FORM 2
THE PATENTS ACT, 1970
(39 Of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
NOVEL PHARMACEUTICAL COMPOSITIONS OF CLOPIDOGREL
MESYLATE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat

The following specification describes the nature of the invention

NOVEL PHARMACEUTICAL COMPOSITIONS OF CLOPIDOGREL
MESYLATE
FIELD OF THE INVENTION
The present invention relates to stabilized pharmaceutical compositions of clopidogrel mesylate, which is highly hygroscopic, unstable salt and the process for preparing such compositions.

.CH3SO3H Clopidogrel Mesylate
BACKGROUND OF THE INVENTION
Clopidogrel and its salts, by virtue of its anti platelet aggregation effect, acts as an anti thrombotic agent. Clopidogrel is a compound disclosed in US4847265. Clopidogrel (Clopidogrel bisulfate) is available in the United States and elsewhere under the trade name of PLAVIX®. (Sanofi Pharma/Bristol-Myers Squibb Partnership, New York, USA). PLAVIX® contains Hydrogenated Castor Oil, Hydroxypropylcellulose, Mannitol, Microcrystalline Cellulose and Polyethylene Glycol 6000 as inactive ingredients. The pink film coating contains ferric oxide, Hydroxypropyl Methylcellulose 2910, Lactose Monohydrate, Titanium Dioxide and Triacetin. The tablets are polished with Carnauba Wax. (Physician's Desk Reference, 59th Ed, pp. 1052-1055 (2005).)
In US4847265, it is acknowledged that various salts namely acetate, benzoate, fumarate, maleate, citrate, tartrate, gentisate, mesylate, benzene sulfonate, lauryl sulfonate, dobesilate, tosylate and hydrochloride of clopidogrel are hygroscopic and thus makes them difficult to handle on industrial scale. Furthermore, these
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salts are amorphous. For preparation of pharmaceutical composition the compound i.e., active pharmaceutical ingredient (API) is preferred in the form of crystalline nature. The pharmaceutical usage always demands pure compounds, as it goes for human consumption. However, the impure compounds, which are the results of purification difficulty, cannot lead to a drug in the market.
WO2004026879 discloses clopidogrel, or a pharmaceutically acceptable salt thereof, in an amorphous form. This prior art describes stabilization of amorphous clopidogrel salts by complexation of at least a homopolymer or copolymer of N-vinyl pyrrolidone.
WO2004074215 discloses various salts of clopidogrel along with compositions and process related with the same. The prior art describes hygroscopic nature of various salts of clopidogrel. This prior art discusses variety of formulations like
tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs, creams, ointments, gels, lozenges, aerosol, parenteral (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing.
It is discussed in this prior art that the tablets of clopidogrel salts can be coated with polymers like ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, Eudragit E l00 and their combinations thereof for providing protection against moisture.
It is also discussed in this prior art, that the tablets can be moisture protected by suitable excipients by making tablet in tablet formulation by compression coating. The problem associated with this type of technology is that it is not production friendly.
A similar prior art WO2005048992 also teaches about the process of preparing clopidogrel compositions. The composition described comprises a) a polymer coating selected from polyvinyl acetate or a polyvinyl alcohol, and b) a hydrophobic component comprising a hydrogenated vegetable oil on clopidogrel.
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The process is carried out in a low or ultra low humidity environment. The said prior art describes manufacturing of clopidogrel composition by compaction of clopidogrel with other excipients then compressing the granules into tablets, which is coated with moisture barrier coating. This moisture barrier coating of tablet prevents the hygroscopic active ingredient from degradation.
WO 2005048992 doesn't provide any conclusive evidence to prove the stability of the formulation. Also, the prior art emphasizes on film coating of tablets with Opadry AMB, due to single coat over the moisture labile core, any small damage to coated tablet can result in product detonation and cause stability problems. This damage to the coat may happen during coating, or packaging. Also, coating of compacted granules or particles as discussed in the prior art may cause problems due to friable nature of the compacted granules.
Thus there exists a need to prepare stabilized pharmaceutical compositions of clopidogrel salts, which are unstable and hygroscopic in nature.
In the instant invention it has surprisingly been found that the hydrophobic seal coating between pluralities of individual inert core units and drug layer along with moisture resistance coating over the plurality of individual active compound units resulted in stable and rugged formulation.
SUMMARY OF THE INVENTION
The present invention relates to stabilized pharmaceutical compositions of clopidogrel mesylate, which is highly hygroscopic, unstable salt and the process for preparing such compositions. In the instant invention the inert granular core is seal coated with hydrophobic polymers or waxes to provide a strong core for drug loading, and then subsequent drug loading on core is done. These drug layered multiple units are again seal coated using polymers and other moisture barrier agents. These coated plurality of individual active compound units are then
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compressed into tablets by using suitable excipients. These tablets are filmcoated with moisture barrier agent and other excipients required for film coating.
OBJECTS OF THE INVENTION
It is an object of the present invention is to provide a stabilized oral composition for hygroscopic, unstable salt of clopidogrel, Clopidogrel Mesylate.
Another object of the present invention is to provide a process for the preparation of stabilized compositions of clopidogrel mesylate.
DETAILED DESCRIPTION
Present invention provides stabilized pharmaceutical compositions of clopidogrel mesylate.
According to general aspect of the present invention there is provided an improved stabilized pharmaceutical composition for manufacturing oral dosage form of clopidogrel mesylate, which is liquid, unstable, and highly hygroscopic in nature.
It has now surprisingly been found that an administration form, which comprises a plurality of individual active compound units, along with various excipients compressed into tablets, shows good stability. The compaction of clopidogrel is not done to produce the core.
