FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
CRYSTALLINE CLOPIDOGREL HYDORGEN SULPHATE SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at 17/B, Mahal Industrial Estate, off Mahakali Caves Road, Andheri -E, Mumbai -400093.
The following specification particularly describes the nature of this invention and the manner in which it is io be performed.

FIELD OF INVENTION
The invention relates to clopidogrel hydrogen sulphate in the form of a tree-flowing powder characterized by agglomerates of crystalline clopidogrel hydrogen sulphate, free of added excipients and having a particle size distribution such that D10 is not less than 75 urn. The invention also relates to the process of preparing clopidogrel hydrogen sulphate in a powder form.
BACKGROUND OF THE INVENTION
Clopidogrel hydrogen sulphate is chemically S-(+)-methyl-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-C]pyrid-5-yl) acetate sulphate (1:1), or Methyl(+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulphate (1:1) and is well known antithrombotic agent. It was first reported by Sanofi in European Parent Application EP99802 and was claimed as racemic product. U.S. Pat. No. 4,847,265 described the separation of the optical isomers from the racemic clopidogrel base by using (+)-10-camphor sulphonic acid. Subsequently, U.S. Patent 6,429,210 (herein referred to as US'210 patent) and U.S Patent 6,504,030 disclosed crystalline, Form II of clopidogrel hydrogen sulfate and processes of making it.
The physical characteristics of the active pharmaceutical ingredient (API) plays a very important role in determining the nature of process to be convert the API into a solid dosage form such as tablet or capsule. Most of the APIs do not possess the desirable physical characteristics and therefore, other inactive ingredient like diluents, lubricants, disintegrants, binders and the like are supplemented to assist the API to convert into a dosage form. Particularly, in case where the active ingredient represents a high overall percentage of the total tablet, it is essential that the active must flow, compress, and eject from the tablet press and disintegrate properly without the inclusion of large amount of the other inactive ingredients. Some active pharmaceutical ingredients have a wide particle size distribution such as having combination of fines as well as coarse particles. Further, there may be variation in the density of such particles. All these factors can alter the flowability of the powder which is very important in making a tablet having right hardness, friability. Some active pharmaceutical ingredients may have poor flowability due to

their static charges on the particles or due to hygroscopicity or due to their non spherical shape of the particles, inspite of having a desirable particle size distribution.
Clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by agglomerates of crystalline clopidogrel hydrogen sulphate, free of added excipients and having a particle size distribution such that D10 is not less than 75 urn, is not known in the art.
A process for preparing clopidogrel hydrogen sulphate in the form of a free-flowing powder has now been found. The process is very simple, easy and can be scaled up at commercial scale. The process provides a powder which does not have any added excipients and yet has novel and advantageous characteristics making it suitable for conventional tableting processes especially direct compression. Particularly, the clopidogrel hydrogen sulphate of the present invention has improved flow properties and compactability. As a result, the clopidogrel hydrogen sulphate of the present invention can be tableted with minimal quantity of excipients providing more compact tablets.
DRAWINGS AND FIGURES
Figure 1 provides the microscopic photograph of the agglomerates of crystalline clopidogrel hydrogen sulphate particles at 92X magnification. The figure shows the agglomerated particles having spherical or oval shape.
Figure 2 provides the diagrammatic representation of controlled stirring in an axial mixing mode.
Figure 3 provides histogram determined by lazer diffraction technique using a Malvern Mastersize analyzer for clopidogrel hydrogen sulphate prepared according to the process of Example 1

