Polymorphism and thermal behavior of sodium cyclamate

Article abstract of DOI:10.1007/s10973-019-08037-7

Due to its potential thermal degradation or polymorphic transformation, thermal stability of a food additive may limit its use in food preparations, when heating process is involved. In this paper, we present an investigation on thermal behavior of sodium cyclamate, one of the most frequently used components in tabletop sweeteners. Thermogravimetric data revealed that sodium cyclamate exists in two polymorphic forms: sodium cyclamate di-hydrated (C₆H₁₂NSO₃Na·2H₂O) and anhydrous sodium cyclamate (C₆H₁₂NSO₃Na). X-ray powder diffraction data revealed that hydrate and anhydrate sodium cyclamate are true polymorphs. Under heating conditions, the hydrated form dehydrated in a complex multiple-step process. Finally, thermal decomposition of sodium cyclamate was studied and a degradation mechanism is proposed. At 170?°C, sodium cyclamate sublimates and dimerizes, by condensation of two cyclamate moieties, leading to formation of highly pure N,N-diciclohexyl sulfamide, a potential anxiolytic compound.

Full text of DOI:10.1007/s10973-019-08037-7

Journal of Thermal Analysis and Calorimetry
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Polymorphism and thermal behavior of sodium cyclamate
D. A. V. Medina1 A. P. G. Ferreira1 E. T. G. Cavalheiro1
•
•
Received: 25 September 2018 / Accepted: 19 January 2019
´
´
Ó Akademiai Kiado, Budapest, Hungary 2019
Abstract
Due to its potential thermal degradation or polymorphic transformation, thermal stability of a food additive may limit its
use in food preparations, when heating process is involved. In this paper, we present an investigation on thermal behavior
of sodium cyclamate, one of the most frequently used components in tabletop sweeteners. Thermogravimetric data
revealed that sodium cyclamate exists in two polymorphic forms: sodium cyclamate di-hydrated (C6H12NSO3NaÁ2H2O)
and anhydrous sodium cyclamate (C6H12NSO3Na). X-ray powder diffraction data revealed that hydrate and anhydrate
sodium cyclamate are true polymorphs. Under heating conditions, the hydrated form dehydrated in a complex multiple-step
process. Finally, thermal decomposition of sodium cyclamate was studied and a degradation mechanism is proposed. At
170 °C, sodium cyclamate sublimates and dimerizes, by condensation of two cyclamate moieties, leading to formation of
highly pure N,N-diciclohexyl sulfamide, a potential anxiolytic compound.
Keywords Cyclamate Á Phase change Á Polymorphism Á Thermal decomposition Á Dimerization
Introduction
degradation pathways and products eventually generated
under food-processing conditions became very important.
Thermal analysis offers valuable data about potential
usability of food additives [6, 7] and has been previously
used to evaluate polymorphism and thermal properties of
artificial sweeteners [8, 9]. Nevertheless, determination of
solid state transitions and thermal degradation products of
sodium cyclamate has not been fully accomplished yet.
Sodium cyclamate is a white powder, a strong elec-
trolyte, with low buffering capacity, whose solutions had
been described as stables under heat and light. In solid
state, sodium cyclamate crystalizes in a monoclinic cell
setting, with the cyclamate moieties into linear chains
along b axis, linked by hydrogen bonds. The cations are
situated among the chains and coordinate by oxygen atoms
of sulfo groups. Similar crystalline structures have been
reported for potassium, ammonium and rubidium cycla-
mates [10].
Sodium cyclamate (sodium N-cyclohexylsulfamate salt) is
a noncaloric artificial sweetener derived from cyclamic
acid, 30–80 times as sweet as sucrose [1]. It was first
synthesized in 1937 [2] that became commercially avail-
able since 1950 and nowadays is one of the most widely
consumed sweetener, especially as tabletop or noncaloric
beverages and dietetic foods [3, 4].
Safety of cyclamate to human consumption is not
completely clear; it was suggested that cyclamate is a
potential carcinogenic agent, once it is metabolized as
cyclohexylamine [5]. As food additive, sodium cyclamate
can be submitted to food processing under heating or
cooling. Whereby, the understanding of its thermal
behavior regarding polymorphism, thermal stability,
A polymorphic transition for cyclamic acid at room
temperature, from monoclinic to orthorhombic cell setting,
had been previously described [11]. Nevertheless, there are
no previous reports regarding polymorphism in sodium
cyclamate or other cyclamates.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10973-019-08037-7) con-
tains supplementary material, which is available to autho-
rized users.
& E. T. G. Cavalheiro
cavalheiro@iqsc.usp.br
On the other hand, to the best of our knowledge, there is
only one report regarding thermal behavior of sodium
cyclamate [9]. In such study, the thermal degradation of
sodium cyclamate in oxidant atmosphere was carried out
1
´
Instituto de Quımica de Sa˜o Carlos, Universidade de Sa˜o
Paulo, Av. Trabalhador Sa˜o-carlense, 400, Sa˜o Carlos,
SP 13566-590, Brazil
123