In the instant invention the plurality of individual active compound units is manufactured by using inert granular core, the inert granular core is seal coated with hydrophobic polymers or waxes to provide a strong core for drug loading, and then subsequent drug loading on core is done. These drug layered multiple units are again seal coated using polymers and other moisture barrier agents. These coated plurality of individual active compound units are either filled in to
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capsules or compressed into tablets by using suitable excipients. These tablets are film coated with moisture barrier agent and other excipients required for film coating.
In one aspect of invention, the pluralities of inert cores are seal coated with hydrophobic agents, anti tacking agents and suitable non-aqueous solvents. The seal coating of inert cores will provide following advantages:
a) The seal coated pluralities of inert cores will reduce the friability of the inert granular core, which will improve the further coating quality.
b) The seal coating of pluralities of inert cores will reduce the drug loss during further coating.
c) The seal coating of inert core with hydrophobic agents may improve the stability of the product.
The hydrophobic agent for the seal coating may be selected from ethylcellulose or cellulose derivatives, waxes or the combination thereof.
These seal coated pluralities of inert cores, are further coated with clopidogrel mesylate, binder, anti tacking agent and suitable non-aqueous solvents.
These pluralities of active cores are then coated with moisture barrier layer.
The seal coating moisture barrier agent may be selected from ethyl cellulose, hydrogenated castor oil, beeswax, or Eudragit. In preferred embodiment,
moisture barrier agent may be ethyl cellulose, beeswax and hydrogenated castor oil.
These coated cores are either filled into capsules or compressed in tablets using suitable excipients known to the person skilled in the art. The tablet is film coated, which has moisture barrier properties. The polymers used in the coating may be
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selected from hydroxypropyl methylcellulose, hydroxy propyl cellulose, ethyl cellulose or the mixtures thereof.
Hence, the moisture barrier is applied in several steps; this will result in improved stable product. Also, a friability issue related with coating of compacted granules is resolved in instant invention by using seal coated mannitol core followed by drug layering.
The inert granular core in the instant invention can be selected from mannitol (Pearlitol SD 200), microcrystalline cellulose, sugar globules or non-peril seed. In a preferred embodiment, the inert granular core is granular mannitol.
The brief procedure is as under:
Step I: Preparation of seal coated drug layered pellets of Clopidogrel Mesylate:
The inert granular core is seal coated with hydrophobic agents to provide a strong core for drug loading, and then subsequent drug loading with binder on core is done. To this drug layered multiple units again seal coating with polymers and other moisture barrier agent is done.
Step II: Preparation of film coated immediate release formulation:
The coated plurality of individual active compound units is then compressed into tablets by using suitable excipients. These tablets are filmcoated with moisture barrier agent and other excipients required for film coating.
In another general aspect, there is provided a process to reduce the moisture level below 0.75%w/w in tablet formulation, where the active compound that is clopidogrel mesylate is unstable, very hygroscopic and liquid in nature. This surprising finding of low moisture level in tablets may be related with the stability of clopidogrel mesylate.
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In another general aspect, there is provided an immediate release pharmaceutical composition of clopidogrel mesylate comprising of plurality of individual active compound units coated by Wurster process in Fluid bed processor (Glatt) alongwith at least one or more excipients to give stable product, which can be packed in HDPE containers.
In another general aspect, there is provided an immediate release pharmaceutical composition comprising plurality of inert cores coated with clopidogrel mesylate solution, which is further coated with moisture barrier agents.
In another general aspect, there is provided an immediate release pharmaceutical composition comprising a drug; wherein the pharmaceutical composition is manufactured under controlled humidity, for example relative humidity of less than about 40% and, more particularly, less than about 20%.
Pharmaceutical composition according to the present invention can be prepared in a form of tablet, hard gelatin or soft gelatin capsule, sachet, preferably in the form of a tablet or capsule.
The active ingredient used in the present pharmaceutical composition is clopidogrel mesylate.
The term 'pharmaceutical composition' as used herein includes solid dosage forms such as tablet, capsule, pill, and the like. The tablets can be prepared by techniques known in the art and contain a therapeutically effective amount of the active ingredient and such excipients as are necessary to form the tablet by such techniques.
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The pharmaceutical composition of the present invention typically comprises from 30mg to 180mg of clopidogrel mesylate. The formulation of this invention preferably comprises 25mg to 150mg clopidogrel
The term " individual active compound unit" as used herein refers to an individual unit comprising at least one active compound particle. Preferably in the individual units, the active compound is surrounded by at least one polymer.
The solid dosage form tablet or capsule of the present invention is prepared using active ingredient i.e., clopidogrel mesylate and pharmaceutically acceptable excipients selected from the group comprising of diluents, disintegrants, binders, lubricants, glidants and optionally an anti oxidants as a stabilizer with other pharmaceutically acceptable excipients.
Diluents can be selected from the group comprising of lactose, starch, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, kaolin, sucrose, mannitol, precipitated calcium carbonate, sorbitol, maltodextrin, cellulose derivatives including powdered cellulose, microcrystalline cellulose or other materials known to one of ordinary skill in the art. The diluents in the dosage form ranges from 5% to 80% by weight.