DESCRIPTION OF THE INVENTION
Cclopidogrel hydrogen sulphate of the present invention is in the form of a free-flowing powder characterized by agglomerates of crystalline clopidogrel hydrogen sulphate, free of added excipients and having a particle size distribution such that D10 is not less than 75 μm. It is also substantially free of fines.
The term 'agglomerates' may be interpreted as coarse particles or micropellets or aggregates of particles of the crystalline clopidogrel hydrogen sulphate that are free of excipients. It also means that the agglomerated free flowing powder is substantially free of fines. It may be considered that fines are particle having particle size which is less than 75 microns.
The crystalline clopidogrel hydrogen sulphate of the present invention provides advantages in that it is free flowing and is substantially free of fines. This allows it to be incorporated into a solid dosage form with minimum inactive ingredients leading to a tablet that is small in size compared to a tablet which has fines and not free flowing. The crystalline clopidogrel hydrogen sulphate having a particle size distribution profile such that fines are present, the flow properties are affected. Such material was also found to be hygroscopic, less dense and causing sticking problems to the punches of a tablet press. In order to overcome these problems, help of inactive ingredients like lubricants, glidants is required, leading to a table that is bulky. The Clopidogrel hydrogen sulphate of the present invention solves these problems and advantageously allows manufacturing of smaller tablets with minimum losses. In one embodiment, the clopidogrel hydrogen sulphate of the present invention is having bulk density in the range of about 0.8 g/cc to about 1 g/cc. In a particular embodiment, the clopidogrel hydrogen sulphate of the present invention is having bulk density of 0.82 g/cc.
The present invention also provides a process for preparing clopidogrel hydrogen sulphate in the form of a free-flowing powder has now been found. The process is very simple, easy and can be scaled up at commercial scale. The process provides a powder which does not have any added excipients and yet has novel and advantageous characteristics making it suitable for conventional tableting processes especially direct compression. Particularly, the clopidogrel hydrogen sulphate

of the present invention has improved flow properties and compactability. As a result, the clopidogrel hydrogen sulphate of the present invention can be tableted with minimal quantity of excipients providing more compact tablets.
According to various embodiments of the present invention, particle size distribution may be determined by stream scanning methods or by light diffraction techniques. Stream scanning is a technique where a fluid suspension passes through a sensing zone where individual particles are electronically sized, counted and tabulated. Light diffraction techniques operate by measuring light diffraction from suspended particles without forming an image of the particles onto a detector. Preferred mode of characterizing the particle size is light scattering using the Malvern Mastersize analyzer. The methods are applied to a suspension of the particles of clopidogrel hydrogen sulphate prepared by mild agitation generally using sonication fro about 20 seconds, sufficient to disperse the agglomerate but insufficient to break the agglomerates.
The term Dx as used herein means the size in micrometers below which x % of the particles are found when measured by Malvern Mastersize analyzer using a lazer diffraction technique. For example, D10 of not less than 75 microns means at least 10 % of the particles are not less than 75 microns, that is at least 10 % of the particles are more than 75 microns. Similarly, D50 of not less than 150 microns means at least 50 % of the particles are not less than 150 microns, that is at least 50 % of the particles are more than 150 microns. For D90, it can be interpreted as D90 of not more than 750 microns means at least 90 % of the particles are not more than 750 microns, that is at least 90 % of the particles are less than 750 microns. In general, it may be said that D10, D50, D90 refer to the size in micrometers below which 10, 50, 90%, respectively, of the particles are found.
The term "free of added excipients " as used herein means that the clopidogrel hydrogen sulphate in the form of free-flowing powder obtained in the present invention is free of any pharmaceutically acceptable inactive ingredients generally used in pharmaceutical formulation. The added excipients include, but are not limited to, category of excipients such as diluents, binders, fillers, disintegrants, lubricants and the like.