D. A. V. Medina et al.
using thermoanalytical methods (TG/DTG and DTA).
Decomposition started above 180 °C, with a residue
equivalent to 34.8% of initial mass at 800 °C, suggested as
sodium sulfate. However, intermediate products or the
decomposition mechanism was not identified.
Evolved gas analysis
The TG-FTIR apparatus consisted in a SDT-Q600 simul-
taneous TG–DTA thermal analyzer coupled with Nicolet
S10 Fourier transform spectrometer. The measurements
were carried out under nitrogen atmosphere flowing at
50 mL min-1 for TG; the temperature was set from 25 to
1000 °C, with heating rate of 10 °C min-1. The FTIR
spectral region was set as 4000–400 cm-1 with resolution
of 4 cm-1. The temperature in the gas cell was 2508C and
in transfer line was 230 °C. Sample mass used was 15 mg
(with the senstivity of the thermobalance of 0.1 lg). The
transfer line consisted of an insulated 1200 mm long 9 2
mm internal diameter stainless still tube.
In this paper, a new solid form of sodium cyclamate is
described (NaC6H12SNO3Á2H2O), which was characterized
by thermoanalytical (TG/DTG/DTA and DSC) and struc-
tural (PXRD) methods. In addition, it was established that
under heating conditions (up to 170 °C), sodium cyclamate
reacts to form pure N,N0-diciclohexylsulfamide. That
reaction product was isolated and characterized by infrared
spectrometry (FTIR), high-resolution mass spectrometry
(MS) and magnetic resonance (1H-NMR and 13C-NMR).
Powder X-ray diffraction
Materials and methods
Powder diffractograms were obtained in a Rigaku Rotaflex
RU200B equipment. The operating conditions were copper
Preparation of sodium cyclamate polymorphs
˚
anode (Cu Ka, k = 1.542 A), voltage 50 kV, current
Sodium cyclamate crystals were obtained by dissolving
0.25 mg of commercial sodium cyclamate (Natural
Pharma, technical grade) in 1.0 mL distilled water. The
suspension was sonicated (UNIQUE ultrasonic cleaner,
USC 1400) until a limpid solution was achieved. Slow
evaporation of solvent at room and refrigerated tempera-
ture (25 and 8 °C, respectively) leads to the formation of
transparent flat-sheet crystals after four days.
100 mA, scan with step of 0.02° 2h and scan speed
2 °C min-1
.
Elemental analysis
The C, H and N contents were determinate by elemental
analysis carried out in a CHNS-O Instrument, model EA-
1110 CE (Fisons).
Thermal Analysis
Infrared spectroscopy
Thermogravimetry (TG/DTG) and differential thermal
analysis (DTA) were carried out using a SDT-Q600
simultaneous TG–DTA thermal analyzer controlled by
Thermal Advantage (v. 2.5.0.256) software (both from TA
Instruments), under non-isothermal conditions. Measure-
ments were performed in dynamic nitrogen atmosphere,
flowing at 100 mL min-1, in the 25–1000 °C temperature
range. Sample mass used was around 3.0 0.1 mg (pre-
cision 0.1 lg) using 10 °C min-1 heating rate in open a-
alumina sample holders.
Infrared absorption spectra were obtained using an IRAf-
finnity-1S FTIR spectrophotometer (Shimadzu), in the
range of 4000–400 cm-1, 4 cm-1 resolution, 32 scan s-1
.
The samples were prepared in KBr pellets (KBr/sam-
ple = 1% m/m).
NRM analysis
NMR 1H and 13C spectra were obtained in deuterated
chloroform (CDCl3), in a 499,85 MHz spectrometer (Bru-
ker, Billerica, Massachusetts, EUA).
DSC curves were obtained in Q10 Differential Calori-
metric Module, controlled by Thermal Advantage Series
software (v. 2.5.0.256), both from TA Instruments, using
sample masses of ca. 9.0 mg ( 0.1 mg) in a covered
aluminum sample holder with a 0.7-mm pinhole in the
center of the lid, at 10 °C min-1 heating rate. The mea-
surement was taken between room temperature and 300 °C
under dynamic nitrogen atmosphere flowing at
Mass spectrometry analysis
Exact mass was measured by direct infusion in a hybrid
quadrupole/time-of-flight mass spectrometer (Bruker Dal-
tonics), using chemical ionization (APCI) in positive mode.
50 mL min-1
.
123

