Claims:1. A stable pharmaceutical composition comprising (7aS,2’S)-2-oxoclopidogrel or its pharmaceutically acceptable salt and at least one pharmaceutical adjuvant(s), initially containing less than 0.2% by weight of a corresponding Hydroxy-impurity of formula IX, which after one year of storage at 25°C±2°C and 60%±5% atmospheric humidity wherein the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel.

2. The pharmaceutical composition of claim 1, wherein the composition initially containing not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and after storage for one year or more at 25°C±2°C and 60%±5% atmospheric humidity, where in impurities of formula X & XI remain less than 0.2%.

3. The pharmaceutical composition of claim 1, wherein at least one adjuvant is selected from the group consisting of Microcrystalline cellulose (MCC), HPMC, Mannitol, Croscarmellose sodium, Colloidal silicon dioxide, Magnesium stearate (vegetable grade), Hypromellose, Polyethylene glycol, Talc, and Titanium Dioxide.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical salt is bisulphate salt.

5. The pharmaceutical composition of claim 3, wherein the adjuvants are substantially free from peroxides or other oxidizing agents wherein their contents are below 100 ppm.

6. The pharmaceutical composition of claim 1, wherein the in-use period is 60 days after one year of storage at 25°C±2°C and 60%±5% atmospheric humidity wherein the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel.

7. The pharmaceutical composition of any one of the preceding claim 1 to 6, wherein the storage period is 2 years.

8. (7aS,2’S)-2-oxoclopidogrel or its pharmaceutically acceptable salt containing less than 0.1% of the corresponding Hydroxy-impurity of Formula IX and which, after one year of storage at 25°C±2°C and 60%±5%humidity, the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX does not exceed 0.2% by weight of (7aS,2’S)-2-oxoclopidogrel .

9. The (7aS,2’S)-2-oxoclopidogrel and/or pharmaceutically acceptable salt as claimed in claim 8, wherein the pharmaceutical salt is bisulphate salt.

10. A stable oral solid pharmaceutical formulation containing (7aS,2’S)-2-oxoclopidogrel or its pharmaceutically acceptable salt initially containing not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and less than 0.2% of a corresponding Hydroxy-impurity of Formula IX and after storage for one year or more at 25°C±2°C and 60%±5% atmospheric humidity the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel, where in impurities of formula X & XI remain less than 0.2%.

11. A moisture impervious barrier packing for (7aS,2’S)-2-oxoclopidogrel and/or a pharmaceutically acceptable salt containing not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and contains less than 0.2% of a corresponding Hydroxy-impurity of Formula IX and after storage for one year or more at 25°C±2°C and 60%±5% atmospheric humidity, comprising at least 2 layered packing of moisture impervious HDPE or aluminium foil sheet layers with a gauge of 500 units or more to arrest the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX that does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel, wherein, the impurities of formula X & XI remain less than 0.2%.

12. The moisture impervious barrier packaging as per claim 9, wherein the packaging is three layered moisture impervious HDPE or Aluminium foil sheet having a thickness of 500 gauge and more.

13. A process for preparation of pure and stable (7aS,2’S)-2-oxoclopidogrel and/or its pharmaceutically acceptable salts containing not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and contains less than 0.2% of a corresponding Hydroxy-impurity of Formula IX comprising the following steps:
a) reacting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one HCl with a base such as sodium bicarbonate in a suitable solvent;
b) reacting the reaction mass from step (a) with a solution of Methyl (7)-2-(4-nitrophenylsulfonyloxy)-2(2-chlorophenyl)acetate in a dry solvent at about 45-55oC under nitrogen atmosphere wherein the water content is less than 0.5%;
c) Extracting the reaction residue obtained in step (b) in a suitable solvent such as ethyl acetate, and washing the organic layer with water till the washings pH is below 5 to 6 and concentrating organic layer to a residue;

d)Crystallizing the oily residue from a suitable solvent such as mixture of ethyl acetate & methanol under nitrogen atmosphere wherein the solvent moisture does not exceed 0.5% to yield Methyl (7aS,2'S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate; and

e) Optionally, converting the Methyl (7aS,2'S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate to its bisulphate salt by treating Methyl (7aS,2'S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate with concentrated suphuric acid in a suitable solvent such as dry acetone in an inert gas atmosphere.