The term 'substantially spherical' as used herein means that the word spherical is not used in a strict sense, rather it includes any shape that departs from needles and rods and is more sphere-like such as spherical, oval, elliptical, almond, peanut etc.
The term 'controlled stirring' as used herein means that the solution is stirred under axial mixing mode (as illustrated in Figure 2) at slow speed. Slow speed of stirring of the solution is a condition that is dependent on the size of batch. The kinetics of stirring of a solution are determined by the size and design of vessel, size and design of the stirrer and the rotation speed of the stirrer. Depending on the variation of these factors "controlled stirring" can occur at different speed. In one embodiments, glass lined equipment (manufactured by-GMM Pfaudler, Germany) MSGL reactor (V-507) is used to obtain a free-flowing powder characterized by agglomerates of crystalline clopidogrel hydrogen sulphate. Particularly, the glass lined equipment is used which is a glasslined reactors in stainless steel construction. In one embodiment, the volume capacity of such a reactor is about 4870 litres and the stirrer is of propeller type. The volume of the jacket of the reactor is 600 litres. The area of the heating cooling of the reactor is 12 m and the internal diameter of the shell of the reactor is 1756 mm. The total height of reactor from bottom to the nozzle top is 2285 mm. In another embodiment, Glass lined reactors is used having a range from 63 litres to 50000 litres and are manufactured to DIN 28136 and glasslined as per DIN 28063. In particular embodiment AE series of glass lined reactor is used which is in two piece construction with the main cover clamped to the base unit. The standard range extends from 63 litres to 6300 litres nominal capacity. In particular embodiment BE series of glass lined reactor is used which has small central opening for agitor entry. The standard range extends from 1600 litres to 50000 litres. In particular embodiment CE series of glass lined reactor is used which is in one piece construction eliminating the large main joint of the two-piece AE design. The standard range extends from 1600 litres to 50000 litres. As used herein, "batch" refers to material produced by a single execution of a compounding process of various embodiments of the present invention. The batch is a representative of all the commercial batches. Batches may include all batches prepared by a same process.

The particle size distribution of clopidogrel hydrogen sulphate in the form of free-flowing powder obtained by the process of the present invention can be recorded by various techniques known in the art. The particle size distribution can be measured by performing a sieve analysis or by commercial light scattering instrument based on the theory of Fraunhofer diffraction. This principle is also referred to as static light scattering or low-angle forward light scattering and it applies to particles with dimensions larger than the wavelength of the incoming light. Such systems include Malvern Mastersizer (Malvern Instruments, Malvern, U.K.), and the Microtac Full Range Analyzer (Leeds & Northrup, North Wales Pa). In this technique, a laser light passes through the particles, diffracting the intensity in an angular distribution (Iw). Sieve analysis on the other hand provides essentially a two-dimensional estimate of size because passage through the sieve aperture is frequently more dependent on maximum width and thickness than on length. The particle diameter obtained by sieving represents the minimum square aperture through which the particle can pass. (See 'Physical Characterization of Pharmaceutical solids, by Harry G. Brittain, volume 70, Marcel Dekker, Inc, pp. 157-183). Typical sieve analysis involves a nested column of sieves with wire mesh cloth (screen). A representative weighed sample is poured into the top sieve which has the largest screen openings. Each lower sieve in the column has smaller openings than the one above. At the base is a round pan, called the receiver. The column is typically placed in a mechanical shaker. The shaker shakes the column, usually for some fixed amount of time. After the shaking is complete the material on each sieve is weighed. The weight of the sample of each sieve is then divided by the total weight to give a percentage retained on each sieve. The size of the average particle on each sieve is then analyzed to get a cut-off point or specific size range, which is then captured on a screen. The results of this test are used to describe the properties of the aggregate and to see if it is appropriate for various civil engineering purposes such as selecting the appropriate aggregate for concrete mixes and asphalt mixes as well as sizing of water production well screens. The complete procedure for this test is outlined in the American Society for Testing and Materials (ASTM) C 136. A suitable sieve size for the aggregate is selected and placed in order of decreasing size, from top to bottom, in a mechanical sieve shaker. A pan is placed underneath the nest of sieves to collect the aggregate that passes through the smallest. The entire nest is then agitated, and the material whose diameter is smaller

than the mesh opening pass through the sieves. After the aggregate reaches the pan, the amount of material retained in each sieve is then weighed.
The term 'mesh size' as used herein means that the number of openings in one inch of screen. The number of opening is the mesh size. As the number describing the mesh size increases, the size of the particles decreases. The sieve mesh with corresponding microns is as follows: 14# corresponds to 1400 microns, 28 # corresponds to 700 microns, 60 # corresponds to 250 microns, 100 # corresponds to 150 microns, 200 # corresponds to 74 microns, 270 # corresponds to 53 microns, 325 # corresponds to 44 microns and 400 # corresponds to 37 microns. The clopidogrel hydrogen sulphate of the present invention has a particle size distribution such that not more than 30% by weight of particles pass through sieve ASTM No. 100 sieve and 100% by weight of particles pass through sieve ASTM No. 18.
Accordingly, the present invention provides clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients and
(c) having a particle size distribution such that D10 is not less than 75μm.
In one embodiment, the present invention provides clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients and
(c) having a particle size distribution such that D10 is not less than 75 urn and D50 is not less than 150 μm.
In one embodiment, the present invention provides clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients and