Polymorphism and thermal behavior of sodium cyclamate
Calculations realized according to mass loss corre-
sponding to dehydration event in TG curve bring out the
presence of two moles of water for each unit formula of
sodium cyclamate in agreement with elemental analysis.
The elemental composition (C, H, N) of the transparent
crystal matches with the percentage composition theoreti-
cally expected, as presented in Table 2.
Results and discussion
Polymorphism in sodium cyclamate
The solubility of sodium cyclamate in different solvents
was evaluated, and the results are presented in the sup-
porting information (Table S1). Sodium cyclamate was
soluble in water and partially soluble in ethylene glycol. By
slow evaporation of water, transparent sheet-shaped crys-
tals were obtained. From ethylene glycol solution, no
crystal was obtained, even after several months. Under
storage conditions, after 4 weeks, it was possible to
observe that transparent crystals turned white. Samples of
the two types of crystals (transparent and white) were
analyzed and characterized, separately.
Dehydration of sodium cyclamate occurs through three
endothermic events (TG/DTG curves for transparent crys-
tals in Fig. 1a). It began above room temperature and
process through the unstable intermediates C6H12NSO3Á3/
2H2O and C6H12NSO3Á1/2H2O. According to mass loss for
the distinguishable steps in this event, the dehydration
mechanism can be represented as follows:
NaC6H12NSO3 Á 2H2O ! NaC6H12NSO3 Á 3=2H2O
! NaC6H12NSO3 Á 1=2H2O
TG/DTG and TG/DTA curves for sodium cyclamate
crystals are presented in Fig. 1. Commercial sample and
white crystal presented two endothermic events corre-
sponding to thermal decomposition, which took place
through an initial mass loss of 57–59%, between 200 and
300 °C, followed by an additional mass loss of 3.2%,
between 300 and 800 °C, leading to an inorganic residue at
800 °C with mass equivalent to 35% of the initial mass.
Additionally, during the endothermic decomposition events
of transparent crystals, a mass loss of c.a. 14%, between
room temperature and 155 °C, appeared and was attributed
to dehydration step. Data of temperature intervals and mass
losses corresponding to thermal events are described in
Table 1.
! NaC6H12NSO3
A DSC curve (Fig. 2) of the transparent crystals was
obtained in order to evaluate the dehydration process. From
this curve, obtained in a closed pan, it is possible to observe
a endothermic signal centered at 131.2 °C, with shoulders
at 88.2 and 117.3 °C, referent to the dehydration process.
The area of this peak was calculated as 42.4 kJ mol-1
(21.2 kJ mol-1 per molecule of water). According to Sur-
esh and Naik, the hydrogen bonds in water present
hydrogen bond energy of c.a. 23.3 kJ mol-1 which agrees
with the proposal of dehydration [12].
Structural differences between transparent and white
crystals were observed from the powder diffraction
Fig. 1 (a) TG (solid)/DTG
(dotted) and (b) TG(solid)–DTA
(a)
(b)
Commercial sample
Commercial sample
(dotted) curves of sodium
cyclamate crystals. Nitrogen
dynamic atmosphere
(100 mL min-1); heating rate
10 °C min-1; sample mass
3 mg
Transparent crystal
Transparent crystal
1% °C–1
20%
White crystal
White crystal
1 °C mg–1
20%
100
400
800
100
400
800
Temperature/°C
Temperature/°C
123

