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Thermal decomposition investigation of paroxetine and sertraline
Accepted Manuscript Title: Thermal decomposition investigation of paroxetine and sertraline ´ Authors: A.P.G. Ferreira, B.V. Pinto, E.T.G. Cavalheiro PII: DOI: Reference:
S0165-2370(18)30664-8 https://doi.org/10.1016/j.jaap.2018.09.022 JAAP 4436
To appear in:
J. Anal. Appl. Pyrolysis
Received date: Revised date: Accepted date:
31-7-2018 18-9-2018 24-9-2018
´ Please cite this article as: Ferreira APG, Pinto BV, Cavalheiro ETG, Thermal decomposition investigation of paroxetine and sertraline, Journal of Analytical and Applied Pyrolysis (2018), https://doi.org/10.1016/j.jaap.2018.09.022 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Thermal decomposition investigation of paroxetine and sertraline A.P.G. Ferreira, B.V. Pinto and É.T.G. Cavalheiro Departamento de Química e Física Molecular, Instituto de Química de São Carlos, USP,
SC RI PT
Av. Trabalhador São-Carlense, 400, Caixa Postal 780, São Carlos, São Paulo CEP 13560970, Brazil.
*[email protected]
HIGHLIGHTS
Sertraline and paroxetine were submmited to thermal, and hot satage micrsocopy
U
analysis;
N
Paroxetine presented concomitante dehydration and melting followed by crystallization;
A
It decomposed in three mass loss steps releasing HCl, piperidine, fluorobenzene and CO2;
M
Sertraline undergoes sublimation or solid transformation depending on the heating rate;
D
Decomposition occured in two steps releasing methylamine, tetraline, dichlorobenzene
TE
and HCl;
EP
A complete description of the termal behavior of both pharmaceuticals was presented
CC
Abstract
Antidepressants paroxetine and sertraline both as their hydrochlorides were studied
regarding thermal behavior by TG/DTG-DTA, DSC, hot-stage microscopy, X-ray
A
diffraction and coupled TG-FTIR. Paroxetine presented a single mass loss step after dehydration, in nitrogen. However, DTA curve revealed that such degradation actually occurs in three steps, in which HCl, piperidine, fluorobenzene and CO2 are released. In air decomposition took place in a similar way. DSC showed endothermic peaks related to melting and dehydration of paroxetine. During evolved gases analysis it was possible to observe overlapped signals related to HCl and piperidine absorption. Sertraline, on its turn,
presented sublimation when slowly heated or alternatively a solid transition from Form II to Form III at c.a. 199°C followed by two mass losses when heated at higher heating rates. In the first degradation step methylamine is released. The second step is related to the loss of tetraline, dichlorobenzene and HCl, as revealed by TG-FTIR. Based on these data, thermal
SC RI PT
decomposition mechanisms were proposed for both drugs.
Keywords: paroxetine, sertraline, antidepressant, evolved gas analysis, thermal degradation 1.
Introduction
Paroxetine ((3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)
U
piperidine) and sertraline ((1S-cis)-4-(3,4- dichlorophenyl)-1,2,3,4- tetrahydro-N-methyl-1-
A
N
naftalenamine), whose structural formulas are:
Paroxetine
M
Sertraline
H N
H
O
Cl
CH3 H HN
TE
O
D
H O
Cl
EP
F
CC
use to be largely used in the treatment of humor disorders acting as allosteric serotonin selective reuptake inhibitors (SSRI).
A
By its turn, thermal analysis is defined “as the study of the relationship between a sample
and its temperature while it is heated or cooled in a controlled manner”.[1] Regarding thermal analysis of pharmaceutical samples, these techniques represent important tools once they can provide important information including stability studies, shelf life, investigations on polymorphic and phase transformations, establishment of mechanisms for thermal behavior, drug-excipient interactions in pre-formulation studies, characterization of drug delivery systems,
purity determination among others.[2,3] However relative few studies concerning the thermal behavior of paroxetine and sertraline can be found in the literature. For paroxetine, two polymorphic forms have been identified, called Form I hemihydrate and the anhydrous Form II. Pina et al. studied these polymorphs and also investigated the
SC RI PT
generation of the dehydrated paroxetine hydrochloride from the hemihydrate, using
thermogravimetry, differential scanning calorimetry and X ray diffraction in open and closed sample holders as well as in different heating rates. These authors concluded that dehydration of paroxetine Form I involves a complex and uncommon process. They described a new
isostructural anhydrous Form I after dehydration of Form I hemihydrate. [4] However the authors do not describe how such transition occurs.
U
Investigation concerning hydration/dehydration of paroxetine hydrobromide was reported
N
by Carvalho and co-workers. In that paper, structural and thermochemical studies were
A
performed up to 200°C, however further decomposition steps were not concerned regarding
M
volatiles or residual degradation products.[5] Conclusions are similar to those of Pina et al. [6] Still regarding polymorphism, Murthy e Weeratunga described a new form for paroxetine,
D
that they called Form III. It was obtained by the recrystallization of paroxetine free base from methyl iso-butyl ketone. Based on DSC curves these authors found that this new Form III melts
TE
between 156 and 162 °C. [7]
Differential scanning calorimetry (DSC) was used in drug delivery systems and
EP
drug/excipient compatibility studies in which paroxetine is a component.[8-11] Concerning sertraline thermal behavior, Sysko and Allen [12], described five different
CC
polymorphic forms. According to these authors Form II undergoes a solid-solid transition to Form III, when heated at c.a. 180 °C. On the other hand, Johnson and Chang [13] described the
A
DSC behavior of four polymorphs of sertraline, that includes a solid-solid-transformations of Forms I and II to Form III. On further heating, Form III decomposes and sublimates, according to Hot Stage Microscopy data. He and co-workers characterized sertraline racemates and enantiomers by differential scanning calorimetry and spectroscopic techniques [14]. Hot stage microscopy was used to elucidate the melting point of binary mixtures [15], while the compatibility with liposomal systems was investigated by Harbi et al..[16]
Thermogravimetry and differential scanning calorimetry were used to characterize cyclodextrin complexes with sertraline [17,18], as well as in polymorphism studies.[19] Zayed et al. used TG and DTA to investigate thermal behavior of sertraline and compared these results with electron ionization mass spectrometry (EI-MS) spectroscopy in order to
SC RI PT
propose a fragmentation mechanism. Theoretical calculations were also performed to support the results. [20]
Thus, there are relatively few studies regarding thermal behavior of these antidepressants, pointing to the need of a deeper evaluation of the thermal properties of paroxetine and sertraline including a better description of polymorphic transformation and/or sublimation. In this work studies involving thermogravimetry (TG), differential thermal analysis (DTA), differential
U
scanning calorimetry (DSC), hot stage microscopy, powder X-ray diffraction (PXRD) and
N
evolved gas analysis (TG-FTIR) have been performed in order to propose a complete thermal
1.
Material and Methods
M
A
behavior mechanism for both drugs.
D
Paroxetine and sertraline hydrochlorides of pharmaceutical grade were obtained from
TE
Fagron Farmacêutica (Brazil) and used as received. TGA/DTG-DTA curves were collected in a simultaneous TG–DTA SDT-Q600 modulus,
EP
controlled with Thermal Advantage software (v. 2.5.0.256), both from TA Instruments. TG curves were taken using sample masses of ca. 7.0 mg (± 0.1 mg) in open -alumina sample
CC
holders, at 10 ºC min-1 heating rate from room temperature to 1000ºC, under dynamic air and nitrogen atmosphere flowing at 50 mL min-1. When considered necessary to better understand some events, experiments were conducted using other heating rates (5 and 20 ºC min-1) and
A
sample masses (c.a. 0.50 mg). DSC curves were obtained in a Q10 Differential Calorimetric Module, controlled by the
Thermal Advantage Series software (v. 2.5.0.256) both from TA Instruments, using sample masses of c.a. 5.0 mg ± 0.1 mg in covered aluminum sample holder with a 0.7 mm pinhole in the center of the lid, using heating rate of 10ºC min-1. For paroxetine, data were collected between room temperature and 170ºC (1st cycle) and -60 to 170ºC (other cycles). For sertraline, data were
collected between room temperature and 150ºC (1st cycle) and -60 to 150ºC (other cycles). In all cases, dynamic nitrogen atmosphere flowing at 50 mL min-1 was used. In the case of paroxetine, runs using open sample holders, temperature intervals and different heating rates of 5 and 20 ºC min-1 were also used to study its dehydration and melting process. For Sertraline different
SC RI PT
temperature ranges were used. These conditions were described when used.
SDT-Q600 (TA Instruments), coupled to a Nicolet iS10 FTIR Spectrometer were used to characterize gaseous products evolved during decomposition of the drugs. The transfer line was composed of a thermally insulated stainless steel tube of 120 cm length and 2 mm inner diameter, heated at a constant temperature of 225ºC. FTIR measurements were carried out with a DTGS detector in a gas cell heated at a constant temperature of 250ºC. The interferometer and the gas
U
cell compartments were purged with nitrogen. In this case, thermogravimetric curves were taken
N
in N2 flowing at 50 mL min-1, at 10ºC min-1 heating rate and sample of 15 mg.
A
Hot stage microscopy was performed using a Mettler-Toledo HS82 hot stage coupled to an Olympus BX51 microscope equipped with a digital camera. Samples were heated at 10º C
Results and discussion
TE
2.
D
M
min-1 up to temperatures close to the event and at 4°C min-1 during the event of interest.