14. The process according to claim 13, wherein the dry solvent in step (b) is ethyl acetate.
, Description:Technical field of invention:
The present invention relates to stable oral pharmaceutical composition containing therapeutically effective amount of (7aS,2’S)-2-oxoclopidogrel and/or its salts or derivatives, in combination with pharmaceutically acceptable adjuvants or carriers. More particularly, the present invention relates to highly pure (7aS,2’S)-2-oxoclopidogrel and/or its salts, processes for manufacturing pure and stable (7aS,2’S)-2-oxoclopidogrel and stable compositions having a shelf-life of at least one year or more.

Background of the invention:
Conditions resulting from thrombotic or thromboembolic events are the leading causes of illness and death in adults in western civilization. Intravascular thrombosis and embolism are common clinical manifestations of many diseases. Unregulated activation of the hemostatic system has the potential to cause thrombosis and embolism, which can reduce blood flow to critical organs like the brain and myocardium. Certain patient groups have been identified that are particularly prone to thrombosis and embolism. These include patients (1) immobilized after surgery, (2) with chronic congestive heart failure, (3) with atherosclerotic vascular disease, (4) with malignancy, or (5) who are pregnant. The majority of "thrombosis prone" individuals have no identifiable hemostatic disorder, although there are certain groups of individuals having inherited or acquired "hypercoagulable" or "prethrombotic" conditions predisposing them to recurrent thrombosis (Harrison's Principles of Internal Medicine, 12th ed. McGraw Hill).

Effective primary hemostasis requires three critical events: platelet adhesion, granule release, and platelet aggregation. Within a few seconds of injury, platelets adhere to collagen fibrils in vascular subendothelium. This interaction is facilitated by von Willebrands factor, an adhesive glycoprotein which allows platelets to remain attached to the vessel wall despite the high shear forces generated within the vascular lumen. Von Willebrand's factor accomplishes this task by forming a link between platelet receptor sites and subendothelial collagen fibrils.

As the primary hemostatic plug is being formed, plasma coagulation proteins are activated to initiate secondary hemostasis. There is little difference between hemostatic plugs, which are a physiological response to injury, and pathologic thrombi. Thrombosis is often described as coagulation which has occurred in the wrong place or at the wrong time. Hemostatic plugs or thrombi that form in veins where blood flow is slow are richly endowed with fibrin and trapped red blood cells and contain relatively few platelets. These thrombi often form in leg veins and can break off and embolize to the pulmonary circulation. Conversely, clots that form in arteries under conditions of high flow are predominantly composed of platelets and have little fibrin. These arterial thrombi may readily dislodge from the arterial wall and embolize to distant sites to cause temporary or permanent ischemia. This is particularly common in the cerebral and retinal circulation and may lead to transient neurologic dysfunction (transient ischemic attacks) including temporary monocular blindness (amaurosis fugax) or strokes. In addition, there is increasing evidence that most myocardial infarctions are due to thrombi which form within atherosclerotic coronary arteries. (The preceding discussion is taken primarily from Harrison's Principles of Internal Medicine, 12th ed., McGraw Hill.