D. A. V. Medina et al.
Table 1 Thermal events
presented in thermogravimetric
curves of sodium cyclamate
crystals
Sample
Event
Temperature/°C Mass loss/%
DTA peak/°C
TG
Calculated
Commercial sample Decomposition
Decomposition
210–287
297–800
–
57.7
3.1
–
266 (endo)
734 (endo)
–
–
Residue at 800 °C
35.6
35.3
Transparent crystal Dehydration -0.5 H2O 24.2–63.6
3.42 3.80
6.85 7.6
3.86 3.80
-1 H2O
63.6–103
103–155
198–302
–
60.4; 103 (endo)
-0.5 H2O
Decomposition
Residue at 800 °C
Decomposition
Decomposition
Residue at 800 °C
49.8
–
253 (endo)
27.7
58.6
29.9
–
–
White crystal
197–312
312–800
–
264 (endo)
724 (endo)
–
3.20
35.9
–
35.3
Table 2 Experimental and
calculated percentage
Sample
Percentage compositiona/% Exp
d
composition (C, H, N) in
sodium cyclamate white and
transparent crystals
C
H
N
Exp
Cal
Exp
Cal
Exp
Cal
White crystals (NaC6H12SNO3)
35.9 0.2 (35.8) 7.0 0.2 (6.1) 7.1 0.1 (7.0)
Transparent crystals (NaC6H12SNO3Á2H2O) 31.1 0.1 (30.3) 6.7 0.2 (6.7) 6.2 0.2 (6.0)
Exp experimental; Cal calculated; d = standard deviation
an = 3
0.0
– 0.2
– 0.4
– 0.6
– 0.8
– 1.0
– 1.2
– 1.4
– 1.6
Hydrated sodium cyclamte
20%
endo
Anhydrous sodium cyclamte
0
50
100
150
200
250
300
0
10
20
30
40
50
60
70
80
90 100
Temperature/°C
Scattering angle/2θ
Fig. 2 DSC curve of sodium cyclamate under nitrogen flowing at
50 mL min-1, using closed aluminum sample holder, with a pin hole
in the lid and heating rate of 10 °C min-1, using sample mass of
9.0 mg
Fig. 3 PXRD patterns for transparent and white sodium cyclamate
crystals
Thermal decomposition of sodium cyclamate
patterns. This diffraction profiles can be observed in Fig. 3
and suggested the presence of two different crystalline
structures for anhydrate and di-hydrate sodium cyclamate.
(Spectral data are presented in Table S2.)
As previously reported, under oxidant conditions [9],
thermal decomposition of sodium cyclamate occurs
through two successive endothermic events, the same was
observed under inert atmosphere in the present work
(Fig. 1). The process started with a mass loss of 59%
between 197 and 312 °C, followed by a decomposition step
123

Polymorphism and thermal behavior of sodium cyclamate
that extends up to 800 °C, with a mass loss equivalent 9%
of the initial mass. A stable residue is formed at 800 °C,
representing 30% of initial mass of the sample.
differences between FTIR spectra of residue 1 and sodium
cyclamate were found in the absorption region of S–O
(1000–1200 and 600–640 cm-1) which suggests that
molecular structure of residue 1 preserves hydrocarbon and
amine segments. By comparison with FTIR spectrum in the
spectral data base for organic compounds (SDBS), residue
1 was identified as N,N0-diciclohexylsulfamide (C12H24-
N2O2S, CAS number 14041-87-3). Figure S2 shows
experimental FTIR spectrum of residue 1 with the recon-
structed SDBS spectrum for N,N0-diciclohexylsulfamide
(spectral data base for organic compounds—SDBS).
The exact mass of the residue 1 was measured by high-
resolution mass spectrometry. A protonated ion with m/
z ratio 261.16379, attributed to the molecular formula
[C12H24N2O2S]?, with Dmi= 2.56 ppm, verifies the iden-
tity of the residue 1 as N,N0-diciclohexylsulfamide. The
spectra in Figure S3 shows the mass spectrum obtained
experimentally for the product of the reaction and the
molecular formula attributed to the molecular ion in this
spectrum, as well as for the main ion fragment.
Cyclamate degradation products were studied by mon-
itoring of evolved gas through coupled TG/FTIR. FTIR
spectrum of gas generated was regarded simultaneously
with heating sample (10 °C min-1). Absorption bands’
characteristics
of
water
(4000–3400 cm-1
,
200–1400 cm-1) and carbon dioxide (2400–2300 cm-1
)
were observed along entire experiment. Between 20 and
30 min (175–275 °C), absorptions bands of N–H
(1000–900 cm-1), S–O (1400–1300 cm-1) and organic
moieties (3100–2800 cm-1) were observed. Figure 4a
shows the Gram–Schmidt plot and Fig. 4b one of the
spectra obtained in this interval. The comparison between
experimental and reference spectra found in the Aldrich
phase vapor library set up three possible identities for this
organic
product:
cyclohexane,
hexylamine
or
cyclohexylamine.
These results were better understood after conducting
heating tests until decomposition of sodium cyclamate in
test tube. Up to 170 °C, the condensation of white needle
crystals in the upper part of the test tube was observed
(residue 1). Up to 190 °C, the formation of a brown residue
in the bottom of the tube was observed (residue 2). Residue
1 was a crystalline white powder, without sweet taste,
slightly soluble in water and with putrefied smell charac-
teristic of the amines. Residue 2 was a brown-yellowish
powder with sulfur smell.
1
Finally, H and 13C NRM spectra for samples of the
residue 1 were obtained (Figures S4 and S5). The observed
chemical shifts were compared with those reported in the
literature for N,N0-diciclohexylsulfamide (Table S4). In this
way, the identity of the residue 1, as being N,N0-diciclo-
hexylsulfamide, was stablished.
N,N0-diciclohexylsulfamide has been previously descri-
bed as an anticonvulsant drug, an anxiolytic compound,
with medium affinity for the benzodiazepine site of the
GABAA receptor, that would improve the quality of life of
patients with epilepsy [13]. Recently, anticonvulsant effect
has been described for sodium cyclamate too [14].
Typically, the N,N0-diciclohexylsulfamide is prepared
by condensation of cyclohexylamine in excess with sul-
furyl choride, in dichloromethane, in dark conditions [15].
In that process, the reaction mixture is stirred for 5–30 h
Samples of the two residues were removed and analyzed
by FTIR (KBr disk). Figure S1 presents the comparison
between FTIR spectra of the residues and sodium cycla-
mate. Characteristic absorption bands of sodium cyclamate
were also observed in FTIR spectra of residue 1 (Table S3).
Bands related to m NH, d NH and symmetrical/asymmet-
rical stretching of SO2 group were observed. Main
(a)
(b)
Cyclohexane
Hexylamine
Cyclohexylamine
100
80
60
40
20
0
CO2
SO2
0.050
0.025
NH3
0.000
– 0.025
– 0.050
4000
3500
3000
2500
2000
1500
1000
500
0
10 20 30 40 50 60 70 80 90 100
Time/min
Wave number/cm–1
Fig. 4 a Gram–Schmidt plot for thermal decomposition of sodium cyclamate; b FTIR for effluent gas of sodium cyclamate decompositions at
28 min (260 °C)
123