(c) having a particle size distribution such that D10 is not less than 75 urn and D90 is not more than 750 μm.
In one embodiment, the present invention provides clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients and
(c) having a particle size distribution such that D10 is not less than 75 μm, wherein the agglomerates are substantially spherical.
In another embodiment, the present invention provides clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by;
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients and
(c) having a particle size distribution such that D10 is not less than 75 μm,
wherein the agglomerates are substantially spherical and the agglomerates have a size in the range from about 10 to about 1000 urn.
In preferred embodiment, the present invention also provides clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients

(c) having a particle size distribution such that D10 is not less than 75 μm
(d) having a particle size distribution such that D50 is not less than 150 μm
(e) having a particle size distribution such that D90 is not more than 750 μm.
In one embodiment, the present invention provides clopidogrel hydrogen sulphate in the form of free-flowing powder characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients

(c) having a particle size distribution such that D10 ranging from about 75 μm to about 250 μm, D50 ranging from 150 μm to 500 urn and D90 ranging from 300 μm to 750 μm.
In one particular embodiment, the present invention provides clopidogrel hydrogen sulphate in the form of free-flowing powder characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) having a particle size distribution such that D10 ranging from about 75 um to about 150 μm, D50 ranging from 150 μm to 500 μm and D90 ranging from 300 μms to 750 μm.
More preferably, clopidogrel hydrogen sulphate in the form of free-flowing powder is characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) having a particle size distribution such that D10 ranging from about 75 um to about 150 μm, D50 ranging from about 250 μm and D90 is about 500 μm.
Alternatively, when the particle size distribution is determined by sieve analysis, the present invention is said to provide clopidogrel hydrogen sulphate in the form of a free-flowing is characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) having not more than 10 % of the powder pass through a sieve mesh of 100 having an aperture size of 150 microns and 100 % of the powder pass through a sieve mesh 18 having an aperture size of 1000 microns.
Preferably, the present invention is said to provide clopidogrel hydrogen sulphate in the form of a free-flowing is characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients

(c) having not more than 30 % of the powder pass through a sieve mesh of 100 having an
aperture size of 150 microns and 100 % of the powder pass through a sieve mesh 20
having an aperture size of 840 microns.
Preferably, when the particle size distribution is determined by sieve analysis, the present
invention is said to provide clopidogrel hydrogen sulphate in the form of a free-flowing is
characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) having not more than 10 % of the powder pass through a sieve mesh of 100 having an aperture size of 150 microns and 100 % of the powder pass through a sieve mesh 20 having an aperture size of 840 microns.
In another aspect, the present invention provides an industrially feasible process of obtaining clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) wherein the powder is substantially free of fines.
According to this aspect of the present invention, there is provided a process consisting of steps of
a. dissolving clopidogrel base in acetone at a concentration of about 5 to 15 % weight by
volume
b. cooling the solution and gradually adding an aqueous sulphuric acid wherein the
concentration of sulphuric acid is at least 75 % by weight and maintaining a temperature
of 10-15°C under controlled stirring
c. drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing
powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) having a particle size distribution such that Dio is not less than 75 [am.

Particularly, the present invention provides a process consisting of steps of
a. dissolving clopidogrel base in acetone to get a solution at a concentration of about 10
%to 13% by weight
b. cooling the solution and gradually adding an aqueous sulphuric acid wherein the
concentration of sulphuric acid ranges from 85% to 98% by weight and maintaining a
temperature of 10-15°C under controlled stirring
c. drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing
powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) having a particle size distribution such that D10 is not less than about 150 μm, and
(c) having a particle size distribution such that D50 is not less than 150 μm
Preferably, the present invention provides a process consisting of steps of
a. dissolving clopidogrel base in acetone to get a solution at a concentration at about 11
% to 12% by weight
b. cooling the solution and gradually adding an aqueous sulphuric acid wherein the
concentration of sulphuric acid ranges from 90% to 96 % by weight and maintaining a
temperature of 10-15 °C under controlled stirring
c. drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing
powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) having a particle size distribution such that D10 not less than 75 μm,
(d) having a particle size distribution such that D50 is not less than 150 μm and
(e) having a particle size distribution such that D90 is not more than 750 μm.
In another embodiment, the present invention provides a process consisting of the steps of
a. dissolving clopidogrel base in acetone to get a solution at a concentration of about 5 to 15% by weight