Extracellular nucleotides and their receptors of platelets are important components of the cardiovascular system and are involved in functions like platelet activation and the control of vascular tone. Adenosine diphosphate (ADP) and Adenosine Triphosphate (ATP), are playing crucial roles in the physiological process of haemostasis and in the development and extension of arterial thrombosis (2). By itself ADP is a weak agonist of platelet aggregation inducing only reversible responses as compared to strong agonists such as thrombin or collagen. However, due to its presence in large amounts in the platelet dense granules and its release upon activation at sites of vascular injury, ADP is an important so-called secondary agonist which amplifies most of the platelet responses and contributes to the stabilization of the thrombus. The receptors for extracellular nucleotides belong to the P2 family which consists of two classes of membrane receptors: P2X ligand-gated cation channels (P2X1–7) and Glycoprotein-coupled P2Y receptors (P2Y1,2,4,6,11,12,13,14). Each of these receptors has a specific function during platelet activation and aggregation, which naturally has implications for their involvement in thrombosis.

Since ADP and ATP play a crucial role in platelet activation, their receptors are potential targets for antithrombotic drugs. The ATP-gated cation channel P2X1 and the two G protein-coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus. Owing to its central role in the growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs mainly the thienopyridine class of compounds like ticlopidine, clopidogrel, prasugrel etc...

The mainstay of antiplatelet therapy for patients with acute coronary syndromes (ACS), including those undergoing early percutaneous coronary intervention (PCI) and stents implantation is administration of a combination of Aspirin and clopidogrel. Aspirin inhibits platelet thomboxane A2 production and platelet activation, and reduces the risk of recurrent ischemic events in patients at high risk of vascular events by 22% (absolute risk reduction (ARR) about 2%) at the expense of an increase in the odds of major bleeding events by about 60% (Absolute risk increase (ARI) about 0.5%. Clopidogrel inhibits ADP induced platelet activation by blocking the platelet receptor P2Y12, which when combined with Aspirin therapy in patients with ACS, reduces the risk of recurrent ischemic events by a further 20% (ARR about 2.1%), in which the major bleeding events are not increased statistically from aspirin monotherapy.

Clopidogrel (Formula I), chemically named as “’ (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate”, is currently considered to be the gold standard in the inhibition of blood platelet aggregation. Clopidogrel is marketed as its hydrogen sulphate (also termed as bisulphate), hydrochloride, and benzene sulphonate salts. It is widely used for controlling the ischemic events and other cardiovascular disorders efficiently for last 20 years or more.

Formula I: Clopidogrel

2-oxo-clopidogrel is an intermediate metabolite formed during the oxidative metabolic step, as shown in below scheme 1.

Scheme 1: Metabolic path of clopidogrel

The active metabolite of clopidogrel has the structure given in formula III, and it has been documented that only one of the isomer is found to inhibit platelet, however, its absolute configuration is not yet determined. Active metabolite of 4R,1’S-isomer is reported in literature (Hagihara et al, Drug Metab. Pharmacokinet. 23 (6): 412–420 (2008) & Proceedings of the 54th ASMS Conference on Mass Spectrometry and Allied Topics, 2008). Use of the active metabolite as a therapeutic compound is not proposed in literature for none of the thienopyridine derivatives due to its transient & highly reactive character. In the 1st oxidative metabolic step, Clopidogrel metabolizes to 2-oxoclopidogrel, and three different isomers are expected from the oxidation of clopidogrel at 2-position, all may be interchangeable to each other, which are as follows:

(7aS,2’S)-2-oxo-clopidogrel is proposed as improved alternative to Clopidogrel in Patent No. US8536337 (Incorporated herein by reference), wherein (7aS,2’S)-2-oxo-clopidogrel in free form or as acid addition salt like bisulphate salt is suggested to reduce the inter-individual variability and clopidogrel resistance in certain patient groups. (7aS,2’S)-2-oxo-clopidogrel bisulphate at nearly 1/10th of the dose of clopidogrel is also reported to provide an equivalent activity to clopidogrel while providing platelet inhibition to patients those are non-responsive to clopidoogrel. Non-responsiveness to clopidogrel may be due to certain CYP polymoprhisms in some patient groups or may be due to resistance to clopidogrel in certain patients for reasons not known so far.

