FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1.Title of the invention: "PROCESS FOR THE PREPARATION OF CLOPIDOGREL BASE OR ITS ALCOHOLIC SOLUTION/SUSPENSION WITH IMPROVED STABILITY"
2. Applicant (s)
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road,
Chandivali, Andheri (East), Mumbai-400072, India.
PREAMBLE TO THE DESCREPTION
The following specification particularly describes the invention and the manner in which it is to be performed

Title:
Process for the preparation of clopidogrel base of formula I or its alcoholic solution/suspension with improved stability
Technical field of the invention:
The present invention relates to a novel process for the preparation of stable clopidogrel base in neat form or its alcoholic solution/suspension form having improved stability during storage over extended periods of time suitable for pharmaceutical use and as an intermediate for making pharmaceutically acceptable salts or for its use for the preparation of pharmaceutical formulation in dosage form. The present invention relates to a process comprising contacting clopidogrel base with a suitable base selected form the group of organic amines like primary, secondary, tertiary or quaternary ammonium salts or mixture thereof preferably alkyl amines selected from the group comprising mono methyl amine, diethyl amine, triethyl amine more preferably triethyl amine as a stabilizer which enables the clopidogrel base to retain significant pharmaceutical activity by controlling the degradation which results in the formation of unknown impurity during storage and also increases shelf life without any adverse impact on purity, therefore pharmaceutical activity.
Background of the invention:
Clopidogrel is an inhibitor of induced platelet aggregation which acts by inhibiting the binding of adenosine diphosphate to its receptor.

Clopidogrel is metabolized by the liver into active form. Its antiplatelet activity is extended in that it stops any platelet activity even up to ten days after administration.
The chemical name of clopidogrel is methyl (+)-(S)-.varies.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)—acetate and is represented by a compound of formula I

US4, 529,596 discloses a racemic mixture of clopidogrel and processe for preparing such mixture.
US4847265 describes enantiomers of tetrahydrothienopyridine derivatives and their pharmaceutically acceptable salts. US4847265 specifically claims clopidogrel hydrogen sulfate, i.e. the dextrorotatory isomer which possesses an excellent platelet aggregation inhibiting activity whereas the levorotatory isomer is less active and less well tolerated.
Clopidogrel's platelet inhibiting activity makes it an effective drug for reducing the incidence of ischemic strokes, heart attacks or claudication

due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks.
Studies have shown that clopidogrel is more effective in platelet aggregation than aspirin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than aspirin even at much lower dosage. A dosage of 75 mg of base equivalent has been shown to be more effective than a dosage of 325 mg of aspirin. In addition to being more effective, clopidogrel produces much less gastrointestinal bleeding than aspirin.
Clopidogrel is administered as its bisulfate salt. It is currently being marketed as PLAVIX™ sold by Bristol Meyers Squibb, tablets, which contain about 98.875 mg clopidogrel bisulfate, which is the molar equivalent of 75 mg clopidogrel base. PLAVIX™ is a white to off-white powder that is practically insoluble in water at neutral pH but highly soluble at acidic pH. It dissolves freely in methanol, somewhat in methylene chloride, and poorly in ethyl ether.
As evident by PLAVIX™ Clopidogrel is administered as a pharmaceutically acceptable salt to a patient. Generally clopidogrel base is not used for formulation inter alia because it exists as oil that is highly contaminated with unacceptable levels of solvents and clopidogrel acid and other known and unknown impurities. Generally clopidogrel base is

oil having high viscosity and so it is difficult to purify. It occurs as an amorphous semisolid paste like mass. Also, it is unstable and during storage at ambient environmental conditions it degrades due to formation of unknown impurity/impurities which renders it unsuitable for pharmaceutical formulation. Keeping these observations in mind, it has become a general trend of converting clopidogrel base into pharmaceutically acceptable salts which are crystalline in nature and easily purifiable and exhibit better stability.
Like any synthetic compound clopidogrel base can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, byproducts of the reaction, products of the side reactions, or degradation products. Impurities in clopidogrel base or any active pharmaceutical ingredient (API) are undesirable, and in some cases some impurity/impurities might even be harmful to a patient being treated with a dosage form of the API in which a sufficient amount of such undesired impurity/impurities is/are present. Furthermore, the undesired enantiomeric impurities reduce the level of the API available in the pharmaceutical composition.
It is also known in the prior art that impurities in an API or their intermediate may arise from their degradation, which is related to the stability of the pure API or intermediate thereof during storage and manufacturing process including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities present in starting materials, synthetic byproducts and