b. cooling the solution and gradually adding an aqueous sulphuric acid wherein the
concentration of sulphuric acid is in the range from at least 75 % by weight and
maintaining a temperature of 10-15°C under controlled stirring,
c. drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing
powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) having a particle size distribution such that D10 is not less than 75 μm and (c) wherein the agglomerates are substantially spherical.
In particular embodiment, the present invention provides a process consisting of the steps of
a. dissolving clopidogrel base in acetone to get a solution at a concentration of about 10
to 13 % by weight
b. cooling the solution and gradually adding an aqueous sulphuric acid wherein the
concentration of sulphuric acid is in the range from 85% to 95% by weight and
maintaining a temperature of 10-15°C under controlled stirring
c. drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing
powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) having a particle size distribution such that D10 is not less than 75 μm and
(d) wherein the agglomerates are substantially spherical and
(e) the agglomerates have an average size in the range from about 10 μm to about 1000 μm.
In most preferred embodiment, the present invention provides a process consisting steps of
i). dissolving clopidogrel base in acetone to get a solution at a concentration of about 11% to 12% by weight
ii). cooling the solution and gradually adding an aqueous sulphuric acid wherein the concentration of sulphuric acid is in the range from 90% to 96% by weight and maintaining a temperature of 10-15°C under controlled stirring

iii). drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) having a particle size distribution such that D10 is not less than 75 μm
(c) having a particle size distribution such that D50 is not less than 150 μm and
(d) having a particle size distribution such that D90 is not more than 750 μm.
In another embodiment, the present invention provides a process consisting of steps of
i). dissolving clopidogrel base in acetone to get a solution at a concentration in the range of about 5 to 15 % by weight
ii). cooling the solution and gradually adding an aqueous sulphuric acid wherein the concentration of sulphuric acid is at least 15 % by weight and maintaining a temperature of 10-15°C under controlled stirring
iii). drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate and
(b) not more than 30 % of the powder pass through a sieve mesh 100 having an opening size of 150 microns and 100 % of the powder pass through a sieve mesh 20 having an opening size of 840 microns.
In another embodiment, the present invention provides a process consisting of steps of
i). dissolving clopidogrel base in acetone to get a solution at a concentration in the range of about 5 to 15 % by weight
ii). cooling the solution and gradually adding an aqueous sulphuric acid wherein the concentration of sulphuric acid is at least 75 % by weight and maintaining a temperature of 10-15°C under controlled stirring
iii). drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate and

(b) not more than 30 % of the powder pass through a sieve mesh 100 having an opening size of 150 microns and 100 % of the powder pass through a sieve mesh 18 having an opening size of 1000 microns.
In another embodiment, the present invention provides a process consisting of steps of
i). dissolving clopidogrel base in acetone to get a solution at a concentration in the range of about 5 to 15 % by weight
ii). cooling the solution and gradually adding an aqueous sulphuric acid wherein the concentration of sulphuric acid is at least 75 % by weight and maintaining a temperature of 10-15°C under controlled stirring
iii). drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate and
(b) not more than 10 % of the powder pass through a sieve mesh 100 having an
opening size of 150 microns and 100 % of the powder pass through a sieve
mesh 20 having an opening size of 840 microns.
During the manufacturing of clopidogrel hydrogen sulphate according to the present invention, it was surprisingly found that mode of stirring and the speed of rotation yielded clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients and
(c) having a particle size distribution such that D10 is not less than 75 μm.
Particularly, speed of rotation was found to alter the particle size of the free flowing powder of clopidogrel hydrogen sulphate. It was particularly, noted that the increase in the speed of rotation of the solution provided very fine particles, i. e. fast rotation yielded clopidogrel hydrogen sulphate in the form of a free-flowing powder characterized by substantially fine agglomerates. The process of the present invention uses acetone to dissolve the clopidogrel base. The concentration of clopidogrel hydrogen sulphate in acetone ranges from about 5% to about 15%,