(7aS,2’S)-2-oxoclopidogrel is having the chemical structure of formula II A, wherein its opposite diasteriomer (7aR,2’S)-2-oxoclopidogrel is having the chemical structure of formula IIB :

(7aS,2’S)-2-oxoclopidogrel, currently under clinical development, is proposed for indications to prevent heart attack and stroke in people who are at high risk of these events, including those with a history of myocardial infarction and other forms of acute coronary syndrome, stroke, and those with peripheral artery disease. One of the main challenges of developing (7aS,2’S)-2-oxoclopidogrel is to isolate the product in substantially pure isomeric form. This problem has been addressed in US8536337, wherein (7aS,2’S)-2-oxoclopidogrel is isolated in substantially pure form having levels of other isomer of formula IIB content less than 1%.

However, there are still major challenges faced to develop (7aS,2’S)-2-oxoclopidogrel as a drug for pharmaceutical use due to following issues:
a) It is difficult to maintain the isomer impurity levels of pure drug on long term storage as it has a tendency to inter-convert to its isomers upon storage for 6 months to 2 years. Repeated purifications from selective solvents do not remove isomer impurities as (7aS,2’S)-2-oxoclopidogrel continue to isomerizes to yield formula IIB through an endo isomer of formula VII to certain equilibrium levels.
b) Its susceptibility to isomeric conversion during physical processing for manufacturing the compound into an oral solid dosage form for pharmaceutical application in a conventional manner. This is a significant challenge, as the product for end use is to be formulated into an oral solid dosage form that is readily accessible to patients and no special precautions for storage would be necessary and remain stable during the end use period when supplied in specific pack sizes like 30 days course.
c) Another major challenge is long term storage & in-use stability of (7aS,2’S)-2-oxoclopidogrel dosage form as the drug assay likey to drop significantly over time without displaying any major impurities under normal analytical conditions of detection, in the parent drug or dosage form. Reasons for degradation in the solid oral dosage form are not known so far.
United States Patent No. US 8536337 to Ashok Kumar et al. discloses preparation of (7aS,2’S)-2-oxoclopidogrel bisulphate in good isomeric purity but long-term storage of (7aS,2’S)-2-oxoclopidogrel presents several problems since (i) during the preparation of oral solid pharmaceutical composition, it shows considerable variations in isomers of Formula IIB, and formula VII without apparent reason, and (ii) the long-term storage of even very pure (7aS,2’S)-2-oxoclopidogrel showed differing stabilities with progressively long storage times. According to Ashok Kumar et al, presence of other isomers of (7aS,2’S)-2-oxoclopidogrel in the final product can be limited, if not eliminated, to their content levels by less than 1%. To combat impurity formation and provide product stability in the formulation, Ashok Kumar et al, stresses the importance of (i) starting with (7aS,2’S)-2-oxoclopidogrel raw material that contains lower content of opposite isomers , and (ii) not allowing the compound to isomerizes in reaction conditions.

According to Ashok Kumar, the following pharmaceutically acceptable adjuvants (or excipients) had no noticeable influence on the stability of (7aS,2’S)-2-oxoclopidogrel , and as such, they were taught to be acceptable adjuvants for use with (7aS,2’S)-2-oxoclopidogrel: calcium phosphates, such as dibasic calcium phosphate, anhydrous dibasic calcium phosphate, tribasic calcium phosphate, etc.; microcrystalline cellulose, powdered cellulose; starch, pre-gelatinized starch; sodium starch glycolate; dextrates; mannitol, sorbitol; povidone; ethyl cellulose; lactose; kaolin; silicic acid; lubricants such as magnesium stearate, calcium stearate, stearic acid, mineral oil, glycerin, sodium lauryl sulfate, polyethylene glycol; Sodium starch glycolate, talc, etc.

The composition and methods disclosed in Ashok Kumar have now been found that Ashok Kumar's reliance for conventional solid oral dosage form lead to degradation of (7aS,2’S)-2-oxoclopidogrel on storage and control of other known external parameters like moisture, air, light etc., alone are not helping to prevent mass degradation of (7aS,2’S)-2-oxoclopidogrel .

