HK1033829B - Polymorphic clopidogrel hydrogenesulphate form - Google Patents

Description

The present invention relates to a new polymorph of clopidogrel hydrogen sulfate or hydrogensulfate of (+) - ((S) -α- ((2-chlorophenyl) -4,5,6,7-tetrahydrothiene [3,2-c]pyridinyl-5-methyl acetate and a process for its preparation. In particular, the invention relates to the preparation of this polymorph called Form 2 and the isolation of this compound in this new crystalline form, as well as to pharmaceutical compositions containing it.

Clopidogrel hydrogen sulphate is an antithrombotic which was first described in EP 281459.The synthesis process claimed in this patent allows the preparation of clopidogrel hydrogen sulphate, which will be called Form 1.

It has now been discovered that clopidogrel hydrogen sulphate can exist in different polymorphic crystalline forms which differ from each other in their stability, physical properties, spectral characteristics and preparation process.

Thus one of these new polymorphic forms is the subject of the present invention, described in the present application and will be called Form 2.

The present invention also relates to a process for the preparation of clopidogrel hydrogen sulphate in its polymorphic form 2.

Patent EP 281459 describes enantiomers of pharmaceutically acceptable tetrahydrothiene pyridine derivatives and their salts. EP 281459 specifically claims clopidogrel hydrogen sulfate, i.e. the dextrogyre isomer, which has excellent platelet anti-aggregant activity whereas the levogyre isomer is less active and less well tolerated.

The patent EP 281459 filed ten years ago makes no reference to the existence of specific polymorphic forms of clopidogrel hydrogen sulphate. The synthesis described in EP 281459 allows the preparation of the clopidogrel polymorph hydrogen sulphate Form 1.

According to all the instructions in the above documents, the dextrogyre isomer of clopidogrel is then prepared by salivation of the racemic compound by an optically active acid such as 10-L-camphosulfonic acid in acetone followed by successive recrystallizations of the salt until a product with constant rotational power is obtained, and then release of the dextrogyre isomer from its salt by a base. Clopidogrel hydrogen sulfate is then obtained in the conventional manner by dissolving the base in the acetone cooled in ice and adding sulfuric acid until precipitated. The precipitate is then obtained by isolation, filtration and severe hydrolysis to provide hydrogenous sulphate in the form of clopidogrel and its melting point is CH1 + 184 °C (1,589 °C) and the melting point is CH1 + 184 °C (1,589 °C).

The synthesis processes described in previous art. allow only the synthesis of clopidogrel Form 1 hydrogen sulphate.

For example, the present invention relates to the polymorphic form of clopidogrel hydrogen sulfate, Form 2, which like Form 1 of this compound is useful as a drug for the prophylaxis and treatment of thrombosis by acting as an antiplatelet agglomerant. For the use of clopidogrel and its salts, refer to Drugs of the Future 1993, 18, 2, 107-112.

It has now been found that clopidogrel hydrogen sulphate crystallization in a solvent can result in either the crystalline form corresponding to the product obtained by the above mentioned EP 281459, Form 1, or a new, very stable crystalline form with a well-defined structure, hereinafter referred to as Form 2. In particular, the new crystalline form of clopidogrel hydrogen sulphate, Form 2, has been found to be at least as stable as the Form 1 described and not to transform spontaneously into the previously known Form 1.

It was also found that Formula 2 has a lower solubility than Formula 1 due to its greater thermodynamic stability.

The difference between the new crystalline form of clopidogrel hydrogen sulphate according to the present invention, Form 2 and Form 1, is shown by examining Figures 1 to 4, while Figures 5 to 7 show the structure in the crystals of Form 2.

Figures 1 to 7 are characterised as follows: Figure 1 shows the X-ray diffractogram of clopidogrel hydrogensulfate Form 1 powder; Figure 2 shows the X-ray diffractogram of clopidogrel hydrogensulfate Form 2; Figure 3 shows the infrared spectrum of Form 2; Figure 4 shows the infrared spectrum of Form 1; Figure 5 shows the developed formula of clopidogrel hydrogensulfate with atom numbering under the crystalline Form 2; Figure 6 shows the spatial conformation of clopidogrel hydrogensulfate Form 2; Figure 7 shows the stacking of clopidogrel hydrogensulfate molecules in the crystal mesh of Form 2.