preferably, 10% to 13% and most preferably 10% to 12% weight by volume. The concentration of aqueous sulphuric acid used is in the range of at least 75% preferably, 85% to 98% and most preferably 90% to 96% by weight.
Hereinafter, the invention will be more specifically described with reference to examples. The examples are no intended to limit the scope of the invention and are merely used as illustrations.
Example 1
S-(+)-Clopidogrel base (174 Kg) was dissolved in 1440 litres of acetone under stirring at about 50 rpm in mild steel glass lined reactor. The contents were cooled to 10-15 °C and a solution of 25.8 litre of concentrated sulphuric acid with 4.8 litres of water was gradually added maintaining the same temperature. After addition, the temperature was gradually raised to 25-30°C and stirring continued at about 50 rpm, under axial mixing mode for 60 minutes. The contents were then cooled to 10-15 °C and further stirred at the same rpm for 60 minutes. The crystallized product was then isolated by filtration at 10-15 °C, washed with 3 00 litres pre-cooled Acetone, to obtain 174 Kg of Clopidogrel hydrogen sulphate after drying at 35-40 °C, under vacuum. The particles obtained showed the following particle size distribution:
By Sieve analysis: 23.97 % of the particles passed through a sieve having a mesh number # 100 having aperture size of the mesh of 149 urn The aspect ratio of the particles was 1. 88 1 /w and the bulk density was 0.83 g/cc.
By Malvern Mastersizer: 50 mg sample was taken into 100 mL beaker and 3-5 drops of chloroform were added. Slurry was prepared using a glass rod. 5 mL cyclohexane solution was added into slurry and beaker was swirled. The contents were sonicated exactly for 20 seconds to get a homogeneous suspension. This homogeneous suspension was used for measurement of particle size distribution.

The particle size distribution was determined by Malvern Mastersizer and the data is given
below:
Table 1: Particle size distribution by Malvern Analysis

RPM Particle size by Malvern Mastersizer

D10μm D50 μm D90μm
50 159 321 548
The above mentioned batch size was manufactured and the particle size distribution was found to be such that D10 is not less than 75 μm and D50 not less than 150 μm.
Example 2
S-(+)-Clopidogrel base (174 Kg) was dissolved in 1440 litres of acetone under stirring at about 50 rpm in mild steel glass lined reactor. The contents were cooled to 10-15 °C and a solution of-25.8 litre of concentrated sulphuric acid with required amount of water was gradually added maintaining the same temperature. After addition, the temperature was gradually raised to 25-30 °C and stirring continued at about 50 rpm, under axial mixing mode for 60 minutes. The contents were then cooled to 10-15°C and further stirred at the same rpm for 60 minutes. The crystallized product was then isolated by filtration at 10-15 °C, washed with 300 litres pre-cooled Acetone, to obtain 170 Kg of Clopidogrel hydrogen sulphate after drying at 35-40°C, under vacuum.
The particles obtained showed the following particle size distribution:
By Sieve analysis: 18.4 % of the particles passed through a sieve having a mesh number # 100
having aperture size of the mesh of 149 urn. The aspect ratio of the particles was 1. 88 1 /w and
the bulk density was 0,83 g/cc.
By Malvern Mastersizer: 50 mg sample was taken into 100 mL beaker and 3-5 drops of
chloroform were added. Slurry was prepared using a glass rod. 5 mL cyclohexane solution was
added into slurry and beaker was swirled. The contents were sonicated exactly for 20 seconds to
get a homogeneous suspension. This homogeneous suspension was used for measurement of
particle size distribution.