Binders can be selected from the group comprising of polyvinylpyrrolidone or hydroxypropyl methylcellulose, acacia, alginic acid, hydroxy propyl cellulose, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch or other materials known to one of ordinary skill in the art. The binders in the dosage form ranges from 0.5% to 50% by weight.
The film coating can be polymer based or wax based and can be selected from hydroxypropyl methylcellulose, hydrogenated castor oil, hydroxypropyl cellulose, ethyl cellulose, beeswax, Eudragit E l00 or their mixture thereof. It was found that hydrogenated castor oil, beeswax and ethyl cellulose provide required protection
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against moisture. The polymers and waxes in the dosage form ranges from 0.5% to 10% by weight.
Disintegrants can be selected from the group comprising of starch, hydroxy propyl cellulose, sodium starch glycolate or croscarmellose sodium, crospovidone, alginic acid, carboxymethyl cellulose sodium, Guar gum or other materials known to one of ordinary skill in the art. The disintegrants in the dosage form ranges from 0.5% to 25% by weight.
Lubricants can be selected from the group comprising of stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel or other materials known to one of ordinary skill in the art. The lubricants in the dosage form ranges from 0.5% to 20% by weight.
Glidants or flow enhancer can be selected from the group comprising of colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, or other materials known to one of ordinary skill in the art. The glidents in the dosage form ranges from 0.25% to 5% by weight.
Anti sticking agents can be selected from talc, magnesium stearate, stearic acid, hydrogenated castor oil or other materials known to one of ordinary skill in the art. The anti sticking agents in the dosage form ranges from 0.25% to 20% by weight.
Plasticizers useful in the invention comprise, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly (propylene glycol), multi-block polymers, single block polymers, poly (ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin.
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Such plasticizers can also include ethyleae glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol, monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetylributycitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation. The plasticizers in the dosage form ranges from 1% to 35% by weight.
The moisture barrier agent may be selected from ethyl cellulose, hydrogenated castor oil, beeswax, or Eudragits. The moisture barrier agent in the dosage form ranges from 0.5% to 25% by weight.
The Anti-oxidant (Stabilizer) may be selected from Butylated hydroxy anisol, Butylated hydroxy toluene, Citric Acid Anhydrous or hydrous, Benzoic acid, Lanoline, Sulphated derivatives, alone or in combinations there of. The antioxidant in the dosage form ranges from 0.1% to 15% by weight
The inert granular core in the instant invention can be selected from mannitol (Pearlitol SD 200), microcrystalline cellulose, sugar globules or non-peril seed. The inert granular core in the dosage form ranges from 10% to 75% by weight.
The solvent may be selected from the group of methanol, methylene chloride or acetone.
Other components may include talc as antitacking agent, titanium dioxide as
opacifier, iron oxides as colouring agents, hydrogenated castor oil as anti sticking agent. Beeswax white can also be used as polishing agent for filmcoating.
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PHARMACEUTICAL COMPOSITION
The preparation of pharmaceutical composition of the present instant invention comprises of two phases:
Step I: Preparation of seal coated drug layered pellets of Clopidogrel Mesylate comprising of ethyl cellulose inert material coated on mannitol of the nature of directly compressible form. These seal coated pellets are further layered by a composition containing active ingredient and binder. Further the said drug layered pellets are coated with a seal coating comprising of inert polymers.
Step II: Preparation of Clopidogrel Mesylate film coated tablets.
Step I: Preparation of seal coated drug layered pellets of Clopidogrel Mesylate comprises the following steps:
1. Mannitol in the form directly compressible powder is taken as an inert
core. Inert coating of inert material coated mannitol is done by spraying
the spraying solution on to the mannitol by a wurster spray (Glatt). The
spraying solution is prepared by the following method:
Binder or film forming polymer(s) is dissolved in a mixture of methanol and Methylene chloride. Anti sticking agent is milled in presence of sufficient mixture of methanol and Methylene chloride in a colloidal mill. Above milled dispersion is added to the binder or the film forming polymer(s) solution and stirred to get a uniform homogenous suspension and the same is passed through sieve 60#.
2. Seal coated mannitol prepared in step 1 are further layered by a suspension
containing active ingredient i.e. Clopidogrel Mesylate in dissolved form.
Binder or film forming polymers) is dissolved in methanol. Anti sticking
agent is milled in presence of sufficient methanol in a colloidal mill.
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Above milled dispersion is added to the binder or the film forming polymer(s) solution to which is added the active ingredient solution and stirred to get a clear homogenous suspension. The layering of active ingredient is done by spraying the coating solution comprising the active ingredient on to the inert material coated mannitol (Prepared in step 1) by wurster apparatus (Glatt).
3. Further, seal coating is applied on to the drug layered mannitol prepared in step 2 above by wurster apparatus (Glatt). The seal coating suspension is prepared by following method:
Film forming polymer(s) is dissolved in a methanol and stirred to get a clear homogenous suspension and the same is passed through sieve 60#. The same solution is applied onto drug layered pellets by wuster apparatus (Glatt).
Step II: Preparation of film coated immediate release formulation of the said seal coated drug layered portion.
1. The seal coated drug layered pellets of Clopidogrel Mesylate and mannitol of the form directly compressible are passed through mesh #24.
2. The compressible mixture comprising of glidants, anti sticking agents and lubricants are sieved through mesh #60.