It was found from crystallographic data that the crystal structure of the Form 1 contains two free cations in the clopidogrel crystal and two free bisulfate anions.

According to crystallographic data from Form 2 it was found that it contains a free cation in the crystal - the pair bisulfate anion.

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

In the molecular arrangement of the two crystalline forms, no site is occupied by solvent molecules.

The anion arrangement is very different from each of the two crystal structures. The crystal structure of Form 2 is less dense (1,462 g/cm3) than the crystal structure of Form 1 (1,505 g/cm3).

Another aspect of the present invention is a process for the preparation of clopidogrel hydrogen sulphate Form 2 characterized by: (a) Camphosulfonate of (+) -S) -α-α-α2-chlorophenyl (-4,5,6,7-tetrahydrothiene methyl[3,2-c]pyridinyl-5-acetate is added to an organic solvent solution, (b) Camphosulfonic acid is extracted from an alkaline aqueous solution of potassium carbonate and washed with water, (c) The organic phase is concentrated under vacuum and the residual concentration is taken up again in the acetone, (d) Sulphuric acid is added to 80%, (e) The product is heated, crystallized, cooled, filtered and washed under pressure, the resulting crystals are reduced to form chlorophosulphate hydrogel, then chlorophosulphate hydrogel, and at the end of 6 months the resulting chlorophosulphate hydrogel is reduced to chlorophosulphate hydrogel, and at the end of 3 months the resulting chlorophosulphate hydrogel is recycled.

Thus, the present invention relates to a process for the preparation of clopidogrel Form 2 (+) - ((S) hydrogen sulphate, characterized by: The hydroacetone water based crystallisation of Clopidogrel Hydrogen Sulphate Form 1 (+) - ((S)) finally releases Clopidogrel Hydrogen Sulphate Form 2 crystals after 3 to 6 months.

The hydroacetone water resulting from the crystallization of Clopidogrel (+) -S) hydrogen sulphate Form 1 contains 0.3 to 1% water.

They contain up to approximately 10% clopidogrel hydrogen sulphate, calculated from the amount of camphosulfonate (+) - ((S) -α- ((2-chlorophenyl) -4,5,6,7-tetrahydrothiene[3,2-c]pyridinyl-5-methyl acetate used in the transformation to hydrogen sulphate.

These hydroacetone water-stores slowly release clopidogrel Form 2 hydrogen sulphate after a period of three to six months at a temperature below 40°C.

In another aspect, the present invention relates to another process for the preparation of clopidogrel hydrogen sulphate Form 2 characterized by: (a) Camphosulfonate of (+) -S-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothiene[3,2-c]pyridinyl-5-methyl acetate is dissolved in an organic solvent, (b) Camphosulfonic acid is extracted from an aqueous alkaline potassium carbonate solution and washed with water, (c) The organic phase is concentrated under vacuum and the concentration residue is taken up in the acetone, (d) Sulphuric acid is added at 96% at 20°C and the product is filtered with clopidogrel hydrosulfate For 2, (e) The product is crystallized, cooled, crystallised and then washed to provide the reduced form of clopidogrel hydrosulfate For 2.

Another alternative is to subject the crystalline suspension to mechanical shearing by means of a shearing device, which can reach a rotational speed of about 10 000 to 15 000 revolutions per minute.

The principle is to obtain by grinding fine particles from a basic solution containing only a fraction of the total sulphuric acid. The remaining portion is then cast slowly to promote crystal growth.

Thus, the present invention relates to the form 2 of clopidogrel hydrogen sulphate characterised by the X-ray diffraction profile of the powder given in TABLE I.