D. A. V. Medina et al.
and posterior steps as washing are required with acidic and
basic aqueous solutions and purification through column
chromatography [16]. In this way, heating of sodium
cyclamate until 170 °C would be a new, faster, economi-
cal, green and easy synthetic method to obtain pure N,N0-
diciclohexylsulfamide [17].
diciclohexylsulfamide and sodium cyclamate in the residue
2 attributed to an incomplete decomposition.
Decomposition process of sodium cyclamate ends with
the formation of stable residue at 1000 °C attributed to
sodium oxide (Na2O; TG = 31%, calculated = 30%).
Finally, thermal decomposition of sodium cyclamate could
be represented according to the mechanism proposed in
Fig. 5.
During the characterization of the residue 2, the pres-
ence of sulfate ion was confirmed by the formation of a
white precipitate, after addition of 5 mL of barium chloride
solution (5% m/m) to 15 mL of the residue 2 solution (5%
m/m). This result is in agreement with the previously
reported from thermogravimetric data [8]. Additionally,
FTIR spectrum of residue 2 was compared with FTIR
spectrum of sodium sulfate commercially available (Fig-
ure S6). FTIR spectrum of residue 2 presents the absorption
bands related to sodium sulfate. Additional bands corre-
sponding to the presence of residual N,N0-
Conclusions
Two polymorphic forms of sodium cyclamate were iden-
tified: hydrated and anhydrate. The PDRX profiles suggest
that these solid forms present differences in their crys-
talline structures; further studies could determine the cell
parameters for the di-hydrate form and be compared with
the previously reported for sodium cyclamate anhydrate.
In addition, the dehydration of sodium cyclamate is a
multiple-step process that occurs spontaneously at room
temperature and the decompositions process takes place up
to 170 °C. It was also determined that sodium cyclamate
decomposes through dimerization process that leads to the
formation of N,N0-diciclohexylsulfamide and sodium
sulfate.
O
2
S
–
O Na+
N
O
Sodium cyclamate
MM 201 g mol–1
`
Funding Funding was provided by Fundac¸a˜o de Amparo a Pesquisa
do Estado de Sa˜o Paulo (Grant No. 2015/09299-7) and Coordenac¸a˜o
´
de Aperfeic¸oamento de Pessoal de Nıvel Superior.
180°C
O
S
Na2SO4
+
(s)
N
N
(g)
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