degradation products formed during storage. Stability issues may adversely affect the cost of commercializing the intermediate and composition to be sold as drug product. In addition to stability which is related to the shelf life of the intermediate or API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts upto the specified quantity and are preferably substantially absent. For example the ICH Q7A guidance for API manufacturers requires that the process impurities be maintained below set limits by specifying the quality of raw materials and intermediates by controlling process parameters, such as temperature, pressure, time and stoichiometric ratios and including purification steps such as crystallization, distillation and liquid-liquid extraction in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by products of the reaction and adjunct regents used in the reaction may also be present in the product mixture. At certain stages during processing for an API such as clopidogrel pharmaceutically acceptable salts, it must be analyzed for purity typically by HPLC for the clopidogrel base wherein it is used as an precursor intermediate to

determine if it is suitable for continued processing and ultimately for making a pharmaceutical product.
US2009/0264460 discloses a pharmaceutical dosage form comprising clopidogrel base as an active ingredient when processed together with certain pharmaceutically acceptable excipients in the presence of solvents that allows the formation of a premix composition containing clopidogrel base and having enhanced stability.
US2006/0223845 discloses a process for the preparation of clopidogrel base substantially free of solvents allowing for use of base in pharmaceutical formulations on an industrial scale. It discloses that preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability. This indicates the unstable nature of the clopidogrel base.
US2006/0223845 also discloses the clopidogrel base containing less than 0.3% of clopidogrel acid as area % by hplc.
In general there are many factors that contribute to the degradation of the pharmaceutical substance or product including increased storage temperature, exposure to light and adverse interactions between the

active ingredient and excipients in case of pharmaceutical product. Thus, there is a need to improve the stability of pharmaceutical substance. There is also a need to do so in a manner that is mild and non-destabilizing for the API. Further, there is a need to improve the overall stability and longer shelf life of the pharmaceutical substance and intermediates sufficient to meet or exceed government standards. Still further there is a need to provide the pharmaceutical substance having improved stability in a convenient and cost effective manner. Prior art cited hereinabove has focused on the stability issue of pharmaceutical formulation and suitable base for pharmaceutical formulation with controlled limits for residual solvents and also the viscous nature that not only bring the limitation to the formulation of clopidogrel base but also makes difficult for purpose of storage and logistics. However, there has been no prior art relating to the stability of clopidogrel base that can be used as a pharmaceutical active ingredient or as a precursor for the preparation of clopidogrel pharmaceutically accepted salts.
There is a dire need to develop a process for the preparation of clopidogrel base which is stable during storage having longer shelf life which is suitable for use as an API for the dosage form or a suitable intermediate for the preparation of pharmaceutically acceptable salt.
The present invention discloses a process comprising contacting the pure clopidogrel base in neat form or in alcoholic solution/suspension form

with a suitable base that imparts stability to the clopidogrel base by increasing its shelf life and maintaining the purity by checking degradation. Clopidogrel base stabilized by the process disclosed herein is suitable for its use for the preparation of pharmaceutical formulation in dosage form and also as a starting material to prepare a pure pharmaceutically acceptable salt.
Objects of the invention:
First aspect of the invention is to develop a process for the preparation of
clopidogrel base with enhanced stability.
Second aspect of the invention to develop a process for the preparation of
clopidogrel base that will provide longer shelf life.
Third aspect of the invention is to provide stable clopidogrel base as a
pharmaceutical active ingredient.
Forth aspect of the invention is to provide the clopidogrel base with
improved stability as an intermediate for making pharmaceutically
acceptable salts.
Fifth aspect of the invention is to provide clopidogrel base in neat form
with improved stability thereby improving the shelf life.
Sixth aspect of the invention is to provide clopidogrel base as solution or
suspension form in alcoholic medium with improved stability.
Seventh aspect of the invention to provide stable clopidogrel base
suitable for its use for the preparation of pharmaceutical formulation in
dosage form.