In particular, Form 2 is also characterised by a melting point, determined by differential enthalpy analysis (DSC), of 176°C and by characteristic absorptions in the infrared and near infrared.

Some physical properties and behaviour of the novel crystalline form of clopidogrel hydrogensulfate according to the present invention are completely different from those of Form 1 as demonstrated by examining both forms using conventional methods and techniques.

The X-ray diffraction profile of the powder (angle of diffraction) was established with a Siemens D500TT diffractometer. The characteristic powder diffractograms between 2 and 40° in 2θ of Bragg (2 theta, deg., for CuKα, λ=1.542 Å) are shown in Figure 1 for Form 1 and in Figure 2 for Form 2.

In TABLES I and II, d is the interreticular distance and I/I0 is the relative intensity, expressed as a percentage of the most intense ray. - What? TABLEAU I :

Forme 2 Raies significatives de la Figure 2.
4,11	100,0
6,86	61,7
3,87	61,4
3,60	56,3
4,80	55,8
5,01	44,4
3,74	37,9
6,49	33,1
5,66	29,8

TABLEAU II :

Forme 1 Raies significatives de la Figure 1
9,60	100,0
3,49	58,8
3,83	52,0
3,80	42,5
4,31	39,0
8,13	37,2
4,80	25,5
3,86	19,1
5,80	16,8
4,95	16,8

The differential enthalpy analysis (DSC) of Forms 1 and 2 was performed comparatively using a DSC7 Perkin Elmer apparatus, calibrated by reference to indium. For the calorimetric analysis, 2.899 mg of Form 1 or 2.574 mg of Form 2 as obtained in EXAMPLE 2 were used in a perforated and closed aluminium cup in a temperature zone of 40 to 230°C at a heating rate of 10°C/min. The melting point and the enthalpy of the melt are given in TABLE III. The melting point corresponds to the characteristic melting temperature obtained by DSC. This value can also be defined as the temperature corresponding to the line of intersection between the base and the peak melting point as observed by DSC tangents. - What?

The difference between the new Form 2 and Form 1 clopidogrel hydrogen sulfate was also highlighted by infrared spectroscopy. IR Fourier Transformed Spectrometers (FTIRs) were obtained with a Perkin Elmer System 2000 4 cm-1 resolution spectrometer from 4000 cm-1 to 400 cm-1. The samples are in the form of a 0.3% KBr tablet in Form 1 or Form 2. The tablet was compressed under 10 tonnes for 2 minutes. Each sample was examined after 4 accumulations. The comparison of characteristic lines in terms of wavelength (in cm-1) and intensity (in percent of transmittance) is shown in TABLE IV. - What? TABLEAU IV

Spectre infra-rouge
	% de transmittance		% de transmittance
2987	42	2551	43
1753	14	1753	13,4
1222	16	1497	63,7
1175	12	1189	18
841	40	1029	33,2

It is shown from TABLE IV that Form 2 has 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 Form 2 powder was revealed by X-ray diffraction analysis of the monocrystal of the powder using an MSC-Rigaka AFC6S diffractometer and SHELXS-90 and SHELXS-93 software on an IRIS Indigo SG workstation. The position of the C-H hydrogens was generated at a distance of 0.95Å. Crystallographic data, including interplanar distances (a,b,c), angles (α,β,γ) and the volume of each unit cell, are given in TABLE V. TABLEAU V

Données cristallographiques et établissement de la structure de la Forme 2
Dimensions de la cellule unitaire :
a	10,321 (6) Å
b	20,118 (9) Å
c	9,187 (7) Å
α	90 degrés
β	90 degrés
γ	90 degrés
volume
Z	4
densité (calculée)
réflexions collectées	2134
facteur R	0,0473

The atomic coordinates of the Form 2 are given in TABLE VI, the bond lengths in TABLE VII, the bond angles in TABLE VIII and the characteristic torsion angles in TABLE IX. TABLEAU VI