2.1. Paroxetine hydrochloride
EP
TG/DTG-DTA curves of paroxetine hydrochloride are presented in Figure 1, while the quantitative data regarding mass losses (experimental and calculated), temperature interval and
CC
peak temperatures are summarized in Table 1. In nitrogen, the sample presented a water loss from the start of the run up to 162.8°C
attributed to dehydration of paroxetine hydrochloride equivalent to the loss of 0.5 water molecule
A
in agreement with Pina et al. [4,6], although those authors did not presented TG curves. This is in agreement with previous reports [5] for the similar salt paroxetine hydrobromide. After dehydration the sample apparently decomposed in a single mass loss step according to the TG curve. However the DTG curve revealed that the decomposition actually took place in three steps, with the loss of HCl, followed by the release of piperidine and fluorobenzene and finally CO2. Details of the identification of volatiles will be described later in evolved gas analysis
(EGA) results. After these events a carbonaceous residue was formed at c.a. 800°C, which slowly decomposes until the end of the experiment at 1000°C resulting in 21.1% of the initial mass. The inset in Figure 1.a obtained with lower samples mass (3.0 mg) and at 5.0 °C min-1 revealed that melting process causes a turbulence in the sample holder that led to a
SC RI PT
drift in TG signal, suggesting that dehydration is accompanied by melting or other more complex process, resulting in an accommodation of the sample during melting, since DTA (Figure 1.b) did not present any additional event at this temperature. (a)
100
TGA
100
150
200
250
0.4
Temperature / °C
0.2
-1
20
0.0
600
-0.2 1000
800
0
0
200
400
600
-0.7 1000
800
Temperature / °C
M
Temperatura / °C
-0.6
endo
A
400
-0.5
-1
200
40
20
0 0
-0.4
U
50
N
0
0.6
-0.3
60
Mass / %
Mass / %
DTG
80
Derivative Mass / % °C
0.8 60
40
-0.2
1.0
2.0 %
Temperature Difference / °C mg
80
-0.1
(b)
100
1.2
Fig. 1 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. N2 (50 mL min-1). Inset: TG/DTG curve using
TE
D
sample mass of 3.0 mg (± 0.1 mg) and heating rate of 5.0 °C min-1.
0.5 0.4 0.3 0.2
20
0.1
A
0.1 60 0.0 40
-0.1 -0.2
20
endo
400
600
Temeprature / °C
800
-0.1 1000
-0.3
0 0
200
400
600
800
-0.4 1000
Temperature / °C
Fig. 2 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
-1
200
0.2
0.0
0
0
-1
CC
40
0.3
80
Mass / %
EP
0.6
Derivative Mass / % °C
60
(a)
100
0.7
Temperature Difference / °C mg
80
Mass / %
0.8
(a)
100
N U SC RI PT
Table 1. Proposed events, mass losses, temperature ranges and DTA peaks of paroxetine hydrochloride TG analysis under N2 and air TG data
DTA data
Trange / ºC
Mass Loss / % TG Calculated
Peak / °C
C19H20FNO3 • HCl • 0.5H2O C19H20FNO3 • HCl + 0.5H2O
25-162.8
1.7
2.5
122.3
C19H20FNO3 • HCl C19H20FNO3 + HCl
162.8-295.4
9.8
10.0
272.8
C19H20FNO3 C8H4O3 + C5H5F + C5H11N
295.4-368.7
49.4
49.6
303.7
C8H4O3 carbonaceous residue + CO2
368.7-515.1
11.3
12.0
carbonaceous residue decomposition
515.1-1000
6.1
---
residue
1000
21.1
---
C19H20FNO3 • HCl • 0.5H2O C19H20FNO3 • HCl + 0.5H2O
25-131.8
2.3
2.5
123.2
C19H20FNO3 • HCl C19H20FNO3 + HCl
131.8-308.7
9.9
10.0
274.4
C19H20FNO3 carbonaceous residue
308.7-440.5
39.6
-
380.1
Carbonaceous residue burn
440.5-651.6
47.3
-
537.8
residue
1000
0.7
-
Process
A
M
ED
PT
CC E
Air
A
Nitrogen
Carvalho and co-workers [21] investigated the dehydration of both paroxetine hydrobromide and nitrate salts and described their melting. These authors concluded that dehydration is not associated with polymorphic transitions or change in crystalline habit before melting. However, any detailed description of decomposition of paroxetine hydrochloride has
SC RI PT
been found in literature.
In air atmosphere the dehydration process occurred in a similar way, including the
turbulence in the TGA signal. However, after releasing HCl the decomposition undergoes via formation of the carbonaceous residue that burns in the 440-650°C range, with practically no residue remaining at such temperature.
Figure 3 depicts DSC heat-cool-heat curves of paroxetine hydrochloride obtained in
U
closed sample holders with a central pin hole at 10 ºC min-1 and reveals an endothermic event at
N
c.a. 130 °C and a shoulder at 138 °C, during the first heating. On subsequent cooling and second
A
heating, only second order transitions were observed, demonstrating the presence of amorphous material. In this first approach the events can be attributed to dehydration and melting
M
respectively. However, careful look to such process suggests that it can be more complex than a
D
single dehydration/melting event which is in agreement with previous studies. [4-6] st
EP
cooling
-1
1.5 W g
-1
0.15 W g
CC
Heat Flow / W g
-1
endo
TE
1 heating
nd
2 heating
-1
A
0.20 W g
-40 -20 0
20 40 60 80 100 120 140 160 180 Temperature / °C
Fig.3 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in closed with a pin hole with sample mass of 5.0 mg and heating rate of 10 °C min-1, in heat-cool-heat mode.
Thus DSC curves were also obtained in nitrogen in covered with a central pinhole in the lid and open (Fig. 4.a) sample holders in order to better characterize these events.
From the DSC curve obtained in covered sample holder with a pinhole it was possible to observe two endothermic events, the first centered at 130°C followed by a shoulder at 138°C (Fig. 4.a). These results are quite similar to those obtained by Pina. [Pina et al., 2014] who attributed these events to dehydration followed by melting of the hemihydrate Form I,
SC RI PT
represented by two endothermic events.
However the results in open sample holder suggested the presence of a third event (Fig. 4.a), this one exothermic, centered at 131.6ºC, which is plausible once the superimposition of exothermic and endothermic DSC peaks results in the summation of heats evolved and absorbed resulting in non-resolved signals.
DSC curves were also obtained under different heating rates in an attempt for better
U
attributing these events resulting in the curves presented in Fig. 4.b. When heating at 5.0
°C min-1, a first peak is evidenced at 124 °C followed by a poorly defined shoulder at 130 °C. At
N
20 °C min-1, a single broad peak is observed centered at 140°C, suggesting that all events are
A
superimposed. The onset temperature changes go from 113.5, 119.8, 123.2 ºC, respectively at
M
5.0, 10 and 20 ºC min-1.
Other experiments were also performed in different temperature ranges as represented in
D
Fig. 4.c. The sample was heated until 115°C, cooled until 25 °C and reheated until 180 °C. During the second heating it was possible to observe, that the endothermic peak remains at
TE
124.2°C, while a second order transition is observed at 73.3 °C (mid-point), suggesting that the first heating reached a temperature in which the melting process took place, so the transition at
EP
73.3 °C is due to the fact the sample melted with no recrystallization on cooling. Thus, combined TGA and DSC results led to conclude that the first endothermic peak
CC
observed is related to concomitant dehydration and melting of paroxetine. In this way the poorly resolved exothermic peak at 131.6 ºC in open sample holder (Fig. 4.a), can be related to a
A
crystallization of a different form, after dehydration of paroxetine hydrochloride hemihydrate.
Heat Flow / W g
open (a) endo
40
60
80
100
120
140
160
180
Temperature / °C
= 5 °C min
-1
-1 0.1 W g
U
-1
-1 0.2 W g
N
(b)
= 20 °C min
-1 0.5 W g
60
M
endo 40
-1
A
Heat Flow / W g
-1
= 10 °C min
SC RI PT
-1
closed -1 0.2 W g
80
100
120
140
160
180
D
Temperature / °C
st
1 heating until 115 °C
A
CC
EP
Heat Flow / W g
-1
TE
-1 0.1 W g
-1 0.1 W g
cooling until 25°C
(c)
nd
2 heating until 200°C -1 0.15 W g
endo 40
60
80
100
120
140
160
180
Temperature / °C
Fig.4 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in aluminum crucible. (a) using open and closed (with a pinhole in the lid) sample holder and heating rate of 10 °C min-1, (b) heating curves using sample mass of 3.0 mg and different heating rates () and (c) heat-cool-heat curves with sample mass of 3.0 mg and heating rate of 10 °C min-1, heating until dehydration and then reheating until 175 °C.
These processes were also investigated using hot stage microscopy. Results are presented in Figure 5 and from these micrographies, it was possible to see that melting started at 123°C (Fig. 5.b), while a crystallization takes place at 129 ºC (Fig. 5.c). The new solid than melts slowly (Fis 5.d-g), being liquid at 135 °C (Fig. 5.h). Small temperature differences regarding the DSC
SC RI PT
data can be related to the distinct heating rates and lower sample mass used in hot stage. No
evidences of water release were observed once the water content is only c.a. 2.5 % (0.5 H2O per mol of sertraline) of the total mass of the sample.
Thus according to the hot stage images the paroxetine·HCl·0.5H2O crystals are
dehydrated and concomitantly melted. Then a new form crystallizes from the liquid phase, probably as an anhydrous Form I After that this new form also melted.
U
The whole process is better visualized in the footage presented as Supplementary
N
material. This new form could not be insulated for deeper analysis, but it can be the anhydrous
A
A
paroxetine hydrochloride described by Pina et al [4].
C
D
F
G
H
TE
D
M
B
CC
EP
E
A
Fig. 5 Hot stage microscopy photographs of paroxetine from 88 to 127 °C, in air at 2.0 °C min-1 heating rate (magnification 50x).
These results complete the observations from Pina [Pina et al. 2014]. However those authors did not describe the crystallization of the anhydrous form from the melted dehydrate, once they do not described the shoulder referent to the crystallization observed in the DSC curves. Here, it is clearly confirmed by the hot stage experiment.
Characterization of gases evolved during thermal decomposition was performed by TGFTIR. According to the Gram-Schmidt graph (not presented), the largest amount of gases reached the FTIR detector at 35 min (approximately 360-370°C). Signals before that time are related to dehydration step.
SC RI PT
Figure 6 depicts the FTIR spectrum of the gases evolved at 31 min (345.7 °C) of TG run. It is clear the presence of bands related to H-Cl vibration, in the region from 3250 to 2500 cm-1, which is in agreement with the calculations made from TG curves (Table 1), revealing the release of the salt counter ion. When these calculations are considered, the next step is the release of piperidine and fluorobenzene. Both piperidine and fluorobenzene present vibrational bands in the same region that those from HCl, making difficult to discriminate these signals. However, it was
U
possible to observe that at 35 minutes (368.7°C) the set of bands related to H-Cl is distorted at
N
around 2950 cm-1 region in which piperidine absorbs, confirming its presence in the gas phase
A
(Fig. 7).