Table 2: Particle size distribution by Malvern Analysis

Particle size by Malvern Mastersizer
RPM D10μm D50 μm D90μm
50 155.258 263.027 431.244
The above mentioned batch size was manufactured and the particle size distribution was found to be such that D10 is not less than 75 μm and D50 not less than 150 μm.
Example 3
S-(+)-Clopidogrel base (174 Kg) was dissolved in 1440 litres of acetone under stirring at about 50rpm in mild steel glass lined reactor. The contents were cooled to 10-15 °C and a solution of -25.8 litres of concentrated sulphuric acid with required amount of water was gradually added maintaining the same temperature. After addition, the temperature was gradually raised to 25-30 °C and stirring continued at about 50 rpm, under axial mixing mode for 60 minutes. The contents were then cooled to 10-15 °C and further stirred at the same rpm for 60 minutes. The crystallized product was then isolated by filtration at 10-15°C, washed with 300 litres pre-cooled Acetone, to obtain 170,6 Kg of Clopidogrel hydrogen sulphate after drying at 35-40 °C, under vacuum.
The particles obtained showed the following particle size distribution:
By Sieve analysis: 15.6 % of the particles passed through a sieve having a mesh number # 100 having aperture size of the mesh of 149 μm. The aspect ratio of the particles was 1. 88 1 /w and the bulk density was 0.83 g/cc.
By Malvern Mastersizer: 50 mg sample was taken into 100 mL beaker and 3-5 drops of chloroform were added. Slurry was prepared using a glass rod. 5 mL cyclohexane solution was added into slurry and beaker was swirled. The contents were sonicated exactly for 20 seconds to get a homogeneous suspension. This homogeneous suspension was used for measurement of particle size distribution.

Table 3: Particle size distribution by Malvern Analysis

Particle size by Malvern Mastersizer
RPM D10nm D50 μm D90 μm
50 204.758 328.400 5I9.II4
The above mentioned batch size was manufactured and the particle size distribution was found to be such that D10 is not less than 75 μm and D50 not less than 150 urn.
Table 4: Compilation of the particle size distribution of the batches prepared according to example 1, 2 and 3

Example Particle size by Malvern Mastersizer

D10 μm D50 μm D90 μm
1 159 321 548
2 155.258 263.027 431.244
3 204.758 328.400 519.114
Above all the examples show the consistency in the particle size distribution. Despite of preparation of different batches the particle size was found to be within the limits i.e., D10 found to be not less than 75 μm and D50 found to be not less than 150 μm and D90 found to be not more than 750μm.

We claim
1. Clopidogrel hydrogen sulphate in the form of a free-flowing powder which is characterized
by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients and
(c) having a particle size distribution such that D10 is not less than 75 μm.

2. Clopidogrel hydrogen sulphate as claimed in claim 1, having a particle size distribution such that D50 is not less than 150 μm.
3. Clopidogrel hydrogen sulphate as claimed in claim 1, having a particle size distribution such that D90 not more than 750 μm.

4. Clopidogrel hydrogen sulphate as claimed in claim 1, wherein the agglomerates are substantially spherical.
5. Clopidogrel hydrogen sulphate as claimed in claim 1, wherein the agglomerates have an average size in the range from about 10 to about 1000 μm.
6. Clopidogrel hydrogen sulphate in the form of a free-flowing powder which is characterized by
(a) agglomerates of crystalline clopidogrel hydrogen sulphate
(b) free of added excipients
(c) having not more than 30 % of the powder pass through a sieve mesh of 100 having an aperture size of 150 microns and 100 % of the powder pass through a sieve mesh 20 having an aperture size of 840 microns.

7. A process comprising the steps of
a. dissolving clopidogrel base in acetone at a concentration of about 5 to 15 % weight by
volume
b. cooling the solution and gradually adding an aqueous sulphuric acid wherein the
concentration of sulphuric acid is at least 75 % by weight and maintaining a temperature
of 10-15°C under controlled stirring
c. drying to obtain crystalline clopidogrel hydrogen sulphate in the form of a free-flowing
powder characterized by:
(a) agglomerates of crystalline clopidogrel hydrogen sulphate.
8. A process as claimed in claim 7 wherein clopidogrel hydrogen sulphate is having a particle
size distribution such that D10 not less than 75 μm, D50 not less than 150 μm and D90 not more
than 750 μm.