Paramètres de position de la Forme 2
Cl(1)	0,2223(3)	0,21728(12)	0,4295(3)	0,0835(8)
S(1)	0,8085(2)	-0,00068(11)	0,3557(3)	0,0724(7)
S(2)	0,2840(2)	0,01908(8)	0,0013(2)	0,0412(4)
O(1)	0,3030(7)	0,2376(3)	-0,0528(7)	0,087(2)
O(2)	0,4630(6)	0,1637(3)	-0,0860(6)	0,060(2)
O(3)	0,2175(6)	-0,0350(3)	0,0957(6)	0,0551(14)
O(4)	0,2728(6)	-0,0093(3)	-0,1432(5)	0,074(2)
O(5)	0,4174(4)	0,0241(2)	0,0497(6)	0,0503(13)
O(6)	0,2146(5)	0,0800(2)	0,0199(7)	0,065(2)
N(5)	0,4936(6)	0,1343(3)	0,1946(7)	0,0380(14)
C(2)	0,9111(10)	0,0427(5)	0,2500(13)	0,081(3)
C(3A)	0,7214(7)	0,1002(3)	0,2215(9)	0,047(2)
C(3)	0,8554(8)	0,0950(5)	0,1824(11)	0,060(2)
C(4)	0,6332(7)	0,1548(4)	0,1706(10)	0,044(2)
C(6)	0,4750(8)	0,1100(4)	0,3487(9)	0,045(2)
C(7)	0,5487(8)	0,0450(4)	0,3722(10)	0,051(2)
C(7A)	0,6833(8)	0,0526(3)	0,3144(9)	0,050(2)
C(8)	0,3940(8)	0,1880(4)	0,1574(9)	0,043(2)
C(9)	0,4119(7)	0,2523(3)	0,2360(9)	0,044(2)
C(10)	0,3435(8)	0,2688(4)	0,3613(10)	0,057(2)
C(11)	0,3630(10)	0,3292(4)	0,4290(11)	0,076(3)
C(12)	0,4545(10)	0,3734(4)	0,3773(12)	0,080(3)
C(13)	0,5223(10)	0,3579(4)	0,2550(12)	0,067(3)
C(14)	0,5019(8)	0,2980(3)	0,1863(10)	0,052(2)
C(15)	0,3823(8)	0,1995(4)	-0,0079(11)	0,053(2)
C(16)	0,4462(16)	0,1687(6)	-0,2422(11)	0,096(4)

TABLEAU VII

Distances intramoléculaires dans la Forme 2
CI(1)	C(10)	1,742(8)
S(1)	C(2)	1,682(12)
S(1)	C(7A)	1,722(8)
S(2)	O(6)	1,429(5)
S(2)	O(4)	1,450(5)
S(2)	O(5)	1,450(5)
S(2)	O(3)	1,551(5)
O(1)	C(15)	1,195(9)
0(2)	C(15)	1,314(10)
O(2)	C(16)	1,448(10)
N(5)	C(6)	1,510(10)
N(5)	C(4)	1,515(9)
N(5)	C(8)	1,530(9)
C(2)	C(3)	1,350(13)
C(3A)	C(7A)	1,341(10)
C(3A)	C(3)	1,432(10)
C(3A)	C(4)	1,501(10)
C(6)	C(7)	1,528(10)
C(7)	C(7A)	1,495(11)
C(8)	C(9)	1,493(10)
C(8)	C(15)	1,541(12)
C(9)	C(14)	1,384(10)
C(9)	C(10)	1,390(11)
C(10)	C(11)	1,379(11)
C(11)	C(12)	1,382(12)
C(12)	C(13)	1,359(13)
C(13)	C(14)	1,378(11)

The distances are in Ångstroms. The estimated standard deviations on the decimal point are in parentheses. TABLEAU VIII