M
Based on all data obtained, a tentative mechanism for the thermal degradation of
3200
TE
D
paroxetine hydrochloride is presented in Fig. 8.
3100
3000
2900
2800
2700
2600
2500
-1
EP
31.2 min / 327.7°C
0.05
A
CC
Absorbance / a.u.
Wavenumber /
HCl from database
0.5
4000
3500
3000
2500
2000
1500
Wavenumber / cm
1000
500
-1
Fig. 6 FTIR spectra obtained at 327.7°C, during paroxetine heating, and HCl from database.[22] Insert: detail of the region from 3250 – 2500 cm -1.
31.2 min / 327.7°C
SC RI PT
35.3 min / 368.7°C
0.002
41.8 min / 433.7°C 0.002
3200 3100 3000 2900 2800 2700 2600 2500 -1
N
Wavenumber / cm
U
Absorbance / a.u.
0.002
A
Fig. 7 FTIR spectra obtained at different temperatures, during paroxetine heating, in the region of HCl
A
CC
EP
TE
D
M
absorption.
H N
H N
H
H O
.HCl.0.5 H2O
H
O
O
O
melting (s)
.HCl (l) + 0.5 H2O (g)
H
O
F
F
SC RI PT
O
25 - 162.8 °C
H N
H N
H
H
.HCl (l)
O
O
162.8 - 295.4°C
F
U
295.4 - 515.1°C
O
(l)
+
(g)
+ CO2 (g) + carbonaceous residue
A
H
(g)
+ HCl (g)
N
H N
H
O
O
F
H N
.HCl (s)
O
H
H
O
O
O
melting
M
F
F
515.1 - 1000°C
TE
D
complete decomposition
EP
Fig. 8 Proposed thermal mechanism to describe the behavior of paroxetine hydrochloride.
3.2 Sertraline Hydrochloride It is worthwhile to note that literature has two different descriptions for the thermal
CC
behavior of sertraline. Sysko and Allen [12] observed that polymorphic Form II undergoes a solid-solid transition to Form III, when heated at c.a. 180 °C while Johnson and Chang reported
A
the sublimation/decomposition of the drug on heating after such transition [13]. In the present work TG curves revealed that sertraline hydrochloride was stable up to
161.4 °C under nitrogen (Figure 9). Table 2 presents TG/DTG results for mass losses, temperature intervals and DTA peaks. TGA curve suggests a single mass loss between 161.4 and 249.5 °C, resulting in 2.7 % of residue at the end of the run (1000°C). However, DTG curve (Figure 9a) reveals a slight shoulder suggesting that decomposition actually takes place in two consecutive events from 161.4 – 249.5 and 249.5 – 329.5 °C.
Under air atmosphere, the sample also presents two decomposition steps at 155.4 – 238.6ºC and 238.6 – 307.6 ºC, with mass losses of 8.62 and 87.4 %, respectively, according to DTG curve (Figure 10a). A third step was also observed, between 307.6 and 583.7 °C (3.04%) due to the burning of carbonaceous material formed in the earlier steps.
SC RI PT
Under nitrogen, DTA curve for sertraline presented three endothermic peaks at 199.6, 248.9 and 298.1°C, referent to the solid transition to Form III [12], and the other two events initially attributed to melting of Form III and decomposition, respectively. Under air, an
additional exothermic peak is also observed due to the burning of carbonaceous material at c.a. 550 °C.
DSC curve of sertraline (Figure 11) presented an endothermic peak at 193.3 °C attributed
U
to a solid-solid transition of Form II to Form III. No other events, such as recrystallization were observed in the cooling neither on the second heating. This event is in agreement with the
N
descriptions of Sysko and Alen [12] and Johnson and Chang [13].
A
Figure 12.a depicts the DSC curve of sertraline heated up to 260 ºC, while Fig. 12.b and
M
12.c present the X-ray diffraction patterns of commercial sertraline hydrochloride and the sample collected after heating up to 230ºC, after the solid transition to Form III, respectively.
D
When the drug is heated up to 260 ºC (Fig. 12.a), two endothermic events were observed during the first heating with peaks at 197.6 and 249.5°C. The first one related to the transition
TE
Form II Form III. The attribution of the second signal is not so simple. According to Sysko and Allen [12] when Form II is heated it undergoes a transition to Form III, which by its turn
EP
melts at c.a. 246ºC, followed by immediate decomposition. When Form III is heated a single melting endothermic event is observed at 246ºC, also followed by thermal decomposition. The
CC
studies were carried out at 20 ºC min-1. However the second peak appeared in a region in which the TGA curve reveals a mass
A
loss higher than 12%, suggesting that it is actually related to the decomposition of the sample and not exclusively with its melting, or at least it represents a melting accompanied (and not followed) by decomposition.
4.0
(a)
100
(b)
100
0.0
3.5
1.5
40
1.0
-1.0 60 -1.5 40 -2.0
o
o
0.5
20
-1
20
-2.5
0
100
200
300
400
500
600
700
800
900
-1
endo
0.0 0
-3.0
0
-0.5 1000
SC RI PT
2.0
Mass / %
Mass / %
60
-0.5
80
Derivative Mass / % C
2.5
Temperature Difference / C mg
3.0
80
0
100
200
o
300
400
500
600
700
800
900
1000
o
Temperature / C
Temperature / C
Fig. 9 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample mass
3.5
(a)
100
U
of 7.0 mg (±0.1 mg), in open -alumina crucible. N2 (50 mL min-1).
100
A
-3.0
20
endo
300
400
500
600 o
700
800
TE
Temperature / C
D
200
900
-3.5
0 0
100
200
300
400
500
600
700
800
900
-4.0 1000
o
Temperature / C
Fig. 10 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample
A
CC
EP
mass of 7.0 mg (±0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
-1
100
-2.5
o
0
-0.5 1000
-2.0
40
0.0
0
-1.5
60
o
0.5
20
Mass / %
1.0
M
Mass / %
1.5 40
Derivative Mass / % C
2.0
-1.0
80
2.5
60
-0.5
Temperature Difference / C mg
80
(b)
N
3.0
N U SC RI PT
Table 2. Proposed events, mass losses, temperature ranges and DTA peaks of sertraline hydrochloride TG analysis under N2 and air TG data DTA data Mass Loss / % Process Trange/ºC Peak / ºC TG Calculated Nitrogen
M
A
C17H17Cl2N • HCl(s) Form II C17H17Cl2N • HCl(s) Form III C17H17Cl2N • HCl C16H12Cl2 • HCl(l) + CH5N(g) C16H12Cl2 • HCl C10H12 (g) + C6H4Cl2(g) + HCl(g) complete decomposition
ED
Air C17H17Cl2N • HCl(s) Form II C17H17Cl2N • HCl(s) Form III C17H17Cl2N • HCl C16H12Cl2 • HCl(l) + CH5N(g) C16H12Cl2 • HCl C10H12 (g) + C6H4Cl2(g) + HCl(g) carbonaceous material burning
199.6
161.4 - 249.5 249.5 - 329.5 1000
8.99 8.06 88.6 91.1 residue = 2.7 ---
151.4 - 431.8 431.8 - 585.1 585.1 – 1000 1000
8,62 89.9 1.25 0.38
8.06 91.1 -----
248.9 298.1
195.3 243.6 288.3
PT
st
A
CC E
Heat Flow / W g
-1
-1 0.15 W g
1 heating
cooling
-1 0.04 W g
-1 0.04 W g
nd
2 heating
endo -50
0
50
100
150
200
250
Temperature / °C
Fig. 11 DSC curves of sertraline hydrochloride up to 220°C in N2 flowing at 50 mL min-1, sample mass of 5.0 mg and heating rate of 10 °C min-1.
The DXR diffractogram of the commercial product (Fig. 12.b) used in the present study revealed that it is the solid Form II, as presented in Table 3, in which the main reflectance signals from previous studies are also presented for sertraline solid Forms II and III. [12] DRX of the sample heated up to 230ºC (Fig. 12.c) confirmed the presence of Form III (Table 3).
SC RI PT
Thus in this work, the polymorph used is the called Form II which is the most used in pharmaceutical formulations due to its better bioavailability.[23]
Heat Flow W g
-1
(a) -1 2.5 W g
25
50
75
100
125
150
175
200
225
250
U A
N
(b)
500
0
10
20
30
40
50
(c)
60
D
2 º
M
Intensity / a.u.
Temperature / °C
Fig. 12 (a) DSC curve of sertraline hydrochloride, N2 (50 mL min-1), heated up to 260 ºC at
TE
10ºC min-1, and diffractograms of (b) sertraline hydrochloride and (c) sertraline hydrochloride heated up to
EP
230ºC.
Observing these events by Hot Stage Microscopy, it was possible to see the solid
CC
transformation followed by the sublimation of the product of this transition, once the top plate of the furnace was coated by a white solid. However such experiment was performed at 4 ºC min-1 and using very small sample mass, which make the conditions totally different from the DSC.
A
Sublimation of sertraline was previously reported by Johnson and Chang.[13] In order to investigate this possibility a simulation of the Hot Stage experiment was performed in the TG furnace using an initial mass of 0.50 mg, heated up to 200ºC at 10ºC min-1 and then kept in isotherm. A complete sublimation of the sample occurred after 55 min (average Δm = 0.008 mg min-1) as in Fig. 13.a. FTIR spectrum of sublimate collected in a glass tube after heating sertraline sample up to 200ºC, confirmed the presence of the sertraline hydrochloride as a volatile once it is quite similar to the spectrum of sertraline hydrochloride itself (Figure 13.b).
Sublimation is facilitated in hot stage analysis once the sample holder is a completely open system and a small sample mass is used, while in DSC the sample holder is a closed pan, in the present study. Thus it is possible to say that if a small amount of sertraline is slowly heated above 200
SC RI PT
ºC, the Form III sublimates in a slow rate. However, if heated at 10 ºC min-1, in covered crucible, the decomposition takes place. On the other hand, it was not confirmed that Form III melts before decomposition, once the sharp endotherm appeared in a region in which there is a significant mass loss.
