J. Sulfonylurea receptor as a
target for molecular imaging of pancreas beta cells with 99mTc-DTPA-glipizide. Ann. Nucl. Med. 2012, 26, 253–261. [CrossRef]
[PubMed]
3
4
.
.
Proks, P.; Reimann, F.; Green, N.; Gribble, F.; Ashcroft, F. Sulfonylurea Stimulation of Insulin Secretion. Diabetes 2002, 51,
S368–S376. [CrossRef] [PubMed]
Tan, B.; Yang, A.; Yuan, W.; Li, Y.; Jiang, L.; Jiang, J.; Qiu, F. Simultaneous determination of glipizide and its four hydroxylated
metabolites in human urine using LC–MS/MS and its application in urinary phenotype study. J. Pharm. Biomed. Anal. 2017, 139,
1
79–186. [CrossRef]
5
6
7
8
9
1
1
1
.
.
.
.
.
Brogden, R.N.; Heel, R.C.; Pakes, G.E.; Speight, T.M.; Avery, G.S. Glipizide: A Review of its Pharmacological Properties and
Therapeutic Use. Drugs 1970, 18, 329–353. [CrossRef]
Artini, D.; Abbiati, R.; Orsini, G.; Parenti, M.A.; Bloch, K.; Daturi, S.; Mandelli, V. Pharmacodynamic aspects of two sulphonylurea
derivatives glipizide and glibenclamide. Diabetologia 1973, 9, 311–316. [CrossRef]
Matsuda, R.; Li, Z.; Zheng, X.; Hage, D.S. Analysis of glipizide binding to normal and glycated human serum albumin by
high-performance affinity chromatography. Anal. Bioanal. Chem. 2015, 111, 44–50. [CrossRef]
Seedher, N.; Kanojia, M. Co-solvent solubilization of some poorly-soluble antidiabetic drugs. Pharm. Dev. Technol. 2009, 14,
1
85–192. [CrossRef]
Jamzad, S.; Fassihi, R. Development of a controlled release low dose class II drug-Glipizide. Int. J. Pharm. 2006, 312, 24–32.
CrossRef]
[
0. Li, Q.; Wena, H.; Jiac, D.; Guana, X.; Pand, H.; Yanga, Y.; Yua, S.; Zhua, Z.; Xiang, R.; Pana, W. Preparation and investigation of
controlled-release glipizide novel oral device with three-dimensional printing. Int. J. Pharm. 2017, 525, 5–11. [CrossRef]
1. Thakral, S.; Madan, A.K. Urea co-inclusion compounds of glipizide for the improvement of dissolution profile. J. Incl. Phenom.
Macrocycl. Chem. 2007, 60, 203–209. [CrossRef]
2. Pandey, N.K.; Sehal, H.R.; Garg, V.; Gaur, T.; Kumar, B.; Singh, S.K.; Gulati, M.; Gowthamarajan, K.; Bawa, P.; Rajesh, S.Y.; et al.
Stable Co-crystals of Glipizide with Enhanced Dissolution Profiles: Preparation and Characterization. AAPS PharmSciTech 2017
,
1
8, 2454–2465. [CrossRef]
1
3. Samie, A.; Desiraju, G.R.; Banik, M. Salts and cocrystals of the antidiabetic drugs gliclazide, tolbutamide, and glipizide: Solubility
enhancements through drug-coformer interactions. Cryst. Growth Des. 2017, 17, 2406–2417. [CrossRef]
4. Singh, S.K.; Gulati, M.; Kaur, I. Characterization of solid state forms of glipizide. Powder Technol. 2014, 264, 365–376. [CrossRef]
5. Xu, K.; Xiong, X.; Zhai, Y.; Wang, L.; Li, S.; Yan, J.; Wu, D.; Ma, X.; Li, H. Effect of milling conditions on solid-state amor-phization
of glipizide and characterization and stability of solid forms. J. Pharm. Biomed. Anal. 2016, 129, 367–377. [CrossRef]
6. Xu, K.; Xiong, X.; Li, S.; Tang, P.; He, J.; Yang, H.; Li, H. A new polymorph of glipizide with enhanced properties obtained using
environmentally friendly methods. CrystEngComm 2016, 18, 4508–4512. [CrossRef]
1
1
1
1
7. Kuang, Y.; Gao, X.; Niu, Y.; Shi, X.; Zhou, W. Polymorphic characterization, pharmacokinetics, and anti-inflammatory activity of
ginsenoside compound K polymorphs. Molecules 2021, 26, 1983. [CrossRef]
1
1
8. Haleblian, J.; McCrone, W. Pharmaceutical applications of polymorphism. J. Pharm. Sci. 1969, 58, 911–929. [CrossRef]
9. Abdul-jabbar, S.; Wong, D.W.; Martin, G.P.; Woodhead, B.; Royall, G. Repurposing melt degradation for the evaluation of mixed
amorphous crystalline blends. AAPS PharmSciTech 2021, 22, 105. [CrossRef]
2
2
2
2
0. Chieng, N.; Zujovic, Z.; Bowmaker, G.; Rades, T.; Saville, D. Effect of milling conditions on the solid-state conversion of ranitidine
hydrochloride form 1. Int. J. Pharm. 2006, 327, 36–44. [CrossRef]
1. Willart, J.-F.; Durand, M.; Briggner, L.-E.; Marx, A.; Danède, F.; Descamps, M. Solid-State Amorphization of Linaprazan by
Mechanical Milling and Evidence of Polymorphism. J. Pharm. Sci. 2013, 102, 2214–2220. [CrossRef]
2. Descamps, M.; Willart, J.F.; Dudognon, E.; Caron, V. Transformation of pharmaceutical compounds upon milling and comilling:
The role of T(G). J. Pharm. Sci. 2007, 96, 1398–1407. [CrossRef]
3. Desprez, S.; Descamps, M. Transformations of glassy indomethacin induced by ball-milling. J. Non-Cryst. Solids 2006, 352,
4
480–4485. [CrossRef]

Molecules 2021, 26, 3142
20 of 20
2
2
2
2
2
4. Starink, M. The determination of activation energy from linear heating rate experiments: A comparison of the accuracy of
isoconversion methods. Thermochim. Acta 2003, 404, 163–176. [CrossRef]
5. Pourmortazavi, S.; Kohsari, I.; Teimouri, M.; Hajimirsadeghi, S. Thermal behaviour kinetic study of dihydroglyoxime and
dichloroglyoxime. Mater. Lett. 2007, 61, 4670–4673. [CrossRef]
6. Shamsipur, M.; Pourmortazavi, S.M.; Beigi, A.A.M.; Heydari, R.; Khatibi, M. Thermal Stability and Decomposition Kinetic Studies
of Acyclovir and Zidovudine Drug Compounds. AAPS PharmSciTech 2013, 14, 287–293. [CrossRef]
7. Fednuik-Hofman, L.; Bayon, A.; Donne, S.W. Kinetics of solid-gas reactions and their application to carbonate looping systems.
Energies 2019, 12, 2981. [CrossRef]
8. ASTM International. Standard Test Method for Kinetic Parameters for Thermally Unstable Materials Using Differential Scanning
Calorimetry and the Flynn/Wall/Ozawa Method; E698-16; ASTM International: West Conshohocken, PA, USA, 2016.