Angles entre les liaisons intramoléculaires impliquant des atomes non hydrogène
C(2)	S(1)	C(7A)	91,2(4)
O(6)	S(2)	O(4)	114,0(4)
O(6)	S(2)	O(5)	112,3(3)
O(4)	S(2)	O(5)	112,6(3)
O(6)	S(2)	O(3)	108,2(3)
O(4)	S(2)	O(3)	101,6(3)
O(5)	S(2)	O(3)	107,3(3)
C(15)	O(2)	C(16)	115,3(9)
C(6)	N(5)	C(4)	110,1(6)
C(6)	N(5)	C(8)	110,6(6)
C(4)	N(5)	C(8)	114,5(5)
C(3)	C(2)	S(1)	113,7(7)
C(7A)	C(3A)	C(3)	113,0(8)
C(7A)	C(3A)	C(4)	122,8(7)
C(3)	C(3A)	C(4)	124,1(8)
C(2)	C(3)	C(3A)	110,7(9)
C(3A)	C(4)	N(5)	109,5(6)
N(5)	C(6)	C(7)	110,2(7)
C(7A)	C(7)	C(6)	108,9(6)
C(3A)	C(7A)	C(7)	124,9(7)
C(3A)	C(7A)	S(1)	111,4(6)
C(7)	C(7A)	S(1)	123,7(6)
C(9)	C(8)	N(5)	114,9(6)
C(9)	C(8)	C(15)	110,9(6)
N(5)	C(8)	C(15)	112,2(7)
C(14)	C(9)	C(10)	117,1(7)
C(14)	C(9)	C(8)	119,9(8)
C(10)	C(9)	C(8)	123,0(7)
C(11)	C(10)	C(9)	120,7(8)
C(11)	C(10)	Cl(1)	117,8(7)
C(9)	C(10)	Cl(1)	121,4(6)
C(10)	C(11)	C(12)	120,7(9)
C(13)	C(12)	C(11)	119,3(9)
C(12)	C(13)	C(14)	120,0(9)
C(13)	C(14)	C(9)	122,2(9)
O(1)	C(15)	O(2)	126,7(9)
O(1)	C(15)	C(8)	119,3(9)
O(2)	C(15)	C(8)	114,0(7)

The angles are in degrees. The estimated standard deviations to the last decimal place are in parentheses. - What? TABLEAU IX

Angles de conformation et torsion caractéristique
C(7A)	S(1)	C(2)	C(3)	-1,1(9)
S(1)	C(2)	C(3)	C(3A)	0,9(12)
C(7A)	C(3A)	C(3)	C(2)	0,0(12)
C(4)	C(3A)	C(3)	C(2)	177,1(8)
C(7A)	C(3A)	C(4)	N(5)	-19,7(11)
C(3)	C(3A)	C(4)	N(5)	163,4(8)
C(6)	N(5)	C(4)	C(3A)	50,2(8)
C(8)	N(5)	C(4)	C(3A)	175,7(7)
C(4)	N(5)	C(6)	C(7)	-67,3(8)
C(8)	N(5)	C(6)	C(7)	165,0(6)
N(5)	C(6)	C(7)	C(7A)	47,8(9)
C(3)	C(3A)	C(7A)	C(7)	-179,1(8)
C(4)	C(3A)	C(7A)	C(7)	3,8(13)
C(3)	C(3A)	C(7A)	S(1)	-0,8(9)
C(4)	C(3A)	C(7A)	S(1)	-177,9(6)
C(6)	C(7)	C(7A)	C(3A)	-17,6(12)
C(6)	C(7)	C(7A)	S(1)	164,3(6)
C(2)	S(1)	C(7A)	C(3A)	1,1(7)
C(2)	S(1)	C(7A)	C(7)	179,4(8)
C(6)	N(5)	C(8)	C(9)	68,9(8)
C(4)	N(5)	C(8)	C(9)	-56,3(10)
C(6)	N(5)	C(8)	C(15)	-163,2(6)
C(4)	N(5)	C(8)	C(15)	71,6(8)
N(5)	C(8)	C(9)	C(14)	81,4(9)
C(15)	C(8)	C(9)	C(14)	-47,2(10)
N(5)	C(8)	C(9)	C(10)	-97,3(9)
C(15)	C(8)	C(9)	C(10)	134,2(8)
C(14)	C(9)	C(10)	C(11)	1,9(12)
C(8)	C(9)	C(10)	C(11)	-179,4(8)
C(14)	C(9)	C(10)	Cl(1)	176,9(6)
C(8)	C(9)	C(10)	Cl(1)	-4,4(11)
C(9)	C(10)	C(11)	C(12)	-2,6(14)
Cl(1)	C(10)	C(11)	C(12)	-177,8(8)
C(10)	C(11)	C(12)	C(13)	3(2)
C(11)	C(12)	C(13)	C(14)	-2(2)
C(12)	C(13)	C(14)	C(9)	1,1(14)
C(10)	C(9)	C(14)	C(13)	-1,1(12)
C(8)	C(9)	C(14)	C(13)	-179,9(8)
C(16)	O(2)	C(15)	O(1)	-4,3(13)
C(16)	O(2)	C(15)	C(8)	174,5(8)
C(9)	C(8)	C(15)	O(1)	-54,0(10)
N(5)	C(8)	C(15)	O(1)	176,0(7)
C(9)	C(8)	C(15)	O(2)	127,1(7)
N(5)	C(8)	C(15)	O(2)	-2,8(9)