It has been found that though protective coating of the dosage forms are helpful, however, in the present case do not arrest degradation of the (7aS,2’S)-2-oxoclopidogrel within the dosage form as evident from generation of a darker discolouration within the tablet core. In-use stability is, therefore, a major concern due to unavoidable exposure of dosage form during the use by patients and stabilizing the (7aS,2’S)-2-oxoclopidogrel is indeed a serious challenge to both synthetic chemist and pharmaceutical chemists.

It has been found that storage of pure (7aS,2’S)-2-oxoclopidogrel at freezing temperatures 0-8oC adds more stability, though control of many factors were necessary for maintaining adequate stability for active ingredient. It is been a major challenge to make solid dosage forms stable for storage at ambient temperature conditions and during transport across globe and it is impractical to use cold conditions for storage and transport. It has been found that certain impurities present in (7aS,2’S)-2-oxoclopidogrel is likely triggering more degradations of parent molecule and thereby significantly dropping the product assay of parent drug in dosage form as well as in pure drug. The pharmaceutical formulations of (7aS,2’S)-2-oxoclopidogrel thus cannot be prepared and stored for long term use as such with the available domain expertise/knowledge.

Therefore there are unmet medical needs, which are not being offered by available knowledge for production of the active ingredient (7aS,2’S)-2-oxoclopidogrel in stable from.

Therefore there is a need to provide improved (7aS,2’S)-2-oxoclopidogrel or its salts which is stable for long term storage for at least 1 year, more preferably more than 2 years, still more preferably over 3 years of storage and qualify an in-use stability for dosage forms to carry out safe administrations of required strength of doses for intended medical uses during the purported shelf-life.

Summary of the Invention:
Surprisingly, it has been found that certain impurities, generated during synthesis of (7aS,2’S)-2-oxoclopidogrel or being generated during storage of (7aS,2’S)-2-oxoclopidogrel, are likely to act as initiators & accelerators for degradation of (7aS,2’S)-2-oxoclopidogrel into small fragments that may not be detected in standard HPLC/GC analytical conditions and as such reflects on significant loss of drug as expressed by drop of assay of parent drug in dosage forms or active ingredient.
A multitude of factors may trigger the degradation of (7aS,2’S)-2-oxoclopidogrel while the impurities formation is found to be major impediment for obtaining a stable (7aS,2’S)-2-oxoclopidogrel or its salt, thereby hindering its conversion into a pharmaceutical oral solid dosage form for end use.

Accordingly, the present invention provides a solid oral pharmaceutical composition containing a pharmaceutically effective amount of (7aS,2’S)-2-oxoclopidogrel, which initially contains less than 0.2% of a corresponding Hydroxy-impurity of Formula IX and after one year of storage at 25°C±2°C and 60%±5% atmospheric humidity, the conversion of (7aS,2’S)-2-oxoclopidogrel into its corresponding Hydroxy-impurity of Formula IX does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel. Preferably the storage period is 2 years or more.

The present invention also provides a process for preparing pure & stable (7aS,2’S)-2-oxoclopidogrel, which initially contains not more than 0.1% of corresponding Hydroxy impurity of formula IX and after one year of storage at 25°C±2°C and 60%±5% atmospheric humidity does not exceed the conversion of (7aS,2’S)-2-oxoclopidogrel into its Hydroxy impurity by not more than 0.2% in the pure (7aS,2’S)-2-oxoclopidogrel active ingradient.

In another embodiment, the present invention provides a solid oral pharmaceutical formulation of (7aS,2’S)-2-oxoclopidogrel containing not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and contains less than 0.2% of a corresponding Hydroxy-impurity of Formula IX and after storage for one year or more at 25°C±2°C and 60%±5% atmospheric humidity, the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel, wherein, the individual impurities of formula X & XI remain less than 0.2%.

Brief description of Figures
Figure 1. A representative HPLC chromatogram of (7aS,2’S)-oxo-clopidogrel bisulphate run on Chiralpak AD-H column.