A) The shifted ingredients of step 1 and 2 are blended together and are compressed in to tablets.
B) The compressed tablets are further film coated by spray coating (Neo cota). The film coating suspension is prepared by following method:
Film forming polymer(s) is dissolved in a mixture of methanol and Methylene chloride. Coloring and opacifying agent are milled in presence of sufficient
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mixture of methanol and Methylene chloride in a colloidal mill. Above milled dispersion is added to the film forming polymer(s) solution and stirred to get a clear homogenous suspension and the same is passed through sieve 60#.
3. Further, the film coated tablets of said composition are polished by spray coating (Neo cota). The polishing solution is prepared by following method:
Polishing agent is dissolved in Methylene chloride by the aid of gentle heating to get clear solution.
EXAMPLES:
The invention described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention.
STABILIZED PHARMACEUTICAL COMPOSITION CONTAINING CLOPIDOGREL MESYLATE
STEP-I: Preparation of seal coated on drug layered pellets of Clopidogrel Mesylate:
The ingredients used in the preparation of Clopidogrel Mesylate seal coated on drug layered pellets in the instant invention by wurster spraying (Glatt process) are given below along with the method of preparation of the said pellets.
A) Formula for seal coating of mannitol

Ingredients Function Mg/tablet % w/w
(mg) per Tablet
Mannitol (Directly It is used as 90.88 16.13
compressible) substrate for
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layering of drug
Ethyl cellulose 10 cp Moisture barrier agent 5.45 0.97
Talc purified Anti-sticking agent 1.09 0.19
Methanol Solvent qs —
Methylene chloride Solvent qs —
Total 97.42 17.29
Procedure
0.97 %w/w of ethyl cellulose was dissolved in a mixture of methanol and Methylene chloride. Milled 0.19 %w/w talc purified with sufficient quantity of methanol and methylene chloride. Added the milled dispersion of the above to the binder solution and stirred to get a clear solution and passed through sieve 60#. The above solution was sprayed on to the mannitol by wurster spray (Glatt process)
Sr. No. Test Parameter Acceptance Criteria
1. Description white to off-white free flowing pellets.
B) Formula for drug layering of inert seal coated mannitol