The angles are in degrees, the estimated standard deviations to the last decimal place are in parentheses.

The sign is positive if, looking from atom 2 to atom 3, by a clockwise motion the atom 1 overlaps the atom 4.

X-ray crystallographic study, including the crystallographic data from TABLE I, the atomic coordinates from TABLE VI, the bond lengths from TABLE VII, the bond angles from TABLE VIII and the characteristic torsion angles from TABLE IX, prove the proposed structure as shown in Figures 5 and 6.

Microscopic examination revealed that the crystals of the new Form 2 are morphologically different from those of Form 1.

The crystals of Form 1 are irregular plates, while the crystals of Form 2 are agglomerates.

Due to its low electrostaticity compared to Form 1, it is therefore particularly suitable for the manufacture of pharmaceutical formulations for the treatment of all diseases for which an antithrombotic is indicated.

Thus, according to another aspect of the present invention, the subject matter of the present invention is pharmaceutical compositions containing as active ingredient clopidogrel hydrogen sulphate Form 2 characterized by the X-ray diffraction profile of the powder as shown in TABLE I.

Preferably, the Clopidogrel Hydrogen Sulfate Form 2 of the present invention is formulated in oral pharmaceutical formulations containing 75 mg of active substance per unit of dosage, mixed with at least one pharmaceutical excipient.

When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle, such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic or analogues.

A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules.

Water-dispersible powders or granules may contain the active ingredient mixed with dispersion agents or wetting agents, or suspension agents, such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.

If the active substance is to be formulated for rectal administration, suppositories are used which are prepared with rectal-melting binders, e.g. cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, saline solutions or sterile solutions for injection are used.

The active substance may also be formulated in the form of microcapsules, possibly with one or more media or additives.

THE following examples illustrate the invention without limiting it.

Preparation of camphosulfonate from (+) - ((S) -α- ((2-chlorophenyl) -4,5,6,7-tetrahydrothiene [3,2-c]pyridinyl-5-methyl acetate

In a shaker, 400 kg of α- ((2-chlorophenyl) -4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-methyl acetate racemic acid and 1840 kg of dichloromethane are loaded with hydrochloride. Then 1200 kg of an aqueous solution of sodium bicarbonate at 8% is slowly added. After settling, the organic phase is concentrated under vacuum. The concentration residue is diluted with 1000 litres of acetone. Then a 154 kg solution of 1 R-10 camphosulfonic acid is added at 20-25°C in 620 litres of acetone. When the camphosulfonic acid of α- ((2-chlorophenyl) -4,5,6-tetrahydrothieno (+5,7-tetrahydrothieno)) is cooled and crystallized, the acetone is then washed and cooled to a high temperature, making the camphosulfonic acid of α- ((2-chlorophenyl) -4,5,6-tetrahydrothieno (+5,7-pyridrathieno),5- (5,6-clorophenyl) -5,3-tetrahydrothieno) +5,3-clorophenyl-methacyl-acetrahydrothieno (53,2-clorophenyl) -5,3-tetrahydrothieno) -5,3-acetrahydrothieno) and 33 kg of methylen-acetyl-acetyl acetone, which are then cooled to a high temperature, the water is then cooled to a high temperature.