Characterization of gases evolved during sertraline thermal decomposition was also performed by TG-FTIR. According to the Gram-Schmidt graph (not presented), the largest
U
amount of gases reaches the FTIR detector at 28 min (approximately 303°C). Although the
experiment is performed using a transfer line temperature of 240 °C, the signal intensity was
N
relatively low and noisy, which was attributed to the condensation of the volatiles inside the
A
transfer line.
M
(a)
Transmitance / %
TE
80
60
40
EP
Mass / %
Sertraline
D
100
(b)
25 %
sublimate
20
0
CC
0
20
40
60
Time (min)
80
100
4000 3500 3000 2500 2000 1500 1000 -1 / cm
500
Fig. 13 (a) TG curve of sertraline hydrochloride, sample mass of 0.45 mg, in open -alumina crucible, dry
A
air (50 mL min-1), heated up to 200ºC at 10ºC min-1 and kept in isotherm during 100 min. (b) FTIR spectra of sertraline hydrochloride and de sublimate collected in a glass tube.
N U SC RI PT
Table 3. X-ray diffraction data for sertraline as received and samples collect at different temperatures Sample
Main X-ray diffraction / 2°
Form II*
5.4
10.7
14.6
Sertraline
14.3 5.3
10.7
13.1
A
CC E
PT
ED
M
* Data from literature
14.4
15.5
A
Form III*
16.3
19.0
17.4
16.1
18.8
20.3 19.6
21.5
20.2
21.0
21.8
24.4
27.3
24.0 22.4
23.6
24.7
27.2
Figure 14 depicts FTIR spectrum of the gases evolved at 28 min (303°C) and those for methylamine, tetraline and dichlorobenzene from the database. [22] Although the signals are relatively low it was possible to identify bands related to the presence of methylamine (2940, 778 cm-1), tetraline (3044, 2928, 2857 cm-1) and 1,2-dichlorbenzene (3069, 1158 cm-1) in agreement with the proposed from TG data in Table 2, based on
SC RI PT
stoichiometric calculations. It was not possible to observe signals of HCl in the gas phase, but it is thought that the acid is released in the same step of tetraline and 1,2dichlorbenzene, considering TG data.
Methylamine
0.25
0.10
U
Tetraline
1.2-dichlorbenzene
N
Absorbance
0.10
28 min
3500
3000
2500
2000
1500
Wavenumber / cm
M
A
0.006
1000
500
TE
D
Fig. 14 FTIR spectra obtained at 303°C, during sertraline heating, and methylamine, tetraline and 1,2-dichlorbenzene from database.
EP
These results are not totally in agreement with the findings of Zayed and coworkers.[20] Those authors proposed that sertraline hydrochloride decomposed by release of dichlorobenzene in the first step followed by methylamine and butane in the
CC
second one, based in stoichiometric calculations and in TG curves that were not presented. In the present study methyl amine was detected in the first step, followed by tetraline and
A
dichlorobenzene in the second one, using TG-FTIR coupling. Thus, the use of hyphenated techniques is highly recommended, when the establishment of thermal decomposition mechanism is the goal. Based on TG, DSC and TG-FTIR data, a tentative mechanism for the thermal degradation of sertraline hydrochloride is presented in Fig. 15.
Sublimate 4 ºC min-1
H 3C
Cl
Cl
H 3C
H
HN
H
HN
198.0 ºC
. HCl
. HCl
Solid Form III
N
U
Solid Form II
A
198.0 - 249.5 ºC
10 ºC min-1
M
Cl
D
Cl
EP
TE
. HCl
+ H 2N
CH3
249.5 - 329.5 ºC
CC A
Cl
SC RI PT
Cl
Cl Cl +
+
HCl(g) + carbonaceous residue
Fig. 15 Proposed mechanism to describe the thermal behavior of sertraline hydrochloride.
Conclsion
A mechanism for thermal behavior of paroxetine and sertraline hydrochloride has been proposed concerning mass losses during heating, calorimetric processes and volatiles evolved during the thermal degradation of the drugs. Paroxetine decomposed after a
SC RI PT
complex dehydration/melting process, releasing HCl, piperidine, fluorobenzene and CO2. Hemihydrate paroxetine hydrochloride crystals are dehydrated and melted concomitantly after what a new form crystallizes, probably as an anhydrous salt. Sertraline, on its turn,
goes through sublimation if slowly heated or solid transition from Form II to Form III and after that decomposes releasing methylamine, tetraline, dichlorobenzene and HCl when
U
heated at faster heating rates.
A
N
Acknowledgments
Authors are grateful to agencies FAPESP (processes: 2014/22142-4 and 2015/09299-4)
A
CC
EP
TE
D
M
and CNPq for support.
References
[1] T. Lever, P. Haines, J. Rouquerol, E.L. Charsley, P.V. Eckeren, D.J. Burlett, ICTAC nomenclature of thermal analysis (IUPAC Recommendations 2014). Pure Appl. Chem. 86
SC RI PT
(2014.) 545-553. [2] D. Giron, Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates. Thermochim. Acta. 248 (1995) 1-59.
[3] J.J. Ford, P. Timmins, Pharmaceutical Thermal Analysis: Techniques & Applications. Ellis Horwood Ltd Publisher, (1989) 108-248.
U
[4] M.F. Pina, M. Zhao, J.F. Pinto, J.J. Sousa, C.S. Frampton, V. Diaz, O, Suleiman, L.
N
Fabian, D.Q.M. Craig, An Investigation into the Dehydration Behavior of Paroxetine HCl
A
Form I Using a Combination of Thermal and Diffraction Methods: The Identification and
M
Characterization of a New Anhydrous Form. Cryst. Growth Des. 14 (2014) 3774-3782. [5] P.S. Carvalho, C.C. de Melo, A.P. Ayala, C.C.P. da Silva, J. Ellena, Reversible Solid-
D
State Hydration/Dehydration of Paroxetine HBr Hemihydrate: Structural and
TE
Thermochemical Studies. Cryst. Growth Des 16 (2016) 1543-1549. [6] M.F. Pina, J.F. Pinto, J.J. Sousa, L. Fabian, M. Zhao, D.Q.M. Craig, Identification and
EP
Characterization of Stoichiometric and Nonstoichiometric Hydrate Forms of Paroxetine HCl: Reversible Changes in Crystal Dimensions as a Function of Water Absorption. Mol.
CC
Pharmaceutics. 9 (2012) 3515-3525. [7] K.S. Murthy, A. Rey, G. Weeratunga, New Form III paroxetine hydrochloride
A
anhydrous for pharmaceutical formulations specified infrared spectra, specified DSC onset, temperature, specified X-ray powder diffraction pattern, specified melting point and specified bulk density and tapped density. CA2187128-A1, 04.08, (1996). [8] M.A. El-Nabarawi, E.R. Bendas, R.T.A. El-Rehem, M.Y.S. Abary, Transdermal drug delivery of paroxetine through lipid-vesicular formulation to augment its bioavailability. Int. J. Pharm. 443 (2013) 307-317.
[9] M.R. Syed, J.B. Naik, Fast Dispersible Tablet of Paroxetine Hydrochloride: Taste Masking and Administration in Depressed Patients Lat. Am. J. Pharm. 29 (2010) 667-373. [10] M.R. Caira, E. De Vrics, L.R. Nassimbeni, V.W. Jacewicz, Inclusion of the Antidepressant Paroxetine in β-cyclodextrin J. Inclusion Phenom. Macrocyclic Chem.
SC RI PT
46(2003), 37-42. [11] G. Bruni, F. Sartor, , V. Berbenni, , C. Milanesi, , M. Maietta, D. Franchi, , A. Marini,
Compatibility of paroxetine hydrochloride and GW597599B. J. Therm. Anal. Calorim.. 108 (2012), 381-388.
[12] R.J. Sysko, D.J. Allen, Sertraline Polymorph. US005248699, (1993).
U
[13] B.M. Johnson, P.L. Chang, Sertraline Hydrochloride. Anal. Profiles Drug Subst. 24
N
(1996) 443-486.
A
[14] Q. He, S. Rohani, J. Zhu, H. Gomaa, Sertraline Racemate and Enantiomer: Solid-State Characterization, Binary Phase Diagram, and Crystal Structures. Cryst. Growth Des. 10
M
(2010) 1633-1645.
D
[15] F. Ghaderi, M. Nemati, M.R. Siahji-Shadbad, H. Valizadeh, F. Monajjemzadeh,
TE
Physicochemical analysis and nonisothermal kinetic study of sertraline–lactose binary mixtures. J. Food Drug Anal. 25 (2017) 709-716.
EP
[16] I. Harbi, B. Aljaeid, K.M. El-Say, A.S. Zidan, Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain
CC
Transport. AAPS Pharm. Sci. Tech. 17 (2016) 1404-1420. [17] N. Ogawa, T. Hashimoto, T. Furuishi, H. Nagase, T. Endo, H. Yamamoto, Y.
A
Kawashima, H. Ueda, Solid-state characterization of sertraline base–β-cyclodextrin inclusion complex. J. Pharm. Biomed. Anal. 107 (2015) 265-272. [18] J.J. Passos, F.B. de Souza, I.M. Mundim, R.R. Bonfim, R. Melo, A.F. Viana, E.D. Stolz, M. Borsoni, S.M.K. Rates, R.D. Sinisterra, In vivo evaluation of the highly soluble oral -cyclodextrin–Sertraline supramolecular complexes Int. J. Pharm. 436 (2012) 478-485.
[19] E. Schwartz, T. Nidam, A, Liberman, M. Mendelovici, J. Aronhime, C. Singer, E. Valdman, Sertraline hydrocloride polymorphs. US0141189A1, (2006). [20] M.A. Zayed, M.F. Hawash, M.A. Fahmey, A.A. El-Habeeb, Structure investigation of sertraline drug and its iodine product using mass spectrometry, thermal analyses and MO-
SC RI PT
calculations. Spectrochim. Acta, Part A. 68 (2007) 970-978. [21] P.S. Carvalho, C.C. de Melo, A.P. Ayala, J. Ellena, X-Ray diffraction, spectroscopy
and thermochemical characterization of the pharmaceutical paroxetine nitrate salt. J. Mol. Struct. 1118 (2016) 288-292.