Ingredients Function Mg/tab %w/w
(mg) per Tablet
Seal coated pellets Base for drug loading 97.42 17.29
of Step A
Clopidogrel Active 97.42 17.29
mesylate solution
Hydroxy propyl It is used as binder as well 20.46 3.63
cellulose (Klucel as adhesive agent for drug
LF) to adhere onto substrate
Talc purified Anti-sticking agent 14.61 2.59
Methanol Solvent qs -
Total 229.91 40.80
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Procedure
3.63 %w/w hydroxy propyl cellulose (Klucel LF) was dissolved in methanol. Milled 2.59 %w/w talc purified with sufficient quantity of methanol. Added the milled dispersion of the above to the binder solution and stirred to get a clear solution and passed through sieve 60#. Added the drug solution to the above solution and stirred to get a clear solution. The above solution was sprayed on to the seal coated mannitol by wurster spray (Glatt process)

Sr. No. Test Parameter

Results

Description

Off-white to light yellow colored
pellets.

C) Formula for seal coating of drug layered pellets

Ingredients

Function

Mg/Tab % w/w per
(mg) tablet

Drug layered Base for seal coating
pellets
Hydroxy propyl It is used as binder as
cellulose well as adhesive agent
(Klucel LF) for drug to adhere onto
substrate
Ethyl cellulose 10 Moisture barrier agent
cp
Methanol Solvent
Total

229.91
13.79
3.45
qs 247.15

40.80
2.45
0.61
43.86

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Procedure
2.45 %w/w hydroxy propyl cellulose (Klucel LF) and 0.61 %w/w of ethyl cellulose l0 cp were dissolved in methanol to get a clear solution and passed through sieve 60#.
The above solution was sprayed on to the drug layered pellets by wurster spray (Glatt process)

Sr. Test Parameter Results
No.
1. Description Off white to light yellow colored free flowing pellets.
2. K F by water 0.68 %
3. Assay (By HPLC) (Each 100 mg of pellets containClopidogrel Mesylate... 41.3 mg) 38.58 mg
4. Residual solvents 1148 ppm
Methanol Methylene Chloride L0 ppm
5. Related substances 0.04
A (Clopi acid) 0.04
BC (R isomer) 0.81
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STEP II: Preparation of Clopidogrel Mesylate film coated Tablets