Preparation of clopidogrel hydrogen sulphate Form 2 The following paragraphs are added:

In a 250 ml nitrogen reactor, 50 g of clopidogrel camphosulfonate prepared as described above is introduced. 100 ml of dichloromethane is added and the reaction mixture is stirred for 10 minutes. Then a 9.1 g solution of potassium carbonate in solution is introduced in 70 ml deionized water. The organic phase is removed and the aqueous phase is washed several times with dichloromethane. The organic phases are collected and concentrated in a vacuum. 229 ml of acetone is added to the concentrate and filtered on a 0.1 to 0.22 μm sinter. The acetone solution containing the base is loaded into a nitrogen reactor and then added 7.4 g of an 80 per cent sulfuric acid solution, then the mixture is reheated for 2 hours at 20 °C; the sulfuric acid is refluxed and the mixture is heated for 2 hours.

Distil the solvent, cool it to 0 to -5°C and separate the crystals by Büchner filtration to obtain after drying 21.4 g of clopidogrel Form 2 hydrogen sulphate; F = 176 ± 3°C.

The following is the list of the products:

In a 6000-liter reactor, with nitrogen, 1200 kg of clopidogrel camphosulfonate prepared as shown above is introduced. 2345 litres of dichloromethane are added and the reaction mixture is stirred for 30 minutes to 1 hour. Then a 214.5 kg solution of potassium carbonate in solution is introduced in 1827 litres of deionized water. The organic phase is removed and the aqueous phase washed several times with dichloromethane. The organic phases are collected and concentrated under vacuum. Acetone is added to the concentrate and filtered on a cartridge filter of 0.1 μ to 1 μ. The aconic solution (3033 litres) containing the base is loaded into a nitrogen reactor and then 264.8 kg of a solution of sulfuric acid is added at 80 °C, 20 °C.

Distil the solvent, cool it to 0 to -5°C and separate the crystals by Büchner filtration to obtain 779.1 kg clopidogrel Form 1 hydrogen sulphate after drying; F = 184 ± 3°C.

The resulting hydroacetone water at a temperature below 40°C finally releases clopidogrel Form 2 hydrogen sulphate crystals after 3 to 6 months; F = 176 ± 3°C.

The following is the list of the products:

In a 6000-liter reactor, with nitrogen, 1200 kg of clopidogrel camphosulfonate prepared as shown above is introduced. 2345 litres of dichloromethane are added and the reaction mixture is stirred for 30 minutes to 1 hour. Then a 214.5 kg solution of potassium carbonate in solution is introduced in 1827 litres of deionized water. The organic phase is removed and the aqueous phase washed several times with dichloromethane. The organic phases are collected and concentrated under vacuum. Acetone is added to the concentrate and filtered on a cartridge filter of 0.1 μ to 1 μ. The aconic solution (3033 litres) containing the base is loaded into a nitrogen reactor and then 264.8 kg of a 96% sulfuric acid solution is added at 20°C.

Distil the solvent, cool it to 0 to -5°C and separate the crystals by Büchner filtration to obtain after drying 785.3 kg of clopidogrel Form 1 hydrogen sulphate; F = 184 ± 3°C.

The resulting hydroacetone water at a temperature below 40°C finally releases clopidogrel Form 2 hydrogen sulphate crystals after 3 to 6 months; F = 176 ± 3°C.