[22] Nicolet-ThermoScientific Co. Nicolet EPA Vapor Phase database. Omnic 8.0
U
software. ThermoScientific, Madison.
N
[23] P.A. Van der Schaaf. F. Schwarzenbach, H.J. Kerner, M. Szelagiewicz, C. Marcolli,
A
CC
EP
TE
D
M
A
A. Burkhard, Polymorphic forms of sertraline hydrochloride. US 7,442,838 B2, (2008).
Figure Captions
Fig. 1 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. N2 (50 mL min-1). Inset: TG/DTG curve using sample mass of 3.0 mg (± 0.1 mg) and heating rate of 5.0 °C min-1.
SC RI PT
Fig. 2 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
Fig.3 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in closed with a pin hole with sample mass of 5.0 mg and heating rate of 10 °C min-1, in heat-cool-heat mode.
U
Fig.4 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in aluminum crucible. (a) using open and closed (with a pinhole in the lid) sample holder and heating rate of 10 °C min-1, (b) heating curves using sample mass of 3.0 mg and different heating rates () and (c) heat-cool-heat curves with sample mass of 3.0 mg and heating rate of 10 °C min-1, heating until dehydration and then reheating until 175 °C.
A
N
Fig. 5 Hot stage microscopy photographs of paroxetine from 88 to 127 °C, in air at 2.0 °C min-1 heating rate (magnification 50x).
M
Fig. 6 FTIR spectra obtained at 327.7°C, during paroxetine heating, and HCl from database. Insert: detail of the region from 3250 – 2500 cm -1.
D
Fig. 7 FTIR spectra obtained at different temperatures, during paroxetine heating, in the region of HCl absorption.
TE
Fig. 8 Proposed thermal mechanism to describe the behavior of paroxetine hydrochloride. Fig. 9 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample mass of 7.0 mg (±0.1 mg), in open -alumina crucible. N2 (50 mL min-1).
EP
Fig. 10 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample mass of 7.0 mg (±0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
CC
Fig. 11 DSC curves of sertraline hydrochloride up to 220°C in N2 flowing at 50 mL min-1, sample mass of 5.0 mg and heating rate of 10 °C min-1.
A
Fig. 12 (a) DSC curve of sertraline hydrochloride, N2 (50 mL min-1), heated up to 260 ºC at 10ºC min-1, and diffractograms of (b) sertraline hydrochloride and (c) sertraline hydrochloride heated up to 230ºC. Fig. 13 (a) TG curve of sertraline hydrochloride, sample mass of 0.45 mg, in open -alumina crucible, dry air (50 mL min-1), heated up to 200ºC at 10ºC min-1 and kept in isotherm during 100 min. (b) FTIR spectra of sertraline hydrochloride and de sublimate collected in a glass tube. Fig. 14 FTIR spectra obtained at 303°C, during sertraline heating, and methylamine, tetraline and 1,2-dichlorbenzene from database.
A
CC
EP
TE
D
M
A
N
U
SC RI PT
Fig. 15 Proposed mechanism to describe the thermal behavior of sertraline hydrochloride.
S0165-2370(18)30664-8 https://doi.org/10.1016/j.jaap.2018.09.022 JAAP 4436
To appear in:
J. Anal. Appl. Pyrolysis
Received date: Revised date: Accepted date:
31-7-2018 18-9-2018 24-9-2018
´ Please cite this article as: Ferreira APG, Pinto BV, Cavalheiro ETG, Thermal decomposition investigation of paroxetine and sertraline, Journal of Analytical and Applied Pyrolysis (2018), https://doi.org/10.1016/j.jaap.2018.09.022 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Thermal decomposition investigation of paroxetine and sertraline A.P.G. Ferreira, B.V. Pinto and É.T.G. Cavalheiro Departamento de Química e Física Molecular, Instituto de Química de São Carlos, USP,
SC RI PT
Av. Trabalhador São-Carlense, 400, Caixa Postal 780, São Carlos, São Paulo CEP 13560970, Brazil.
*[email protected]
HIGHLIGHTS
Sertraline and paroxetine were submmited to thermal, and hot satage micrsocopy
U
analysis;
N
Paroxetine presented concomitante dehydration and melting followed by crystallization;
A
It decomposed in three mass loss steps releasing HCl, piperidine, fluorobenzene and CO2;
M
Sertraline undergoes sublimation or solid transformation depending on the heating rate;
D
Decomposition occured in two steps releasing methylamine, tetraline, dichlorobenzene
TE
and HCl;
EP
A complete description of the termal behavior of both pharmaceuticals was presented
CC
Abstract
Antidepressants paroxetine and sertraline both as their hydrochlorides were studied
regarding thermal behavior by TG/DTG-DTA, DSC, hot-stage microscopy, X-ray
A
diffraction and coupled TG-FTIR. Paroxetine presented a single mass loss step after dehydration, in nitrogen. However, DTA curve revealed that such degradation actually occurs in three steps, in which HCl, piperidine, fluorobenzene and CO2 are released. In air decomposition took place in a similar way. DSC showed endothermic peaks related to melting and dehydration of paroxetine. During evolved gases analysis it was possible to observe overlapped signals related to HCl and piperidine absorption. Sertraline, on its turn,
presented sublimation when slowly heated or alternatively a solid transition from Form II to Form III at c.a. 199°C followed by two mass losses when heated at higher heating rates. In the first degradation step methylamine is released. The second step is related to the loss of tetraline, dichlorobenzene and HCl, as revealed by TG-FTIR. Based on these data, thermal
SC RI PT
decomposition mechanisms were proposed for both drugs.
Keywords: paroxetine, sertraline, antidepressant, evolved gas analysis, thermal degradation 1.
Introduction
Paroxetine ((3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)
U
piperidine) and sertraline ((1S-cis)-4-(3,4- dichlorophenyl)-1,2,3,4- tetrahydro-N-methyl-1-
A
N
naftalenamine), whose structural formulas are:
Paroxetine
M
Sertraline
H N
H
O
Cl
CH3 H HN
TE
O
D
H O
Cl
EP
F
CC
use to be largely used in the treatment of humor disorders acting as allosteric serotonin selective reuptake inhibitors (SSRI).
A
By its turn, thermal analysis is defined “as the study of the relationship between a sample
and its temperature while it is heated or cooled in a controlled manner”.[1] Regarding thermal analysis of pharmaceutical samples, these techniques represent important tools once they can provide important information including stability studies, shelf life, investigations on polymorphic and phase transformations, establishment of mechanisms for thermal behavior, drug-excipient interactions in pre-formulation studies, characterization of drug delivery systems,
purity determination among others.[2,3] However relative few studies concerning the thermal behavior of paroxetine and sertraline can be found in the literature. For paroxetine, two polymorphic forms have been identified, called Form I hemihydrate and the anhydrous Form II. Pina et al. studied these polymorphs and also investigated the
SC RI PT
generation of the dehydrated paroxetine hydrochloride from the hemihydrate, using
thermogravimetry, differential scanning calorimetry and X ray diffraction in open and closed sample holders as well as in different heating rates. These authors concluded that dehydration of paroxetine Form I involves a complex and uncommon process. They described a new
isostructural anhydrous Form I after dehydration of Form I hemihydrate. [4] However the authors do not describe how such transition occurs.
U
Investigation concerning hydration/dehydration of paroxetine hydrobromide was reported
N
by Carvalho and co-workers. In that paper, structural and thermochemical studies were
A
performed up to 200°C, however further decomposition steps were not concerned regarding
M
volatiles or residual degradation products.[5] Conclusions are similar to those of Pina et al. [6] Still regarding polymorphism, Murthy e Weeratunga described a new form for paroxetine,
D
that they called Form III. It was obtained by the recrystallization of paroxetine free base from methyl iso-butyl ketone. Based on DSC curves these authors found that this new Form III melts
TE
between 156 and 162 °C. [7]
Differential scanning calorimetry (DSC) was used in drug delivery systems and
EP
drug/excipient compatibility studies in which paroxetine is a component.[8-11] Concerning sertraline thermal behavior, Sysko and Allen [12], described five different
CC
polymorphic forms. According to these authors Form II undergoes a solid-solid transition to Form III, when heated at c.a. 180 °C. On the other hand, Johnson and Chang [13] described the
A
DSC behavior of four polymorphs of sertraline, that includes a solid-solid-transformations of Forms I and II to Form III. On further heating, Form III decomposes and sublimates, according to Hot Stage Microscopy data. He and co-workers characterized sertraline racemates and enantiomers by differential scanning calorimetry and spectroscopic techniques [14]. Hot stage microscopy was used to elucidate the melting point of binary mixtures [15], while the compatibility with liposomal systems was investigated by Harbi et al..[16]
Thermogravimetry and differential scanning calorimetry were used to characterize cyclodextrin complexes with sertraline [17,18], as well as in polymorphism studies.[19] Zayed et al. used TG and DTA to investigate thermal behavior of sertraline and compared these results with electron ionization mass spectrometry (EI-MS) spectroscopy in order to
SC RI PT
propose a fragmentation mechanism. Theoretical calculations were also performed to support the results. [20]
Thus, there are relatively few studies regarding thermal behavior of these antidepressants, pointing to the need of a deeper evaluation of the thermal properties of paroxetine and sertraline including a better description of polymorphic transformation and/or sublimation. In this work studies involving thermogravimetry (TG), differential thermal analysis (DTA), differential
U
scanning calorimetry (DSC), hot stage microscopy, powder X-ray diffraction (PXRD) and
N
evolved gas analysis (TG-FTIR) have been performed in order to propose a complete thermal
1.
Material and Methods
M
A
behavior mechanism for both drugs.
