Structure and thermodynamical properties of metformin salicylate

Article abstract of DOI:10.1021/cg400150f

The behavior under thermal conditions of the cocrystal formed by metformin and salicylic acid was studied by DSC, crystallography (single-crystal), and powder diffraction (WAXS). Metformin salicylate crystallizes in space group P2₁/c, with the salicylate anion showing a planar structure, stabilized by strong intramolecular hydrogen bonds. The more flexible metformin cations link through the oxygen atoms of salicylate, forming a dense hydrogen-bonding network. The compound exists initially as a salt, metformin salicylate, but after melting and cooling, it is transformed into a glass form that crystallizes and melts again, showing different behaviors depending on the heating rate.

Full text of DOI:10.1021/cg400150f

Article
pubs.acs.org/crystal
Structure and Thermodynamical Properties of Metformin Salicylate
R. Perez-Fernandez,*,† N. Fresno,† P. Goya,† J. Elguero,† L. Menendez-Taboada,*,‡ S. García-Granda,‡
́
́
́
and C. Marco*,§
†Instituto de Química Med
́
ica, IQM-CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
‡Departamento de Química Física y Analítica, Facultad de Química, Universidad de Oviedo − CINN, Julian
́
Clavería, 8, E-33006
Oviedo, Spain
§Departamento de Física de Polímeros, Elastom
ICTP-CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
́
eros y Aplicaciones Energet
́
icas, Instituto de Ciencia y Tecnología de Polímeros,
S
* Supporting Information
ABSTRACT: The behavior under thermal conditions of the
cocrystal formed by metformin and salicylic acid was studied by
DSC, crystallography (single-crystal), and powder diffraction
(WAXS). Metformin salicylate crystallizes in space group P21/c,
with the salicylate anion showing a planar structure, stabilized by
strong intramolecular hydrogen bonds. The more flexible
metformin cations link through the oxygen atoms of salicylate,
forming a dense hydrogen-bonding network. The compound exists
initially as a salt, metformin salicylate, but after melting and cooling,
it is transformed into a glass form that crystallizes and melts again,
showing different behaviors depending on the heating rate.
metformin hydrochloride 97% (500 mg, 3.03 mmol) was stirred for 12 h
at room temperature. After removing the solvent under reduced
pressure, 2-propanol (20 mL) was added to the reaction crude. The solid
part (sodium chloride) was filtered off. A part of this solution was
concentrated under reduced pressure (40 °C, 200 mbar). The resulting
white solid was studied by DSC. The rest of the solution was slowly
evaporated at room temperature (21 °C), yielding suitable crystals for X-
ray diffraction experiments. mp: 148 °C (Gallenkamp capillary melting
point apparatus). 1H NMR (300 MHz, DMSO-d6): δ = 7.66 (dd, J = 7.5,
1.9 Hz, 1H, CHar), 7.14 [m, 3H, (2 NH + 1 CHar)], 6.87 [m, 4H,
(4NH)], 6.61 [m, 3H, (2 CHar + 1 OH)], 2.93 (s, 6H, 2 CH3). 13C NMR
(75 MHz, CDCl3): δ = 172.2 (CO), 163.1 (C−OH), 159.5 (CN),
160.0 (CN), 131.8 (CHar), 130.3 (CHar), 120.7 (Car), 116.4 (CHar),
37.8 ppm (2CH3). Analysis calculated for C11H17N5O3: C, 49.43; H,
6.41; N, 26.20. Found: C, 49.37; H, 6.68; N, 25.99. Both 1H NMR and
elemental analysis corresponds to a 1:1 stoichiometry.