Figure 2. A representative HPLC chromatogram of (7aS,2’S)-oxo-clopidogrel bisulphate after treating in oxidative condition at 25oC indicating high degradation

Figure 3. A representative HPLC chromatogram of (7aS,2’S)-oxo-clopidogrel bisulphate after treating in oxidative condition at 60oC showing complete degradation

Figure 4. A representative HPLC chromatogram of (7aS,2’S)-oxo-clopidogrel bisulphate run on Chiralpak AD-H column after maintaining (7aS,2’S)-oxo-clopidogrel bisulphate under mild basic condition at ambient temperature of 25oC for 1.5 hours showing significant degradation.

Figure 5. A representative HPLC chromatogram of (7aS,2’S)-oxo-clopidogrel bisulphate after maintaining in mild basic condition at 25oC for 100 hours showing almost complete degradation

Figure 6. A representative HPLC chromatogram of (7aS,2’S)-oxo-clopidogrel bisulphate run on Chiralpak AD-H column after maintaining in acidic condition at 60oC for 1 hour indicating degradation.

Figure 7. A representative HPLC chromatogram of (7aS,2’S)-oxo-clopidogrel bisulphate run on Chiralpak AD-H column upon exposing in atmospheric air for 22 days indication slow degradation..

Detailed description of the preferred embodiments of the invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," “containing”, "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.

It has now surprisingly been found that it is possible to isolate a substantially pure (7aS,2’S)-2-oxo-clopidogrel (Formula IIA) or as a pharmaceutically acceptable salt, free from certain impurities that trigger further conversion & degradation of (7aS,2’S)-2-oxo-clopidogrel into multiple impurities. The present invention meets the long felt need in the treatment of thrombosis and embolism and associated disease conditions, wherein (7aS,2’S)-2-oxo-clopidogrel or its salts can be formulated into a pharmaceutically acceptable solid oral dosage form stable for long term storage and stable for in-use at bed side for patients for the stipulated periods.

The subject invention will now be described in greater detail for preferred embodiments of the invention, it being understood that these embodiments are intended only as illustrative examples and the invention is not to be limited thereto.

As will be illustrated through exemplary embodiments, (7aS,2’S)-2-oxoclopidogrel may be prepared in free form or any salt form such as bisulphate salt of (7aS,2’S)-2-oxoclopidogrel and that in purified form (7aS,2’S)-2-oxoclopidogrel may contain not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and contains less than 0.5% of a corresponding Hydroxy-impurity of Formula IX.

Though there are numerous impurities possible to get generated in (7aS,2’S)-2-oxoclopidogrel, following are the major impurities to be controlled and how each impurity contributes not only to the degradation of parent drug but also to the degradation of impurities present in the product, thus further degrade to secondary impurities are shown below.

Impurity of formula VII (Endo) Impurity of formula IIB (isomer impurity)

Impurity of Formula V (Acid impurity) Impurity of formula IX (Hydroxy impurity)

Impurity of Formula XI (Sulfonic acid) Impurity of formula III (active metabolite)

Impurity of Formula X
It is reported that clopidogrel active metabolite of formula III is formed by metabolic conversion of 2-oxoclopidogrel in the liver after ingestion orally by CYP 450 enzymes. Contrary to current knowledge that the active metabolite structure of formula III is formed due to CYP metabolism, it is now found as a degradation product in (7aS,2’S)-2-oxoclopidogrel. Present invention reveals Degradation of pathway for (7aS,2’S)-2-oxoclopidogrel in generating Impurity of formula III (active metabolite) in scheme II. It is seen that moisture or water can degrade the parent drug to its very reactive & labile active metabolite and thus in turn can degrade or convert to other products.
Scheme II.

Being a very reactive compound, active metabolite impurity degrades or in turn reacts to dimerize to form further impurities in (7aS,2’S)-2-oxoclopidogrel. The degradation pathway of Impurity of formula III (Active metabolite) is shown below scheme III.