D
Paroxetine and sertraline hydrochlorides of pharmaceutical grade were obtained from
TE
Fagron Farmacêutica (Brazil) and used as received. TGA/DTG-DTA curves were collected in a simultaneous TG–DTA SDT-Q600 modulus,
EP
controlled with Thermal Advantage software (v. 2.5.0.256), both from TA Instruments. TG curves were taken using sample masses of ca. 7.0 mg (± 0.1 mg) in open -alumina sample
CC
holders, at 10 ºC min-1 heating rate from room temperature to 1000ºC, under dynamic air and nitrogen atmosphere flowing at 50 mL min-1. When considered necessary to better understand some events, experiments were conducted using other heating rates (5 and 20 ºC min-1) and
A
sample masses (c.a. 0.50 mg). DSC curves were obtained in a Q10 Differential Calorimetric Module, controlled by the
Thermal Advantage Series software (v. 2.5.0.256) both from TA Instruments, using sample masses of c.a. 5.0 mg ± 0.1 mg in covered aluminum sample holder with a 0.7 mm pinhole in the center of the lid, using heating rate of 10ºC min-1. For paroxetine, data were collected between room temperature and 170ºC (1st cycle) and -60 to 170ºC (other cycles). For sertraline, data were
collected between room temperature and 150ºC (1st cycle) and -60 to 150ºC (other cycles). In all cases, dynamic nitrogen atmosphere flowing at 50 mL min-1 was used. In the case of paroxetine, runs using open sample holders, temperature intervals and different heating rates of 5 and 20 ºC min-1 were also used to study its dehydration and melting process. For Sertraline different
SC RI PT
temperature ranges were used. These conditions were described when used.
SDT-Q600 (TA Instruments), coupled to a Nicolet iS10 FTIR Spectrometer were used to characterize gaseous products evolved during decomposition of the drugs. The transfer line was composed of a thermally insulated stainless steel tube of 120 cm length and 2 mm inner diameter, heated at a constant temperature of 225ºC. FTIR measurements were carried out with a DTGS detector in a gas cell heated at a constant temperature of 250ºC. The interferometer and the gas
U
cell compartments were purged with nitrogen. In this case, thermogravimetric curves were taken
N
in N2 flowing at 50 mL min-1, at 10ºC min-1 heating rate and sample of 15 mg.
A
Hot stage microscopy was performed using a Mettler-Toledo HS82 hot stage coupled to an Olympus BX51 microscope equipped with a digital camera. Samples were heated at 10º C
Results and discussion
TE
2.
D
M
min-1 up to temperatures close to the event and at 4°C min-1 during the event of interest.
2.1. Paroxetine hydrochloride
EP
TG/DTG-DTA curves of paroxetine hydrochloride are presented in Figure 1, while the quantitative data regarding mass losses (experimental and calculated), temperature interval and
CC
peak temperatures are summarized in Table 1. In nitrogen, the sample presented a water loss from the start of the run up to 162.8°C
attributed to dehydration of paroxetine hydrochloride equivalent to the loss of 0.5 water molecule
A
in agreement with Pina et al. [4,6], although those authors did not presented TG curves. This is in agreement with previous reports [5] for the similar salt paroxetine hydrobromide. After dehydration the sample apparently decomposed in a single mass loss step according to the TG curve. However the DTG curve revealed that the decomposition actually took place in three steps, with the loss of HCl, followed by the release of piperidine and fluorobenzene and finally CO2. Details of the identification of volatiles will be described later in evolved gas analysis
(EGA) results. After these events a carbonaceous residue was formed at c.a. 800°C, which slowly decomposes until the end of the experiment at 1000°C resulting in 21.1% of the initial mass. The inset in Figure 1.a obtained with lower samples mass (3.0 mg) and at 5.0 °C min-1 revealed that melting process causes a turbulence in the sample holder that led to a
SC RI PT
drift in TG signal, suggesting that dehydration is accompanied by melting or other more complex process, resulting in an accommodation of the sample during melting, since DTA (Figure 1.b) did not present any additional event at this temperature. (a)
100
TGA
100
150
200
250
0.4
Temperature / °C
0.2
-1
20
0.0
600
-0.2 1000
800
0
0
200
400
600
-0.7 1000
800
Temperature / °C
M
Temperatura / °C
-0.6
endo
A
400
-0.5
-1
200
40
20
0 0
-0.4
U
50
N
0
0.6
-0.3
60
Mass / %
Mass / %
DTG
80
Derivative Mass / % °C
0.8 60
40
-0.2
1.0
2.0 %
Temperature Difference / °C mg
80
-0.1
(b)
100
1.2
Fig. 1 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. N2 (50 mL min-1). Inset: TG/DTG curve using
TE
D
sample mass of 3.0 mg (± 0.1 mg) and heating rate of 5.0 °C min-1.
0.5 0.4 0.3 0.2
20
0.1
A
0.1 60 0.0 40
-0.1 -0.2
20
endo
400
600
Temeprature / °C
800
-0.1 1000
-0.3
0 0
200
400
600
800
-0.4 1000
Temperature / °C
Fig. 2 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
-1
200
0.2
0.0
0
0
-1
CC
40
0.3
80
Mass / %
EP
0.6
Derivative Mass / % °C
60
(a)
100
0.7
Temperature Difference / °C mg
80
Mass / %
0.8
(a)
100
N U SC RI PT
Table 1. Proposed events, mass losses, temperature ranges and DTA peaks of paroxetine hydrochloride TG analysis under N2 and air TG data
DTA data
Trange / ºC
Mass Loss / % TG Calculated
Peak / °C
C19H20FNO3 • HCl • 0.5H2O C19H20FNO3 • HCl + 0.5H2O
25-162.8
1.7
2.5
122.3
C19H20FNO3 • HCl C19H20FNO3 + HCl
162.8-295.4
9.8
10.0
272.8
C19H20FNO3 C8H4O3 + C5H5F + C5H11N
295.4-368.7
49.4
49.6
303.7
C8H4O3 carbonaceous residue + CO2
368.7-515.1
11.3
12.0
carbonaceous residue decomposition
515.1-1000
6.1
---
residue
1000
21.1
---
C19H20FNO3 • HCl • 0.5H2O C19H20FNO3 • HCl + 0.5H2O
25-131.8
2.3
2.5
123.2
C19H20FNO3 • HCl C19H20FNO3 + HCl
131.8-308.7
9.9
10.0
274.4
C19H20FNO3 carbonaceous residue
308.7-440.5
39.6
-
380.1
Carbonaceous residue burn
440.5-651.6
47.3
-
537.8
residue
1000
0.7
-
Process
A
M
ED
PT
CC E
Air
A
Nitrogen
Carvalho and co-workers [21] investigated the dehydration of both paroxetine hydrobromide and nitrate salts and described their melting. These authors concluded that dehydration is not associated with polymorphic transitions or change in crystalline habit before melting. However, any detailed description of decomposition of paroxetine hydrochloride has
SC RI PT
been found in literature.
In air atmosphere the dehydration process occurred in a similar way, including the
turbulence in the TGA signal. However, after releasing HCl the decomposition undergoes via formation of the carbonaceous residue that burns in the 440-650°C range, with practically no residue remaining at such temperature.
Figure 3 depicts DSC heat-cool-heat curves of paroxetine hydrochloride obtained in
U
closed sample holders with a central pin hole at 10 ºC min-1 and reveals an endothermic event at
N
c.a. 130 °C and a shoulder at 138 °C, during the first heating. On subsequent cooling and second
A
heating, only second order transitions were observed, demonstrating the presence of amorphous material. In this first approach the events can be attributed to dehydration and melting
M
respectively. However, careful look to such process suggests that it can be more complex than a
D
single dehydration/melting event which is in agreement with previous studies. [4-6] st
EP
cooling
-1
1.5 W g
-1
0.15 W g
CC
Heat Flow / W g
-1
endo
TE
1 heating
nd
2 heating
-1
A
0.20 W g
-40 -20 0
20 40 60 80 100 120 140 160 180 Temperature / °C
Fig.3 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in closed with a pin hole with sample mass of 5.0 mg and heating rate of 10 °C min-1, in heat-cool-heat mode.
Thus DSC curves were also obtained in nitrogen in covered with a central pinhole in the lid and open (Fig. 4.a) sample holders in order to better characterize these events.
From the DSC curve obtained in covered sample holder with a pinhole it was possible to observe two endothermic events, the first centered at 130°C followed by a shoulder at 138°C (Fig. 4.a). These results are quite similar to those obtained by Pina. [Pina et al., 2014] who attributed these events to dehydration followed by melting of the hemihydrate Form I,
SC RI PT
represented by two endothermic events.
However the results in open sample holder suggested the presence of a third event (Fig. 4.a), this one exothermic, centered at 131.6ºC, which is plausible once the superimposition of exothermic and endothermic DSC peaks results in the summation of heats evolved and absorbed resulting in non-resolved signals.
DSC curves were also obtained under different heating rates in an attempt for better
U
attributing these events resulting in the curves presented in Fig. 4.b. When heating at 5.0
°C min-1, a first peak is evidenced at 124 °C followed by a poorly defined shoulder at 130 °C. At
N
20 °C min-1, a single broad peak is observed centered at 140°C, suggesting that all events are
A
superimposed. The onset temperature changes go from 113.5, 119.8, 123.2 ºC, respectively at
M
5.0, 10 and 20 ºC min-1.
Other experiments were also performed in different temperature ranges as represented in
D
Fig. 4.c. The sample was heated until 115°C, cooled until 25 °C and reheated until 180 °C. During the second heating it was possible to observe, that the endothermic peak remains at
TE
124.2°C, while a second order transition is observed at 73.3 °C (mid-point), suggesting that the first heating reached a temperature in which the melting process took place, so the transition at
EP
73.3 °C is due to the fact the sample melted with no recrystallization on cooling. Thus, combined TGA and DSC results led to conclude that the first endothermic peak
CC
observed is related to concomitant dehydration and melting of paroxetine. In this way the poorly resolved exothermic peak at 131.6 ºC in open sample holder (Fig. 4.a), can be related to a
A
crystallization of a different form, after dehydration of paroxetine hydrochloride hemihydrate.
Heat Flow / W g
open (a) endo
40
60
80
100
120
140
160
180
Temperature / °C
= 5 °C min
-1
-1 0.1 W g
U
-1
-1 0.2 W g
N
(b)
= 20 °C min
-1 0.5 W g
60
M
endo 40
-1
A
Heat Flow / W g
-1
= 10 °C min
SC RI PT
-1
closed -1 0.2 W g
80
100
120
140
160
180
D
Temperature / °C
st
1 heating until 115 °C
A
CC
EP
Heat Flow / W g
-1
TE
-1 0.1 W g
-1 0.1 W g
cooling until 25°C
(c)
nd
2 heating until 200°C -1 0.15 W g
endo 40
60
80
100
120
140
160
180
Temperature / °C
Fig.4 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in aluminum crucible. (a) using open and closed (with a pinhole in the lid) sample holder and heating rate of 10 °C min-1, (b) heating curves using sample mass of 3.0 mg and different heating rates () and (c) heat-cool-heat curves with sample mass of 3.0 mg and heating rate of 10 °C min-1, heating until dehydration and then reheating until 175 °C.