INTRODUCTION
■
There is a great interest in salts or cocrystals formed by two APIs
(active pharmaceutical ingredients) or drugs.1−4 In some cases,
these salts have low melting points (below 100 °C) belonging to
the ionic liquids class.5,6 After screening a wide range of Brønsted
acid and base mixtures by nuclear magnetic resonance (NMR)
and differential scanning calorimetry (DSC),7 the unusual
behavior showed by metformin salicylate (Figure 1) in DSC
led us to analyze it in depth. Metformin9 is an oral antidiabetic
drug of the biguanide family. It is the first-line drug of choice for
the treatment of type 2 diabetes mellitus,10 in particular, in
overweight and obese people. On the other hand, salicylic acid is
an antipyretic and analgesic drug that is being used for the
treatment of acne and other skin diseases. Note that the charges
in the guanidinium cation and in the carboxylate anion are
delocalized. In addition, as a complication for this study,
metformin hydrochloride presents polymorphism.8
DSC. The thermal properties of metformin salicylate were
investigated by DSC using a METTLER TA 4000/DSC30 differential
scanning calorimeter, calibrated with indium (Tm = 156.6 °C, ΔHm
=
28.45 kJ·kg−1) and zinc (Tm = 419.47 °C, ΔHm = 108.37 kJ·kg−1).11−16
The experiments were carried out in a nitrogen atmosphere with a flow
rate of 25 mL·min−1, using approximately 10 mg of sample sealed in
aluminum pans. Original samples of metformin salicylate were heated
from 5 to 180 °C at a rate of 5 °C·min−1, first heating, and then were
cooled down at 2, 5, and 10 °C·min−1 to 0 °C. Subsequently, each
sample was heated to 180 °C at different rates of 2, 5, and 10 °C·min−1,
second heating. Melting and crystallization temperatures, Tm and Tc
EXPERIMENTAL SECTION
■
Materials and Methods. All chemicals were purchased from
commercial suppliers and used without further purification. Elemental
analysis was determined with a LECO Elemental Analyzer CHNS-932.
1H and 13C NMR spectra were recorded on a Bruker Advance 300
spectrometer operating at 300.13 and 75.47 MHz respectively, in
DMSO-d6 as solvent. Chemical shifts are reported in parts per million on
the δ scale. In the case of multiplets, the signals are reported as intervals.
Signals were abbreviated as s, singlet; d, doublet; and m, multiplet.
Coupling constants are expressed in hertz.
Received: January 25, 2013
Revised: February 22, 2013
Published: February 25, 2013
Synthesis of Metformin Salicylate. A methanol solution (20 mL)
of sodium salicylate puriss. p.a. > 99.5% (485 mg, 3.03 mmol) and
© 2013 American Chemical Society
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Figure 1. Structure of metformin salicylate, precursor salts, and neutral species.
Table 1. Crystal Data and Structure Refinement
metformin salicylate
empirical formula
formula weight
temp (K)
C11 H17 N5 O3
267.30
calculated density (Mg/m3)
1.390
μ (mm−1
)
0.870
122.5(8)
F(000)
568
wavelength (Å)
cryst syst
1.54180
cryst size (mm)
0.175 × 0.108 × 0.028
4863/2390 [R(int) = 0.0244]
99.1%
monoclinic
P21/c
reflns collected/unique
completeness to θ = 68.00
data/restraints/params
goodness-of-fit on F2
final R indices [I > 2σ(I)]
R indices (all data)
space group
a (Å), α (deg)
b (Å), β (deg)
c (Å), γ (deg)
V (Å3)
15.271(5), 90
6.002(5), 119.72(2)
16.050(4), 90
1277.5(12)
4
2390/0/199
1.050
R1 = 0.0561, wR2 = 0.1526
R1 = 0.0761, wR2 = 0.1742
Z
Table 2. Hydrogen Bonds for Metformin Salicylate (Å, deg)
a
D−H···A (Å)
D−H (Å)
H···A (Å)
D···A (Å)
D−H···A (deg)
symmetry
N(2)−H(2B)···O(1)
N(2)−H(2A)···O(2)
N(4)−H(4B)···O(2)
0.99(5)
0.86(7)
0.92(6)
2.04(5)
2.24(6)
2.56(5)
3.004(5)
3.047(5)
3.462(5)
164(4)
157(5)
168(5)
0
1
2
a
Symmetry transformations used to generate equivalent atoms: (0) x, y, z; (1) −x + 1, −y, −z − 1; (2) x, +y − 1, +z.
