Clopidogrel bisulfate

Apotex wove these facts into a prima facie case of obviousness as follows It would be obvious to separate an enantiomer from a known racemate using generally known techniques. Furthermore, there was motivation [19] to do so because enantiomers can have different properties from those displayed by the racemate, and because of a possible future FDA regulatory requirement for separation of enantiomers. Additionally, there was a reasonable expectation of success [20] in achieving the separation because techniques for separating enantiomers from racemates are known. And finally, it would be obvious to form an addition salt of the enantiomer to optimize selected physical properties. Thus, concluded Apotex, dextrorotatory clopidogrel bisulfate was obvious, it is therefore unpatentable, and this renders the 265 patent invalid. 

Adenosine diphosphate inhibitors clopidogrel bisulfate dipyridamole sulfinpyrazone... 

Clopidogrel bisulfate is the hydrogen sulfate salt of clopidogrel, for which the free compound is known by the following systematic names Systematic chemical name... 

Clopidogrel bisulfate has been reported to be freely soluble in methanol, sparingly soluble in methylene chloride, and practically insoluble in ethyl ether and in water at neutral pH. At pH 1, the compound is freely soluble in water [3], which is one of the reasons why the hydrogen sulfate salt is the preferred form of the drug substance. 

The partition coefficient in octanol/water of clopidogrel bisulfate has been reported to be about 3.9 at pH 7.4 [3]. 

Although clopidogrel bisulfate has been found to crystallize in six different polymorphic forms [9, 10], only Form-I and Form-II are used in pharmaceutical products. Although the density of orthorhombic Form-II is less dense (1.462 g/cm3) than is the monoclinic Form-I (1.505 g/cm3), the two crystal forms appear to be fairly equivalent in their relative stability. However, Form-II is more compact and much less electrostatic than is Form-I, making it more useful for secondary processing [9]. 

FIGURE 2.1 X-ray powder diffraction pattern of clopidogrel bisulfate, Form-1. 

Measurements of differential scanning calorimetry (DSC) were obtained on clopidogrel bisulfate Form-I and Form-II using a TA Instruments 2910 thermal analysis system. Samples of approximately 1-2 mg were accurately weighed into an aluminum DSC pan, and then covered with an aluminum lid that was inverted and pressed down so as to tightly contain... 

Sample Clopidogrel bisulfate File C ... clopidogrel DSC clopi Form-l.001... 

FIGURE 2.3 Differential scanning calorimetry thermogram of clopidogrel bisulfate, Form-I. 

Clopidogrel bisulfate was dissolved at a concentration of 5.5 yg/ml in methanol that had been acidified with sulfuric acid. The UV absorption spectrum of this solution was obtained using a Beckman model Lambda 3B spectrophotometer, and the resulting spectrum is found in Fig. 2.5. The most intense absorption band was observed at a wavelength of 220 nm, while (as the inset shows) two very weak peaks were also noted at 270 and 278 nm. 

FIGURE 2.S Ultraviolet absorption spectrum obtained clopidogrel bisulfate, dissolved at a concentration of 5.5 /rg/ml in methanol that had been acidified with sulfuric acid. The inset spectrum represents an expansion of the absorbance scale. 

As shown in Figs. 2.6-2.9, the infrared absorption spectra of the two polymorphic forms of clopidogrel bisulfate are quite different. These differences are summarized in Table 2.1, which lists the energies of the main observed peaks and which contrasts the energies of peaks assigned to the same vibrational mode. 

The Raman spectra of clopidogrel bisulfate Form-I and Form-II were obtained in the fingerprint region using a Raman Systems model R-3000HR spectrometer, operated at a resolution of 5 cm 1 and a laser... 

FIGURE 2.8 Infrared absorption spectrum obtained in the fingerprint region for clopidogrel bisulfate, Form-ll. 

TABLE 2.1 Energies of corresponding bands in the infrared absorption spectra of clopidogrel bisulfate, Forms I and II... 

Clopidogrel bisulfate has several related compounds that are to be impurity species [2, 6, 7]. The molecular structures of these impurities are shown in Fig. 2.12. 

FIGURE 2.12 Structures of four known impurities of clopidogrel bisulfate. 

Related compound (C) is the (R)-enantiomer of clopidogrel bisulfate, and therefore has the systematic name methyl-(—)-(R)-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, hydrogen sulfate salt [2, 6, 7],... 

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