Summary of the invention: The present invention relates to a novel process for the preparation of stable clopidogrel base or its alcoholic solution/suspension preferably ethanol having improved stability during storage over extended periods of time for making it suitable for pharmaceutical use and as an intermediate for making pharmaceutically acceptable salts and also suitable for its use for the preparation of pharmaceutical formulation in dosage form. The present invention discloses a process comprising contacting clopidogrel or its solution/suspension in alcohol preferably butan-2-ol or ethanol more preferably ethanol with a suitable organic base selected from primary, secondary, tertiary or quaternary ammonium salts preferably alkyl amines chosen from the group containing mono methyl amine, diethyl amine, triethyl amine more preferably triethyl amine which imparts stability and retains significant pharmaceutical activity during storage. In the present invention, the inventors have come up with a technical solution to enhance the stability of clopidogrel base that can be mainly used as precursor for the preparation of clopidogrel pharmaceutically acceptable salts or for its use for the preparation of pharmaceutical formulation in dosage form. The main feature of the invention lies in the fact that use of an organic base like alkyl amines selected from the group comprising mono methyl amine, diethyl amine, triethyl amine more preferably triethyl amine increases shelf life of product by controlling the impurity formation and also improves the physical parameters like color.

This stability can be achieved in two ways, Firstly by contacting alkyl amines and neat clopidogrel base and secondly by dispersing the clopidogrel base in alcoholic solvents preferably in butan-2-ol or ethanol more preferably in ethanol and contacting with alkyl amine preferably triethyl amine. The specifications of the intermediate and in process controls cover all essential quality aspects required for making the pharmaceutically acceptable salts those can be used as drug substance or for its use for the preparation of pharmaceutical formulation in dosage form. The invention limits one of the unidentified impurity keeping the specifications of the said intermediate satisfactory.
Detailed description of the invention:
While working on the clopidogrel base it has been observed that the clopidogrel base when kept as such at room temperature for three to four days picks up the color and it changes its color to yellow brown resulting in the formation of some impurities. The degradation process sets in immediately during storage under ambient temperature as formation of impurity was observed within a short time. The stability can be improved to a little extent by storing clopidogrel base at lower temperature about 2 to about 8 °C but instability cannot be eliminated completely as during storage at 2-8°C also a reduced quantity of the impurity is formed. Analysis of the prior art and the experience encountered by the inventors clearly demonstrates that the Clopidogrel base has a very short shelf life

and during storage some impurities are formed which makes it unsuitable for pharmaceutical application and also for its use as an intermediate to prepare the corresponding pharmaceutical salt , therefore, there is an urgent need to develop a process in the art to overcome the problem of the degradation of the clopidogrel base during storage and also to increase the shelf life of Clopidogrel base either in its neat state or in solution/suspension form made in permissible solvents like alcohol preferably butan-2-ol or ethanol more preferably ethanol. Intension behind making the solution/suspension is its ease of handling as mentioned hereinabove clopidogrel base is highly viscous liquid. Secondly it is in a penultimate stage of making clopidogrel pharmaceutically acceptable salts. In case of neat clopiogrel base addition of certain alkyl amines enhances the stability by limiting one of the unidentified impurity and thus increases shelf life of the intermediate and also improves over all impurity profile.
In the present invention stability studies have been performed at storage conditions about 2 to about 8°C and at about 20 to about 25°C both with and without base. It has been observed that by contacting the clopidogrel base with a suitable organic solvent unidentified unknown individual impurity gets limited to permissible limit. Stability results are given herein below in Table-1

In the present invention clopidogrel base is obtained by basification of clopidogrel bisulphate salt and extracting with suitable solvent followed by washing with sodium bicarbonate. Solvent is removed under the reduced pressure and finally alkyl amines preferably triethyl amine is mixed with a neat base or its alcoholic solution to get clopidogrel base or its alcoholic solution preferably in ethanol with improved stability.
Table I

Clopidogrel Base without TEA (2 to 8 °C)

S.No. Test Specifications Initial After 01
week After 02
week After 03 . week After 01
Month After 02 Month
Description Yellow viscous liquid. Yellow viscous liquid. Yellow
viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow
viscous liquid. Yellow
viscous liquid.
Related
Substances 99.27% 99.29% 99.05% 98.92% 98.62% 97.88%

Imp-A NMT 0.2 % BDL BDL BDL BDL BDL 0.03%

Imp-B NMT0.3 % 0.14% 0.12% 0.18% 0.18% 0.17% 0.14%

Imp-C NMT 1.0% 0.50% 0.45% 0.48% 0,47% 0.48% 0.49%

Any other individual impurity NMT 0.1 % 0.04% 0.13% 0.14% 0.23% 0.42% 0.96%

Total imp NMT 1.5% 0.73% 0.71% 0.95% 1.08% 1.38% 2.12%
Remarks Unk 0.11%at RT 1.804
min Unk 0.08%at RT 1.84
min Unk 0.34%al RT2.117
min
Analysis date 12.012.09 20.12.09 29.12.09 04.01.10 11.01.10 12.03.10