The following paragraphs shall apply:

The organic phase is then washed with water. The dichloromethane is concentrated and the residual camphosulfonate is filtered by 1140 litres of acetone. At 20°C, 100 kg of sulfuric acid is added, or 96%. The camphosulfonic acid is then reduced to 0.3%, depending on the pressure of the crystal, with clopidogrel hydrochloride; Foreglycine 2 or Foreglycine 1 is obtained. The clopidogrel hydrochloride is then reduced to ± 1%, depending on the pressure.

The Commission has

In a reactor, 909 litres of dichloromethane and 450 kg of camphosulfonate of (+) - ((S) -α- ((2-chlorophenyl) -4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate methyl are loaded. Camphosulfonic acid is extracted by an aqueous solution of 80 kg of potassium carbonate in 680 litres of water. The organic phase is then washed with water.

The clopidogrel hydrosulfonate crystallizes. The reaction mixture is left to react with Turrax® for 45 minutes. The remaining 90% of the sulphuric acid is then drained to 94-96% (74.6 kg) in about 2 hours, while continuing to operate Turrax®. Turrax® is stopped 30 minutes after the addition of acid and agitated for 30 minutes. Turrax® is washed and dried in a pressure filter.

310 kg of clopidogrel Form 2 hydrogen sulphonate is obtained, giving a yield of 90.9%; F = 176 ± 3°C

Claims (12)

1. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulphate (Form 2) whose powder X-ray diffractogram shows the following characteristic peaks expressed as interplanar distances at approximately 4.11; 6.86; 3.60; 5.01; 3.74; 6.49; 5.66 Å.
2. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulphate (Form 2) whose infrared spectrum exhibits characteristic absorptions expressed in cm^-1 at: 2551, 1497, 1189 and 1029, with respective percentages of transmittance of about: 43; 63.7; 18; 33.2.
3. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulphate (Form 2) having a melting point of 176 ± 3°C.
4. Crystalline polymorph of clopidogrel hydrogen sulphate (Form 2) characterized by the powder X-ray diffractogram according to Figure 2.
5. Crystalline polymorph of clopidogrel hydrogen sulphate (Form 2) characterized by an infrared spectrum according to Figure 3.
6. Crystalline polymorph of clopidogrel hydrogen sulphate (Form 2) characterized by the powder X-ray diffractogram according to Claim 1 and an infrared spectrum according to Claim 2.
7. Method for the preparation of (+)-(S)-clopidogrel hydrogen sulphate Form 2, according to Claims 1, 2 and 3, characterized in that:

   the aqueous-acetone mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulphate Form 1 release, after 3 to 6 months, crystals of clopidogrel hydrogen sulphate Form 2.
8. Method according to Claim 7, characterized in that the aqueous-acetone mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulphate Form 1 contain 0.3 to 1% of water.
9. Method according to Claim 7, characterized in that the aqueous-acetone mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulphate Form 1 contain up to about 10% of clopidogrel hydrogen sulphate, this quantity being calculated from the quantity of methyl (+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphorsulphonate used during the conversion to hydrogen sulphate.
10. Method according to any one of Claims 7 to 9, characterized in that the aqueous-acetone mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulphate Form 1 release slowly, after a period of three to six months, at a temperature of less than 40°C, clopidogrel hydrogen sulphate Form 2.
11. Method for the preparation of clopidogrel hydrogen sulphate Form 2 in which:

    (a) methyl (+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphorsulphonate is dissolved in an organic solvent,

    (b) camphorsulphonic acid is extracted with an aqueous alkaline solution of potassium carbonate and washed with water,

    (c) the organic phase is concentrated under reduced pressure and the concentration residue is taken up in acetone,

    characterized in that 94-96% sulphuric acid is added and the mixture is seeded with clopidogrel hydrogen sulphate Form 2, the product is crystallized, the mixture is cooled, filtered and the crystals are washed and then dried under reduced pressure to give clopidogrel hydrogen sulphate Form 2.
12. Pharmaceutical composition containing, as active ingredient, the Form 2 polymorph of clopidogrel hydrogen sulphate according to Claim 1 in combination with at least one pharmaceutical excipient.