were determined as the maximum and minimum of the endothermic and
exothermic transitions, respectively. The extrapolated peak onset
temperatures, Tmo and Tco, were also considered. The apparent enthalpy
of the transition, ΔHi, was determined as the area under the curve. Glass
transition temperature, Tg, values were determined at the midpoint of
the corresponding change in the specific heat of the baseline in the
thermograms. Heating and cooling cycles have been repeated four times
with new samples, ensuring reproducibility. Temperature and enthalpy
standard deviations were 0.4 °C and 3 J·g−1, respectively.
WAXS. Wide-angle X-ray scattering (WAXS) measurements were
conducted at the A2 beamline of the HASYLAB synchrotron facility
(DESY, Hamburg). The experiments were performed with mono-
chromatic X-rays of 0.15 nm in wavelength using a germanium single
crystal as the dispersing element. The scattering was detected with a
linear Gabriel detector, and the scattering angle of the WAXS pattern
was calibrated with a PET standard. The methodology used in the
crystallization and melting experiments of the samples was similar to
that described for the calorimetric experiments. Measurements were
performed with acquisition times between 30 and 150 s, depending on
the heating rate.
solved by direct methods, using the program Sir92.19 Anisotropic least-
squares refinement was carried out with SHELXL-97.20 Refinement was
made in the space group P21/c. Further details of the X-ray structural
analysis are given in Table 1. Hydrogen bonds are listed in Table 2.
Geometrical calculations were made with PARST9721,22 and
PLATON,23,24 and molecular graphics with ORTEP-325 and MER-
CURY for Windows.26 The crystals were checked at room temperature,
giving the same unit cell and symmetry at both temperatures within the
expected ranges of thermal volume contraction. The structure was
deposited and has the following code number: CCDC 883514.
RESULTS AND DISCUSSION
■
Single-Crystal Structure. The molecular structure of
metformin salicylate is represented in Figure 2. The single-
crystal X-ray data for this compound are listed in Table 1. The
hydrogen-bonding geometry is reported in Table 2.
The crystal packing of metformin salicylate shows infinite
layers in zigzag that are parallel to the bc plane, as shown in
Figures 3 and 4, formed by N−H···O hydrogen bonds.
Layers are formed by tetramers (Figure 5) in which the
molecules are connected by N(2)−H(2B)···O(1) and N(2)−
H(2A)···O(2) hydrogen bonds. Each tetramer is interacting with
four tetramers by N(4)···O(1) hydrogen bonds forming the layer
within the bc plane. The N(4)−H(4B)···O(1) hydrogen bonds
are shown in Figure 6.
Crystal Structure Determination. Suitable crystals for X-ray
diffraction experiments were obtained by slow evaporation of 2-
propanol at room temperature. Data were collected at 123 K to achieve
better intensity and resolution using CuK/α, l = 1.54184 Å. A total of
4863 (−18 ≤ h ≤ 18, −7 ≤ k ≤ 4, −16 ≤ l ≤ 19) reflections were
collected for it with 2390 independent reflections. Data collection was
made using the program CrysAllis CCD.17 Semiempirical absorption
correction18 was applied to the intensity data. The crystal structure was
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Figure 2. Crystal structure of metformin salicylate at 123 K (ORTEP).
Figure 6. N(4)−H(4B)···O(1) hydrogen bond network present in
metformin salicylate.
Figure 7. Tautomerism of the metformin cation.
related to a possible desmotropy of metformin salicylate.27 The
X-ray structure corresponds to tautomer c. All reported
metformin salts and related compounds, such as biguanide
hydrochloride salt, also belong to tautomer c.8,28−31
Figure 3. Crystal packing of metformin salicylate. Parallel layers within
bc plane. View along b axis.
DSC. When an original sample of metformin salicylate is
heated at 5 °C·min−1, an endothermic transition is found with a
maximum at 147.5−147.8 °C and an enthalpy of 102.6−103.4
J·g−1. During its subsequent cooling at 10 °C·min−1, no
crystallization-associated exothermic process was observed in
any case, but a small variation in specific heat at 25.1−25.8 °C can
be assigned to a glass transition (Figure 8).