Clopidogrel Base with TEA (2 to 80C)

S.No. Test Specifications Initial After 01 week After 02 .week After 03 week After 01 Month After
02 Month
1 Description Yellow viscous liquid. Yellow
viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid.
2 Related Substances 99.27% 99.39% 99.11% 98.94% 98.95% 98.92%
3 Imp-A NMT 0.2 % BDL 0.01% BDL BDL 0.01% 0.01%

Imp-B NMT0.3 % 0.14% 0,11% 0.1 fc% 0.17% 0.18% 0.16%

Imp-C NMT 1.0% 0.50% 0.41% 0.4$% 0.47% 0.48% 0.48%

Any other individual
impurity NMT 0.1% 0.04% 0.07% 0.13% 0.21% 0.19% 0.24%

Total imp NMT 1.5% 0.73% 0.61% 0.85% 1.06% 1.05% 1.08%
Remarks Unk 0.09%at RT 12.34
min Unk 0.03%ai RT 12.65
min Unk 0.ll%at RT 11.55 min
Analysis date 12.012.09 20.12.09 29.1>()9 04,01.10 11.01.10 12.03,10
Table I describes the purity pattern when the material is stored at temperature of about 2 to about 8°C without the addition of triethyl amine. Analysis of the table I contents reveal that HPLC purity of the clopidogrel neat base stored at about 2 about 8°C without adding triethyl amine reaches to about 97.88% from initial about 99.27% in a period of about 2 months. During this study it has been observed that there is no change as such in impurity levels of known impurities viz A, B and C but an unidentified unknown impurity increases to about 0.96% from initial about 0.04%, thus affecting the overall purity of the clopidogrel base. The total impurities also increase from 0.73% which is within specified limits of 1.5% to 2.12% which is more than the specified limit of 1.5%. The degradation of clopidogrel base during storage makes the material

unsuitable for its use as a pharmaceutical product for dosage form and also as an intermediate for preparing pure pharmaceutical salt.
However the addition of triethyl amine to the clopidogrel base shows a remarkable change. Analysis of the table II reveal that HPLC purity of the clopidogrel neat base stored at about 2 to about 8°C with addition of triethyl amine shows a less detoriation and purity gets reduced to about 98.92% compared to 97.88% when triethylamine is not used from initial purity of about 99.27% in a period of about 2 months. During this study it has been observed that there is no change as such in impurity levels of known impurities viz A, B and C but an unidentified unknown impurity increases to about 0.24% compared to 0.96% when triethyl amine is not used as an stabilizer from initial 0.04%, thus showing a better result over the finding of table I and improves overall purity of the clopidogrel base. Therefore it can be concluded that addition of triethyl amine base in neat clopidogrel base stored at temperature of about 2-8°C reduces the said impurity by about 75%. The total impurities in an unstabilised clopidogral base after 2 months storage increases from 0.73% to 1.08% compared to specification of 1.5%, therefore, the product after 2 months storage is suitable for pharmaceutical application and also for its use as an intermediate to obtain pure corresponding pharmaceutical salt.

Therefore it can be concluded that safe storage of clopidogrel base can be best achieved at about 2 to about 8°C and by adding triethyl amine as a stabilizer thereby increasing shelf life of the material.
Table III
Clopidogrel Base without TEA (20 to25 °C)

S.No. Test Specifications Initial After 01 week After 02 week After 03 week After 01 Month After 02 Month
1 : Description Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow
viscous liquid. Yellow
viscous liquid. Yellow viscous liquid. Yellow
viscous liquid.
2 Related Substances 99.27% 99.31% 99.06% 99.04% 99.12% 98.25%
3 Imp-A NMT 0.2 % BDL 0.01% BDL BDL BDL 0.03%

Imp-B NMT0.3 % 0.14% 0.11% 0.18% 0.18% 0.17% 0.18%

Imp-C NMT 1.0 % 0.50% 0.49% 0.47% 0.48% 0.47% 0.47%

Any other individual impurity NMT 0.1 % 0.04% 0.07% 0.38% 0.17% 0.13% 0.77%

Total imp NMT 1.5% 0.73% 0.69% 0.94% 0.96% 0.88% 1.75%
Remarks Unk 0.04%at
RT 1.86min Unk 0.03%at RT 1.82
min Unk 0.17%at RT 5.26
min
Analysis date 12.012.09 20.12.09 29.12.09 04.01.10 11.01.10 12.03.10