These processes were also investigated using hot stage microscopy. Results are presented in Figure 5 and from these micrographies, it was possible to see that melting started at 123°C (Fig. 5.b), while a crystallization takes place at 129 ºC (Fig. 5.c). The new solid than melts slowly (Fis 5.d-g), being liquid at 135 °C (Fig. 5.h). Small temperature differences regarding the DSC
SC RI PT
data can be related to the distinct heating rates and lower sample mass used in hot stage. No
evidences of water release were observed once the water content is only c.a. 2.5 % (0.5 H2O per mol of sertraline) of the total mass of the sample.
Thus according to the hot stage images the paroxetine·HCl·0.5H2O crystals are
dehydrated and concomitantly melted. Then a new form crystallizes from the liquid phase, probably as an anhydrous Form I After that this new form also melted.
U
The whole process is better visualized in the footage presented as Supplementary
N
material. This new form could not be insulated for deeper analysis, but it can be the anhydrous
A
A
paroxetine hydrochloride described by Pina et al [4].
C
D
F
G
H
TE
D
M
B
CC
EP
E
A
Fig. 5 Hot stage microscopy photographs of paroxetine from 88 to 127 °C, in air at 2.0 °C min-1 heating rate (magnification 50x).
These results complete the observations from Pina [Pina et al. 2014]. However those authors did not describe the crystallization of the anhydrous form from the melted dehydrate, once they do not described the shoulder referent to the crystallization observed in the DSC curves. Here, it is clearly confirmed by the hot stage experiment.
Characterization of gases evolved during thermal decomposition was performed by TGFTIR. According to the Gram-Schmidt graph (not presented), the largest amount of gases reached the FTIR detector at 35 min (approximately 360-370°C). Signals before that time are related to dehydration step.
SC RI PT
Figure 6 depicts the FTIR spectrum of the gases evolved at 31 min (345.7 °C) of TG run. It is clear the presence of bands related to H-Cl vibration, in the region from 3250 to 2500 cm-1, which is in agreement with the calculations made from TG curves (Table 1), revealing the release of the salt counter ion. When these calculations are considered, the next step is the release of piperidine and fluorobenzene. Both piperidine and fluorobenzene present vibrational bands in the same region that those from HCl, making difficult to discriminate these signals. However, it was
U
possible to observe that at 35 minutes (368.7°C) the set of bands related to H-Cl is distorted at
N
around 2950 cm-1 region in which piperidine absorbs, confirming its presence in the gas phase
A
(Fig. 7).
M
Based on all data obtained, a tentative mechanism for the thermal degradation of
3200
TE
D
paroxetine hydrochloride is presented in Fig. 8.
3100
3000
2900
2800
2700
2600
2500
-1
EP
31.2 min / 327.7°C
0.05
A
CC
Absorbance / a.u.
Wavenumber /
HCl from database
0.5
4000
3500
3000
2500
2000
1500
Wavenumber / cm
1000
500
-1
Fig. 6 FTIR spectra obtained at 327.7°C, during paroxetine heating, and HCl from database.[22] Insert: detail of the region from 3250 – 2500 cm -1.
31.2 min / 327.7°C
SC RI PT
35.3 min / 368.7°C
0.002
41.8 min / 433.7°C 0.002
3200 3100 3000 2900 2800 2700 2600 2500 -1
N
Wavenumber / cm
U
Absorbance / a.u.
0.002
A
Fig. 7 FTIR spectra obtained at different temperatures, during paroxetine heating, in the region of HCl
A
CC
EP
TE
D
M
absorption.
H N
H N
H
H O
.HCl.0.5 H2O
H
O
O
O
melting (s)
.HCl (l) + 0.5 H2O (g)
H
O
F
F
SC RI PT
O
25 - 162.8 °C
H N
H N
H
H
.HCl (l)
O
O
162.8 - 295.4°C
F
U
295.4 - 515.1°C
O
(l)
+
(g)
+ CO2 (g) + carbonaceous residue
A
H
(g)
+ HCl (g)
N
H N
H
O
O
F
H N
.HCl (s)
O
H
H
O
O
O
melting
M
F
F
515.1 - 1000°C
TE
D
complete decomposition
EP
Fig. 8 Proposed thermal mechanism to describe the behavior of paroxetine hydrochloride.
3.2 Sertraline Hydrochloride It is worthwhile to note that literature has two different descriptions for the thermal
CC
behavior of sertraline. Sysko and Allen [12] observed that polymorphic Form II undergoes a solid-solid transition to Form III, when heated at c.a. 180 °C while Johnson and Chang reported
A
the sublimation/decomposition of the drug on heating after such transition [13]. In the present work TG curves revealed that sertraline hydrochloride was stable up to
161.4 °C under nitrogen (Figure 9). Table 2 presents TG/DTG results for mass losses, temperature intervals and DTA peaks. TGA curve suggests a single mass loss between 161.4 and 249.5 °C, resulting in 2.7 % of residue at the end of the run (1000°C). However, DTG curve (Figure 9a) reveals a slight shoulder suggesting that decomposition actually takes place in two consecutive events from 161.4 – 249.5 and 249.5 – 329.5 °C.
Under air atmosphere, the sample also presents two decomposition steps at 155.4 – 238.6ºC and 238.6 – 307.6 ºC, with mass losses of 8.62 and 87.4 %, respectively, according to DTG curve (Figure 10a). A third step was also observed, between 307.6 and 583.7 °C (3.04%) due to the burning of carbonaceous material formed in the earlier steps.
SC RI PT
Under nitrogen, DTA curve for sertraline presented three endothermic peaks at 199.6, 248.9 and 298.1°C, referent to the solid transition to Form III [12], and the other two events initially attributed to melting of Form III and decomposition, respectively. Under air, an
additional exothermic peak is also observed due to the burning of carbonaceous material at c.a. 550 °C.
DSC curve of sertraline (Figure 11) presented an endothermic peak at 193.3 °C attributed
U
to a solid-solid transition of Form II to Form III. No other events, such as recrystallization were observed in the cooling neither on the second heating. This event is in agreement with the
N
descriptions of Sysko and Alen [12] and Johnson and Chang [13].
A
Figure 12.a depicts the DSC curve of sertraline heated up to 260 ºC, while Fig. 12.b and
M
12.c present the X-ray diffraction patterns of commercial sertraline hydrochloride and the sample collected after heating up to 230ºC, after the solid transition to Form III, respectively.
D
When the drug is heated up to 260 ºC (Fig. 12.a), two endothermic events were observed during the first heating with peaks at 197.6 and 249.5°C. The first one related to the transition
TE
Form II Form III. The attribution of the second signal is not so simple. According to Sysko and Allen [12] when Form II is heated it undergoes a transition to Form III, which by its turn
EP
melts at c.a. 246ºC, followed by immediate decomposition. When Form III is heated a single melting endothermic event is observed at 246ºC, also followed by thermal decomposition. The
CC
studies were carried out at 20 ºC min-1. However the second peak appeared in a region in which the TGA curve reveals a mass
A
loss higher than 12%, suggesting that it is actually related to the decomposition of the sample and not exclusively with its melting, or at least it represents a melting accompanied (and not followed) by decomposition.
4.0
(a)
100
(b)
100
0.0
3.5
1.5
40
1.0
-1.0 60 -1.5 40 -2.0
o
o
0.5
20
-1
20
-2.5
0
100
200
300
400
500
600
700
800
900
-1
endo
0.0 0
-3.0
0
-0.5 1000
SC RI PT
2.0
Mass / %
Mass / %
60
-0.5
80
Derivative Mass / % C
2.5
Temperature Difference / C mg
3.0
80
0
100
200
o
300
400
500
600
700
800
900
1000
o
Temperature / C
Temperature / C
Fig. 9 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample mass
3.5
(a)
100
U
of 7.0 mg (±0.1 mg), in open -alumina crucible. N2 (50 mL min-1).
100
A
-3.0
20
endo
300
400
500
600 o
700
800
TE
Temperature / C
D
200
900
-3.5
0 0
100
200
300
400
500
600
700
800
900
-4.0 1000
o
Temperature / C
Fig. 10 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample
A
CC
EP
mass of 7.0 mg (±0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
-1
100
-2.5
o
0
-0.5 1000
-2.0
40
0.0
0
-1.5
60
o
0.5
20
Mass / %
1.0
M
Mass / %
1.5 40
Derivative Mass / % C
2.0
-1.0
80
2.5
60
-0.5
Temperature Difference / C mg
80
(b)
N
3.0
N U SC RI PT
Table 2. Proposed events, mass losses, temperature ranges and DTA peaks of sertraline hydrochloride TG analysis under N2 and air TG data DTA data Mass Loss / % Process Trange/ºC Peak / ºC TG Calculated Nitrogen
M
A
C17H17Cl2N • HCl(s) Form II C17H17Cl2N • HCl(s) Form III C17H17Cl2N • HCl C16H12Cl2 • HCl(l) + CH5N(g) C16H12Cl2 • HCl C10H12 (g) + C6H4Cl2(g) + HCl(g) complete decomposition
ED
Air C17H17Cl2N • HCl(s) Form II C17H17Cl2N • HCl(s) Form III C17H17Cl2N • HCl C16H12Cl2 • HCl(l) + CH5N(g) C16H12Cl2 • HCl C10H12 (g) + C6H4Cl2(g) + HCl(g) carbonaceous material burning
199.6
161.4 - 249.5 249.5 - 329.5 1000
8.99 8.06 88.6 91.1 residue = 2.7 ---
151.4 - 431.8 431.8 - 585.1 585.1 – 1000 1000
8,62 89.9 1.25 0.38
8.06 91.1 -----
248.9 298.1
195.3 243.6 288.3
PT
st
A
CC E
Heat Flow / W g
-1
-1 0.15 W g
1 heating
cooling
-1 0.04 W g
-1 0.04 W g
nd
2 heating
endo -50
0
50
100
150
200
250
Temperature / °C
Fig. 11 DSC curves of sertraline hydrochloride up to 220°C in N2 flowing at 50 mL min-1, sample mass of 5.0 mg and heating rate of 10 °C min-1.