Figure 4. Layer within bc plane. View along a axis.
Figure 8. Metformin salicylate DSC traces at 2, 5, and 10 °C·min−1
heating rates. From bottom to top: cooling (green); first heating at 5
°C·min−1 (black); second heating R2 at 2 °C·min−1 (red), second
heating R10 at 10 °C·min−1 (pink).
The high-temperature exothermic change at 157 °C observed
at cooling is attributed to the initial thermal effect of the cooling
process and not to the crystallization process. Changing the
cooling rate to 2 and 5 °C·min−1 after the first heating cycle did
not affect the DSC thermogram, not showing any crystallization
exotherm during the cooling process. Table 3 compiles the
temperatures and enthalpies for the first heating cycle and for the
Figure 5. Tetramer formed by N(2)−H(2B)···O(1) and N(2)−
H(2A)···O(2) hydrogen bonds. View along c axis.
The metformin cation can exist in three tautomeric structures
a, b, and c, all of them fully delocalized (Figure 7). This could be
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Table 3. DSC Measurements of Metformin Salicylate at 2, 5, and 10 °C·min−1 Heating Rates
a
S
first heating
Tmo (°C)
cooling
second heating
ΔHc (J·g−1
Tm (°C)
142.8
T
m (°C)
ΔHm (J·g−1
)
Tg (°C)
Tg (°C)
Tc (°C)
Tco (°C)
)
Tmo (°C)
ΔHm (J·g−1
)
R10
R5
147.7
147.5
147.8
140.3
140.6
140.4
102.9
102.6
103.4
25.1
25.5
25.8
28.3
25.9
18.8
86.7
79.8
78.0
77.1
70.6
69.2
76.0
66.4
41.9
129.6
128.4
110.1
80.9
70.6
79.1
140.1
R2
115.6−129.1
a
Sample R2 (2 °C·min−1), sample R5 (5 °C·min−1), sample R10 (10 °C·min−1).
Figure 9. WAXS of metformin salicylate: (a) initial sample at 5, (b) 2, and (c) 10 °C·min−1. XRPD: 2θ zone between 10 and 30°. Heating temperatures
from top to bottom: 30, 80, 100, 120, 140, 150 (only in (c)), and 160 °C (only in (a)).
cooling cycle previous to the second heating cycle at different
temperatures.
During the heating at 10 °C·min−1 (sample R10) immediately
after the cooling, a glass transition is observed, followed by an
exothermic transition associated with the cold crystallization of
the system with an exothermic peak located at 86.7 °C and
followed by the melting at 142.8 °C of the crystals generated
during heating (Figure 8).
The aforementioned cold crystallization process is very
dependent on the heating rate employed. When the heating
rate is lower (samples R5 and R2), the cold crystallization
exotherm shifts to lower temperature (79.8 and 78.0 °C,
respectively), as the melting endotherm that splits into a double
endotherm (115.6 and 129.1 °C) when the heating rate is 2
°C·min−1 (Table 3).
WAXS. Taking into account the pKa’s of salicylic acid (2.97)32
Figure 10. Predicted powder pattern from the single-crystal metformin
and metformin (12.4),33,34 the compound must be a salt in
salicylate using a full width at half-maximum (fwhm) 2θ = 0.5.
solution and probably in the solid state. Figure 9 shows the wide-
angle X-ray pattern evolution. The DSC recordings shown in
Figure 8 are in accordance with these WAXS patterns at heating
rates of 5, 2, and 10 °C·min−1.