Ingredients Function Quantity % w/w
(mg /Tab) per tablet
CORE:
Seal coated drug layered As active pellets 252.51* 44.80*
pellets of Clopidogrel
Mesylate
Mannitol (Directly Diluent 216.99 38.50
compressible)
Hydrogenated castor oil Anti-sticking agent 12.50 2.21
(Cutina HR PH)
Stearic acid Anti-sticking agent 20.00 3.54
Hydroxy propyl cellulose Disintegrating agent 44.50 7.89
(HPC LH 11)
Colloidal silicon dioxide Flow enhancer 3.50 0.62
FILM COATING:
Hydroxy propyl methyl Film forming 7.67 1.36
cellulose El 5 LV polymer
Hydrogenated castor oil Anti-sticking agent 1.43 0.25
(Cutina HR PH)
Polyethylene glycol 6000 Plasticizer 0.95 0.16
Titanium dioxide Opacifyer 3.12 0.55
Red oxide of Iron Colouring agent 0.08 0.01
Methylene chloride Solvent q.s -
Methanol Solvent q.s -
POLISHING COMPOSITION:
Beeswax white Polishing and Moisture barrier agent 0.30 0.05
Methylene chloride Solvent q.s. -
Total 563.55 mg 100%
C) Formula for preparation of Tablets
*Pratical assay of seal coated drug layered pellets of Clopidogrel mesylate considered for calculations.
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Procedure:
Seal coated drug layered pellets of Clopidogrel Mesylate 44.8 %w/w was passed through mesh #24, mannitol (directly compressible) 38.50 %w/w was passed through mesh #24, hydrogenated castor oil 2.21 %w/w, stearic acid 3.54 %w/w, hydroxy propyl cellulose (HPC LH 11) 7.89 %w/w and colloidal silicon dioxide 0.62 %w/w was passed through mesh #60. The above passed ingredients were blended together.
The final blend thus obtained was compressed into 550 mg tablets on a tablet compression machine using 11.20 mm biconvex bevel edged punches.
Hydroxypropyl methylcellulose E 15 LV 1.36 %w/w, polyethylene glycol 6000 0.16 %w/w and hydrogenated castor oil 0.25 %w/w were dissolved in a mixture of methanol and methylene chloride. Red oxide of iron 0.01 %w/w and titanium
dioxide 0.55 %w/w were milled in presence of sufficient mixture of methanol and methylene chloride in a colloidal mill. Above milled dispersion was added to the film forming polymer(s) solution and stirred to get a clear homogenous suspension and the same was passed through sieve 60#. The solution was used to film coat the tablet.
Beeswax white 0.05 %w/w was dissolved in sufficient quantity of methylene chloride under gentle heating to get a clear solution which was used to polish the film coated tablets.

Sr. No. Test Parameter Results
1. Description Pink colored, round, biconvex, film coated tablets with "75" embossed on one side.
2. Average weight 562.765 mg
3. Drug release
In 30 min at pH 2.0 91.9%
4. Related Substances
A (Clopi acid) 0.02%
B 0.05%
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Sr. No. Test Parameter

Results

6.

C(R isomer) 0.86%
Total 0.93%
Assay
(Each film coated tablet
contains: Clopidogrel
Mesylate eq. to 101.26%
Clopidogrel 75 mg)
Residual solvents
Methanol 1079 ppm
Methylene Chloride 286 ppm

Stability Data: B. No.: DM 003A.
Manufactured By: Torrent Pharmaceutical limited

% Drug
Assay
Condition/Period dissolution RI KF%
%
30 min
Single
ABC Total
unknown
Initial 101.26 91.9 0.02 0.05 0.86 - 0.93 1.16
101.93 100.0 0.08 0.08 0.86 0.06 1.11 0.89
30°C 65% RH
3M
100.9 95.0 0.52 0.07 1.24 0.11 2.0 1.02
40°C 75% RH
3M
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Stability Data:
Plaviax (B. No . 500481)
Manufactured By: Sanofi Pharma Bristol-Myers squibb SNC
%
%Drug
Assay
Condition/Period dissolution RI KF%
0
30 min
Single
ABC Total
unknown
Initial 101.25 94.2 ND 0.17 0.55 - 0.72 1.74
30°C 65% RH
101.44 94.6 0.10 0.11 0.71 0.04 0.90 1.71 3M
40°C 75% RH
102.27 67.4 0.82 0.09 1.14 0.05 1.30 2.28 3M
Conclusion: Thus it can be concluded that composition of the instant invention of clopidogrel mesylate, which is highly hygroscopic, unstable salt has been found as stable as Clopidogrel Bisulphate ( Plavixx : Manufactured By : Sanofi).
Dated this on 14th September, 2005


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Dr. Rajiv Ghanshyam Shah,
Torrent Pharmaceuticals Limited,
Torrent Research Centre
P.O. Bhat - 382428, Gandhinagar
Gujarat, India

Abstract
The present invention relates to stabilized pharmaceutical compositions of clopidogrel mesylate, which is highly hygroscopic, unstable salt and the process for preparing such compositions.