SHORT COMMUNICATION
Krka d.d.1, Novo mesto; Faculty of Pharmacy2, University of Ljubljana,
Slovenia
Beside the similarity of the thermal behavior of the R-isomer and
form 1 of the S-isomer, FT-IR spectra and XRPD diffractograms
for both samples are comparable.
The 13C solid state NMR spectrum of R-isomer is practically
identical to the spectrum of clopidogrel hydrogensulphate form
1 (Fig. 1). We can therefore conclude that the R-isomer and
the polymorphic form 1 exhibit very similar conformation and
packaging of the molecules in the crystals. 1H solid state NMR
spectra show only a small difference in chemical shift for hydro-
gen bonded acidic proton of hydrogensulphate anion, which
might indicate small difference in strength of hydrogen bonding
when comparing form 1 of the S-isomer and the R-isomer of
clopidogrel hydrogensulphate (data not shown).
Similarity of solid state structures of R- and
S-isomers of clopidogrel hydrogensulphate salt
V. Zupancˇicˇ 1, B. Kotar-Jordan1, M. Plevnik1,
M. Smrkolj1, F. Vrecˇer1,2
Received October 26, 2009, accepted October 30, 2009
ˇ
Prof. Franc Vrecˇer, Krka, d.d., Novo mesto, R&D, Smarjesˇka
cesta 6, 8501 Novo mesto, Slovenia
Experimental
1. Materials
Pharmazie 65: 389–390 (2010)
doi: 10.1691/ph.2010.9345
Clopidogrel hydrogen sulfate form 1 and 2 were prepared by Krka, d.d.,
Novo mesto according to the process described Bosquet et al. 2002 using
acetone as crystallization solvent.
The present study showed, that the crystal structures
of R-isomer and the polymorphic form 1 of clopidrogrel
hydrogensulphate S-isomer are very similar.
2. Methods
2.1. Process for preparation of the crystalline form of the R-isomer
of clopidogrel hydrogen sulphate
(-)-(R)-methyl 2-(2-chlorophenyl)2-(6,7-dihydrothieno(3,2-c)pyridin-5 (4
H)-yl)acetate camphor-10-sulphonate (16.6 g) was dissolved in 66 ml of
methylene chloride at room temperature with addition of 66 ml of a sat-
urated solution of sodium hydrogen carbonate and stirred for 1 h. The
layers were separated and the organic phase was additionally dried with
sodium sulphate. The solvent was evaporated and 9.8 g of oily prod-
uct was dissolved in 41 ml of acetone. 3.16 ml of 93.6% sulphuric acid
was gradually added to the solution at 20◦C and stirred for 20 h. at
20–25◦C. The crystallized product was filtered off and washed with
100 ml of chilled acetone. The crystals were dried in a vacuum drier at
50◦C.
Clopidogrel hydrogensulphate, which exists in two enan-
tiomeric forms, i.e., R(−) and S(+) enantiomer, is a potent
platelet anti-aggregation drug. The corresponding R-isomer at
carbon 8 is less active and less well tolerated in pharmaceutical
use (Kotar-Jordan et al. 2005).
(+)Clopidogrel hydrogensulphate salt of is known to crystallize
in different polymorphic and pseudopolymorphic forms among
which polymorphic forms 1 and 2 are commercially used in solid
dosage forms on the market (Koradia et al. 2004).
It was proposed on the basis of crystallographic data that
arrangement and conformation of organic clopidogrel moiety
and inorganic hydrogensulphate moiety differ among crystalline
forms of the S(+) isomer. The crystalline structure of form 2,
which has already been resolved, is orthorhombic and less dense
than the crystalline structure of form 1 which is monoclinic
(Bosquet et al. 2002).
On the other hand the crystal structure of form 1 has not been
resolved yet. There are also no available data in the literature for
crystallization and crystal structure of the R-isomer.
The aim of our work was to prepare a crystalline form of the
R- isomer of clopidogrel hydrogensulphate salt, and to evaluate
and compare solid state analytical parameters of the R-isomer
with the analytical data for polymorphic forms 1 and 2 of the
S-isomer.
2.2. X-ray powder diffraction (XRPD)
X-ray diffractograms of powder samples were obtained by a Phillips PW
1710 diffractometer (CuK␣ radiation, 3 ≤ 2ꢁ≤31◦).
2.3. Solid state 13C and 1H nuclear magnetic resonance (NMR)
Spectra were obtained by a Varian Unity Inova 300 MHz spectrometer using
5 mm “Magic Angle” and by a Varian Inova 600 MHz NMR spectrometer
using 3.2 mm “NB Double Resonance HX MAS”. Larmor frequencies of
proton and carbon atoms were 302.98 MHz and 76.19 MHz in NMR spec-
tra and 599.77 MHz and 150.83 MHz on the 600 MHz NMR spectrometer.
Carbon and proton chemical shifts were presented relatively to HMB (hex-
amethylbenzene) external standard used as a secondary reference. Rotation
frequencies were 5 kHz on the 300 MHz spectrometer, and 20 kHz during
1H measurements and 10 kHz during 13C measurements on the 600 MHz
NMR spectrometer.
2.4. FT-IR spectroscopy
Optical rotation, melting points and melting enthalpies of two
crystalline polymorphic forms of clopidogrel hydrogensulphate
and R-isomer of clopidrogrel hydrogensulphate are shown in
the Table. Optical purity of the tested samples was confirmed
by measuring their specific optical rotation. Similar values for
onset temperature and melting enthalpy were obtained for the
R-isomer and the polymorphic form 1 of the S-isomer.
ꢀꢁ ꢂꢃ
Infrared spectra in KBr pellets were recorded within the wave number
range of 4000–400 cm−1 with a Perkin-Elmer FTIR spectrometer 1720X
at resolution 4 cm−1
.
2.5. Thermal analysis
DSC was performed by Mettler DSC 822e (dynamic N2 atmosphere, heating
rate 10 ◦C/min). Thermal effects were evaluated using Pyris software.
Table: Optical rotation α2D0 , melting points(Tonst) and enthalpies (ꢀH) for tested samples of clopidogrel hydrogensulphate
ꢁ
ꢂ
20
D
3
Sample
α
DSC; T /ꢀH
DSC(literature data) ; T /ꢀH
XRPD/IR
onst
onst
(+)-Enantiomer (S-isomer) form 1
(+)-Enantiomer (S-isomer) form 2
(−)-Enantiomer (R-isomer)
+56.17 ◦
+56.26 ◦
−55.40 ◦
183.0 ◦C/83 J/g
179.7 ◦C/88.1 J/g
182.0 ◦C/78.6 J/g
181.2 ◦C/77 J/g
176.0 ◦C/87 J/g
–
Clopidogrel hydrogensulphate form 1
Clopidogrel hydrogensulphate form 2
Clopidogrel hydrogensulphate form 1
3
literature data (Bosquet et al. 2002)
3P8h8armazie 65 (2010)
Pharmazie 65 (201308)9
Zupancic