thermogram, the metformin salicylate crystal melts at 147.7
°C, transforming it into a liquid, probably no longer a salt, but a
hydrogen-bonded complex, “liquid” in Figure 11. Upon cooling,
a glass transition is observed and the compound does not
rearrange to the starting metformin salicylate salt (polymorph A)
but transforms into a solid hydrogen-bonded complex, “glass” in
Figure 11. Neither the liquid nor the glass diffracts, which is the
reason why we assumed that they are no longer salts, but
noncrystalline complexes. On heating, the behavior of the glass
differs depending on the heating rate. At the 2 °C·min−1 rate, the
glass crystallizes, but the crystal obtained, as shown by the WAXS
pattern, is another polymorph we have named B. With a faster
heating, 10 °C·min−1, the glass also crystallizes probably to
polymorph A, although the WAXS spectrum is not identical, it
may be because the equilibrium was not reached. Polymorphs A
and B are comparable to polymorphs A (stable) and B
Mercury (CCDC) software35,36 was used to generate a
predicted powder pattern from the single crystal using a full
width at half-maximum (fwhm) 2θ = 0.5 (Figure 10), which was
compared with the observed WAXS patterns (Figure 9a, top).
Taking into account the broadening of the WAXS spectrum,
no extra peaks were found, verifying that the crystal grown in
solution for single-crystal analysis is the same as the ones used for
the DSC/WAXS experiments (polymorph A). The phenomena
observed in the DSC and WAXS experiments are summarized in
Figure 11.
At 5 °C·min−1, the first diffraction peak (2θ = 13.5°) appears
and a dominant diffraction peak can be observed at 2θ = 22°
(polymorph A). At the same heating rate in the DSC
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Figure 11. Metformin salicylate structural changes.
Figure 12. Metformin salicylate IR (4000−2000 cm−1): (a) starting compound, (b) after heating/cooling cycle.
(metastable) in metformin hydrochloride, the transformation
conditions being different.8
CONCLUSIONS
■
The great interest in the properties of compounds resulting from
mixing two drugs or their APIs prompted us to study the case of
the antidiabetic metformin and the analgesic salicylic acid. This
combination could be used, modifying the pharmacokinetics of
each component to treat dermatological illnesses. We have
characterized by single-crystal X-ray diffraction the structure of
metformin salicylate, formed by infinite zigzag layers parallel to
the bc plane, holding together by N−H···O hydrogen bonds. The
evolution of metformin salicylate under heating was studied by
DSC and WAXS.
Spectroscopic data from IR experiments support the structure
of the liquid/glass states. IR experiments from metformin
salicylate before and after the heating/cooling cycle were
performed (Figure 12). The broadening of the O−H stretching
bands due to the stronger hydrogen-bonded hydroxyl group
complex and the peaks shifting suggested a noncharged complex.
As observed in DSC, the WAXS patterns turned out to be very
dependent on the heating rate employed (2, 5, or 10 °C·min−1).
Heating at 2 °C·min−1 gave two main diffraction peaks at 2θ =
25° and 27°, the last one being the predominant. This could
correspond to a more compacted crystal rearrangement
compared to the original metformin salicylate salt. When the
heating rate is 10 °C·min−1, one main diffraction peak is observed
at 2θ = 21.6° and could be mimicking a similar 3D rearrangement
to the starting metformin salicylate salt.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*Tel: +34 91 5622900 (R.P.-F.), +34 91 5622900 (C.M.), +34
985102966 (L.M.-T.). Fax: +34 91 5644853 (R.P.-F.), +34 91
5644853 (C.M.), +34 98 5103125 (L.M.-T.). E-mail: rperezf@
iqm.csic.es(R.P.-F.), cmarco@ictp.csic.es (C.M.),
menendezlaura.uo@uniovi.es (L.M.-T.).
Notes
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2008, 24, x289−x290.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We greatly acknowledged the facilities to carry out X-ray
synchrotron experiments that were performed at the Soft
Condensed Matter A2 beamline at HASYLAB (DESY-Hamburg,
I-20100101 EC). This work was supported by SAF2009-12422-
C02-02 and RTA (RED Trastornos Adictivos RD06/001/0014)
as well as by FEDER funding and the Spanish Ministerio de
́
Economia y Competitividad MAT2006-01997, MAT2010-
́
15094, and the Factoria de Crystalizacion
́
(Consolider Ingenio
2010).
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