The DXR diffractogram of the commercial product (Fig. 12.b) used in the present study revealed that it is the solid Form II, as presented in Table 3, in which the main reflectance signals from previous studies are also presented for sertraline solid Forms II and III. [12] DRX of the sample heated up to 230ºC (Fig. 12.c) confirmed the presence of Form III (Table 3).
SC RI PT
Thus in this work, the polymorph used is the called Form II which is the most used in pharmaceutical formulations due to its better bioavailability.[23]
Heat Flow W g
-1
(a) -1 2.5 W g
25
50
75
100
125
150
175
200
225
250
U A
N
(b)
500
0
10
20
30
40
50
(c)
60
D
2 º
M
Intensity / a.u.
Temperature / °C
Fig. 12 (a) DSC curve of sertraline hydrochloride, N2 (50 mL min-1), heated up to 260 ºC at
TE
10ºC min-1, and diffractograms of (b) sertraline hydrochloride and (c) sertraline hydrochloride heated up to
EP
230ºC.
Observing these events by Hot Stage Microscopy, it was possible to see the solid
CC
transformation followed by the sublimation of the product of this transition, once the top plate of the furnace was coated by a white solid. However such experiment was performed at 4 ºC min-1 and using very small sample mass, which make the conditions totally different from the DSC.
A
Sublimation of sertraline was previously reported by Johnson and Chang.[13] In order to investigate this possibility a simulation of the Hot Stage experiment was performed in the TG furnace using an initial mass of 0.50 mg, heated up to 200ºC at 10ºC min-1 and then kept in isotherm. A complete sublimation of the sample occurred after 55 min (average Δm = 0.008 mg min-1) as in Fig. 13.a. FTIR spectrum of sublimate collected in a glass tube after heating sertraline sample up to 200ºC, confirmed the presence of the sertraline hydrochloride as a volatile once it is quite similar to the spectrum of sertraline hydrochloride itself (Figure 13.b).
Sublimation is facilitated in hot stage analysis once the sample holder is a completely open system and a small sample mass is used, while in DSC the sample holder is a closed pan, in the present study. Thus it is possible to say that if a small amount of sertraline is slowly heated above 200
SC RI PT
ºC, the Form III sublimates in a slow rate. However, if heated at 10 ºC min-1, in covered crucible, the decomposition takes place. On the other hand, it was not confirmed that Form III melts before decomposition, once the sharp endotherm appeared in a region in which there is a significant mass loss.
Characterization of gases evolved during sertraline thermal decomposition was also performed by TG-FTIR. According to the Gram-Schmidt graph (not presented), the largest
U
amount of gases reaches the FTIR detector at 28 min (approximately 303°C). Although the
experiment is performed using a transfer line temperature of 240 °C, the signal intensity was
N
relatively low and noisy, which was attributed to the condensation of the volatiles inside the
A
transfer line.
M
(a)
Transmitance / %
TE
80
60
40
EP
Mass / %
Sertraline
D
100
(b)
25 %
sublimate
20
0
CC
0
20
40
60
Time (min)
80
100
4000 3500 3000 2500 2000 1500 1000 -1 / cm
500
Fig. 13 (a) TG curve of sertraline hydrochloride, sample mass of 0.45 mg, in open -alumina crucible, dry
A
air (50 mL min-1), heated up to 200ºC at 10ºC min-1 and kept in isotherm during 100 min. (b) FTIR spectra of sertraline hydrochloride and de sublimate collected in a glass tube.
N U SC RI PT
Table 3. X-ray diffraction data for sertraline as received and samples collect at different temperatures Sample
Main X-ray diffraction / 2°
Form II*
5.4
10.7
14.6
Sertraline
14.3 5.3
10.7
13.1
A
CC E
PT
ED
M
* Data from literature
14.4
15.5
A
Form III*
16.3
19.0
17.4
16.1
18.8
20.3 19.6
21.5
20.2
21.0
21.8
24.4
27.3
24.0 22.4
23.6
24.7
27.2
Figure 14 depicts FTIR spectrum of the gases evolved at 28 min (303°C) and those for methylamine, tetraline and dichlorobenzene from the database. [22] Although the signals are relatively low it was possible to identify bands related to the presence of methylamine (2940, 778 cm-1), tetraline (3044, 2928, 2857 cm-1) and 1,2-dichlorbenzene (3069, 1158 cm-1) in agreement with the proposed from TG data in Table 2, based on
SC RI PT
stoichiometric calculations. It was not possible to observe signals of HCl in the gas phase, but it is thought that the acid is released in the same step of tetraline and 1,2dichlorbenzene, considering TG data.
Methylamine
0.25
0.10
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Tetraline
1.2-dichlorbenzene
N
Absorbance
0.10
28 min
3500
3000
2500
2000
1500
Wavenumber / cm
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A
0.006
1000
500
TE
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Fig. 14 FTIR spectra obtained at 303°C, during sertraline heating, and methylamine, tetraline and 1,2-dichlorbenzene from database.
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These results are not totally in agreement with the findings of Zayed and coworkers.[20] Those authors proposed that sertraline hydrochloride decomposed by release of dichlorobenzene in the first step followed by methylamine and butane in the
CC
second one, based in stoichiometric calculations and in TG curves that were not presented. In the present study methyl amine was detected in the first step, followed by tetraline and
A
dichlorobenzene in the second one, using TG-FTIR coupling. Thus, the use of hyphenated techniques is highly recommended, when the establishment of thermal decomposition mechanism is the goal. Based on TG, DSC and TG-FTIR data, a tentative mechanism for the thermal degradation of sertraline hydrochloride is presented in Fig. 15.
Sublimate 4 ºC min-1
H 3C
Cl
Cl
H 3C
H
HN
H
HN
198.0 ºC
. HCl
. HCl
Solid Form III
N
U
Solid Form II
A
198.0 - 249.5 ºC
10 ºC min-1
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Cl
D
Cl
EP
TE
. HCl
+ H 2N
CH3
249.5 - 329.5 ºC
CC A
Cl
SC RI PT
Cl
Cl Cl +
+
HCl(g) + carbonaceous residue
Fig. 15 Proposed mechanism to describe the thermal behavior of sertraline hydrochloride.
Conclsion
A mechanism for thermal behavior of paroxetine and sertraline hydrochloride has been proposed concerning mass losses during heating, calorimetric processes and volatiles evolved during the thermal degradation of the drugs. Paroxetine decomposed after a
SC RI PT
complex dehydration/melting process, releasing HCl, piperidine, fluorobenzene and CO2. Hemihydrate paroxetine hydrochloride crystals are dehydrated and melted concomitantly after what a new form crystallizes, probably as an anhydrous salt. Sertraline, on its turn,
goes through sublimation if slowly heated or solid transition from Form II to Form III and after that decomposes releasing methylamine, tetraline, dichlorobenzene and HCl when
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heated at faster heating rates.
A
N
Acknowledgments
Authors are grateful to agencies FAPESP (processes: 2014/22142-4 and 2015/09299-4)
A
CC
EP
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D
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and CNPq for support.
References
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Figure Captions
Fig. 1 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. N2 (50 mL min-1). Inset: TG/DTG curve using sample mass of 3.0 mg (± 0.1 mg) and heating rate of 5.0 °C min-1.
SC RI PT
Fig. 2 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of paroxetine hydrochloride. Sample mass of 7.0 mg (± 0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
Fig.3 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in closed with a pin hole with sample mass of 5.0 mg and heating rate of 10 °C min-1, in heat-cool-heat mode.
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Fig.4 DSC curves of paroxetine hydrochloride in nitrogen flowing at 50 mL min-1, in aluminum crucible. (a) using open and closed (with a pinhole in the lid) sample holder and heating rate of 10 °C min-1, (b) heating curves using sample mass of 3.0 mg and different heating rates () and (c) heat-cool-heat curves with sample mass of 3.0 mg and heating rate of 10 °C min-1, heating until dehydration and then reheating until 175 °C.
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Fig. 5 Hot stage microscopy photographs of paroxetine from 88 to 127 °C, in air at 2.0 °C min-1 heating rate (magnification 50x).
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Fig. 6 FTIR spectra obtained at 327.7°C, during paroxetine heating, and HCl from database. Insert: detail of the region from 3250 – 2500 cm -1.
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Fig. 7 FTIR spectra obtained at different temperatures, during paroxetine heating, in the region of HCl absorption.
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Fig. 8 Proposed thermal mechanism to describe the behavior of paroxetine hydrochloride. Fig. 9 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample mass of 7.0 mg (±0.1 mg), in open -alumina crucible. N2 (50 mL min-1).
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Fig. 10 (a) TG (—), DTG (···) and (b) TG (—), DTA (---) curves of sertraline hydrochloride. Sample mass of 7.0 mg (±0.1 mg), in open -alumina crucible. Dry air (50 mL min-1).
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Fig. 11 DSC curves of sertraline hydrochloride up to 220°C in N2 flowing at 50 mL min-1, sample mass of 5.0 mg and heating rate of 10 °C min-1.
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Fig. 12 (a) DSC curve of sertraline hydrochloride, N2 (50 mL min-1), heated up to 260 ºC at 10ºC min-1, and diffractograms of (b) sertraline hydrochloride and (c) sertraline hydrochloride heated up to 230ºC. Fig. 13 (a) TG curve of sertraline hydrochloride, sample mass of 0.45 mg, in open -alumina crucible, dry air (50 mL min-1), heated up to 200ºC at 10ºC min-1 and kept in isotherm during 100 min. (b) FTIR spectra of sertraline hydrochloride and de sublimate collected in a glass tube. Fig. 14 FTIR spectra obtained at 303°C, during sertraline heating, and methylamine, tetraline and 1,2-dichlorbenzene from database.
A
CC
EP
TE
D
M
A
N
U
SC RI PT
Fig. 15 Proposed mechanism to describe the thermal behavior of sertraline hydrochloride.