Clopidogrel bisulfate is a platelet aggregation inhibitor, medicine for prophylaxis and the treatment of thrombosis by acting as a platelet aggregation inhibitor. It has now been discovered that clopidogrel hydrogen sulfate can exist in different polymorphic crystalline forms which differ from :
  1. stability
  2. physical properties
  3. spectral characteristics
  4. process for their preparation.
The dextrorotatory isomer of clopidrogel bisulfat (Form II) has an excellent platelet aggregation inhibiting activity whereas the levorotatory isomer is less active and less well tolerated (Form II).

Dextrorotary Clopidrogel Bisulfate Preparation :
According to all of the teachings of the above documents, the dextrorotatory isomer of clopidogrel is prepared by :
  1. salt formation from the racemic compound using an optically active acid such as 10-L-camphorsulfonic acid in acetone
  2. recrystallisations of the salt until a product with constant rotatory power was obtained
  3. release of the dextrorotatory isomer from its salt by a base
  4. Clopidogrel hydrogen sulfate is then obtained in a standard manner by the dissolution of said base in acetone cooled in ice and addition of concentrated sulfuric acid to precipitation
  5. The precipitate thus obtained is then isolated by filtration, washed and dried to give clopidogrel hydrogen sulfate in the form of white crystals whose melting point is 184° C. and optical rotation +55.1° (c=1.891/CH3 OH).
The process described in the prior art leads only to the form 1 of clopidogrel hydrogen sulfate.

The Different Between Clopidrogel Bisulfat Form 2 and Form 1
It has now been found that if clopidogrel hydrogen sulfate is crystallised from a solvent, either the crystalline form, Form 1, corresponding to that of the product obtained may be produced or a new, very stable crystalline form having a well-defined structure designated Form 2 below.

More particularly, it has been found that the novel crystalline form of clopidogrel hydrogen sulfate, Form 2, is at least as stable as the Form 1 described and that it does not convert spontaneously into the previously known Form 1. Furthermore, Form 2 bulk solid is more compact and much less electrostatic than Form 1 and may hence be more readily subjected to any treatment under the usual conditions of pharmaceutical technology and, in particular, of formulation on an industrial scale.

It has moreover been observed that Form 2 exhibits a lower solubility than Form 1 as a result of its greater thermodynamic stability.

It was observed from the crystallographic data that the crystalline structure of Form 1 contains two crystallographically independent cations of clopidogrel and two independent bisulfate anions. The two independent cations are of similar conformation.

The crystallographic data of Form 2 show that it contains one crystallographically independent clopidogrel cation-bisulfate anion pair.

In the two forms, the cations are protonated axially and the nitrogen atom has the R configuration; the conformation of the cations in Form 2 is different from that observed in Form 1.

Melting Point and Enthalpy

Form 1Form 2
Melting Point (° C.)181.2176.0
Enthalpy of fusion (J/g)7787

The difference between the new Form 2 and Form 1 of clopidogrel hydrogen sulfate has also been demonstrated by infrared spectroscopy. The Fourier transform (FTIR) IR spectra were obtained with a Perkin Elmer system 2000 spectrometer with a resolution of 4 cm-1 from 4000 cm-1 to 400 cm-1. The samples of Form 1 or Form 2 are prepared in the form of 0.3% KBr disks. The disks were subjected to a compression of 10 tons for 2 minutes. Each sample was examined after 4 accumulated scans.

Form 1From 2
Wavelength%Wavelength%
(cm-1) transmittance(cm-1) transmittance
298742255143
175314175313.4
122216149763.7
117512118918
84140102933.2

Table shows that Form 2 exhibits characteristic absorptions at 2551 cm-1, 1497 cm-1, 1189 cm-1 and 1029 cm-1 which are absent from Form 1.

The particular structure of the crystals of Form 2 was elucidated by single-crystal X-ray diffraction analysis using a MSC-Rigaka AFC6S diffractometer and the software SHELXS-90 and SHELXS-93 at a SG IRIS Indigo work station. The position of the C-H hydrogens was generated at a distance of 0.95 Å. The crystallographic data, in particular the unit cells leghts (a, b, c), the angles (α, β, γ) and the volume of each unit cell are shown in table below.

Crystallographic data and establishment of the structure of Form 2
Crystalline system space group Orthorombic P21 21 21

Dimensions of Unit Cell
a10.321(6) Å
b20.118(9) Å
c9.187(7) Å
α90 degrees
β90 degrees
γ90 degrees
volume1908(2) Å3
Z4
density (calculated)1.462 g/cm3
collected reflexions2134
R factor0.0473

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