Table IV
Clopidogrel Base with TEA (20 to 25°C)

S.No. Test Specifications Initial After 01 week After 02 week After 03 week After 01 Month After 02 Month
1 Description Yellow viscous liquid. Yellow viscous liquid. Yellow
viscous liquid. Yellow
viscous liquid. Yellow viscous
liquid. Yellow viscous liquid. Yellow viscous liquid.
2 Related Substances 99.27% 99.38% 99.19% 99.05% 99.12% 99.08%
3 Imp-A NMT 0.2 % BPL 0.01% BDL BDL 0.01% BDL

Imp-B NMT0.3 % 0.14% 0.10% 0.17% 0.09% 0.17% 0.18%

Imp-C NMT 1.0% 0.50% 0.43% 0.46% 0.48% 0.49% 0.44%

Any other individual impurity NMT 0.1% 0.04% 0.06% 0.09% 0.11% 0,10% 0.18%

Total imp NMT 1.5% 0.73% 0.62% 0.81% 0.95% 0,88% 0,92%
Remarks Unk 0.04%al
RT
13.5 min Unk 0.03%at
RT I2.8min Unk 0.02%at RT11.9
min
Analysis date 12.012.09 20.12.09 29,12,09 04,01.10 11.01.10 12.03.10
Table III describes the purity pattern when the material is stored at temperature of about 20 to about 25°C without the addition of triethyl amine. Analysis of the table III contents reveal that HPLC purity of the clopidogrel neat base stored at about 20 to about 25°C without adding triethyl amine reaches to about 98.25% from initial about 99.27% in a period of about 2 months. During this study it has been observed that there is no remarkable changes as such in impurity levels of known impurities viz A,B and C but an unidentified unknown impurity increases to about 0.77% from initial about 0.04%,thus affecting the overall purity of the clopidogrel base. The total impurities also increase from 0.73% which is within specified limits of 1.5% to 1.75% which is more than the specified limit of 1.5%. The degradation of clopidogrel base during storage makes the material unsuitable for its use as a pharmaceutical

product for dosage form and also as an intermediate for preparing pure pharmaceutical salt.
However the addition of triethyl amine to the clopidogrel base shows a remarkable change. Analysis of the table IV reveal that HPLC purity of the clopidogrel neat base stored at about 20 to about 25°C with addition of triethyl amine shows a better control over the unidentified unknown impurity making it to reach at about 99.08.% compared to 98.25% when triethyl amine is not used from initial purity of about 99.27% during a period of about 2 months. During this study it has been observed that there is no change as such in impurity levels of known impurities viz A,B and C but an unidentified unknown impurity increases only upto about 0.18% from initial about 0.04% indicatingf that addition of triethyl amine improves the stability of clopidogrel base during storage thus increasing its shelf life. Therefore it can be concluded that addition of triethyl amine base in neat clopidogrel base stored at temperature of 20-25°C reduces the said impurity by about 77% during 2 months storage time. The total impurities in an unstabilised clopidogral base after 2 months storage increases from 0.73%) to 0.92% compared to specification of 1.5%, therefore, the product after 2 months storage is suitable for pharmaceutical application and also for its use as an intermediate to obtain pure corresponding pharmaceutical salt.

Therefore it can be concluded that stability and shelf life of the clopidogrel base can be best controlled at temperature of 20-25°C by the addition of triethylamine and without any extra efforts for maintaining cold temperature condition of about 2 about 8°C.
Table V

Clopidogrel base in ethanol (50% w/w) without triethyl amine at 2-8 °C
S.No. Test Specifications Initial After 01 week
Description Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid.
Related Substances 99.06% 99.04%
Imp-A NMT 0.2 % 0.18% 0.17%

Imp-B NMT0.3 % 0.02% 0,02%

Imp-C NMT 1.0% 0.64% 0.63%

Any other individual impurity NMT 0.1% 0.07% 0,10%

Total imp NMT 1.5% 0.88% 0.92%
Remarks
Analysis date 12.012.09 20.12.09

Table VI

Clopido grel base in ethanol (50% wAv) with triethyl amine at 2-8 °C
S.No. Test Specifications Initial After 01
week After 02 week After 01
Month After 02 Month
1 Description Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid. Yellow viscous liquid.
' 2 Related Substances 99.06% 99.04% 99.00% 99.01% 99.08%
3 Imp-A NMT 0.2 % 0.14% 0.14% 0.15% 0.17% 0.18%

lm