Scheme III

Formula XI

Formula XIV
Further, it is known that the primary degradation of (7aS,2’S)-2-oxoclopidogrel in presence of moisture/water is leading to its corresponding acid impurity of formula V, however, contrary to the belief, it has been found that the predominant degradation of (7aS,2’S)-2-oxoclopidogrel in presence of moisture/water is through addition of a water molecule at the endo-cyclic double bond to form hydroxy impurity of formula IXI, which may be predominantly getting generated from (7aS,2’S)-2-oxoclopidogrel endo-impurity of formula VII.

(7aS,2'S)-2-oxoclopidogrel endo-impurity

Formula IX Formula IX
It is apparent that the endo-isomer impurity (Formula VII) is in a kind of equilibrium with (7aS,2’S)-2-oxoclopidogrel and water addition to endo-isomer will trigger further degradation of (7aS,2’S)-2-oxoclopidogrel into its corresponding endo isomer by way of switching the equilibrium to generate more & more Hydroxy-impurity of formula IX. An additional pathway for formation of Hydroxy impurity is via air oxidation of (7aS,2’S)-2-oxoclopidogrel. Surprisingly, the Hydroxy impurity is found to be a very labile structure and apparently undergoes degradation into multiple other impurities according to below pathways and this cycle continuously degrade (7aS,2’S)-2-oxoclopidogrel into various impurities to drop its content in product assay by a great extent.

Formula IX Formula XII


Formula XIII Formula X

Ashok Kumar et el. states in US8536337 that it is a major challenge for them to provide a pure diasteriomer of (7aS,2’S)-2-oxoclopidogrel due to the labile nature of the chiral centre in the endocyclic ring “(7aS)” position, mainly attributed to the tautomeric conversions of the (7aS,2’S)-2-oxoclopidogrel as depicted below, which not only creates the unwanted isomer, but also leads to degradation of the (7aS,2’S)-2-oxoclopidogrel upon further powder processing, storage and in-use.

(7aS,2'S)-2-oxoclopidogrel (2'S)-2-oxoclopidogrel (7aR,2'S)-2-oxoclopidogrel
(Single chiral centre)
It is also been found that the above conversions can be triggered not only by Air, moisture, temperature but also by physical processing or adjuvants used in the pharmaceutical composition as reactive impurities as depicted above are getting generated during processing or storage. Below table shows increase in impurity levels after preparation of oral solid dosage form under two humidity conditions.
Sl. No. Impurity Impurity Content levels in API Content after formulation in controlled humidity <35% RH Content after formulation in normal humidity 50-60% RH
1 Impurity of Formula VII 0.12% 0.492% 0.62%
2 Impurity of Formula IIB 0.11% 0.85 % 1.28%
3 Hydroxy impurity of Formula IX <0.02% 0.1% 0.18%
4 Impurity of formula V Not detected(ND) ND ND
5 Water content by KF 0.15% 2.06% 2.45%
6 Assay by HPLC 99.4% 97.9% 95.9%
Note: (7aS,2’S) -2-oxoclopidogrel prepared according to process of present invention is used to demonstrate above conversion in the manufacture of solid oral dosage form. ND: below detection limit (detection limit is 0.02%)

From the data above, it is clear that even a highly pure sample of API is leading to partial conversion of (7aS,2’S) -2-oxoclopidogrel into its (2’S) -2-oxoclopidogrel endo impurity of Formula IX and thereby generating (7aR,2’S) -2-oxoclopidogrel impurity (Formula IIB) in the drug product immediately after producing the solid dosage form.
[0049] However, upon storage of tablets of (7aS,2’S)-2-oxoclopidogrel bisulphate over few years demonstrates degradation of (7aS,2’S) -2-oxoclopidogrel as per data shown below:
Test Specification Initial In-use stability sample 1 In-use stability sample 1 Storage after 2 years in HDPE bottle with 3 Silica canisters & rayon, packed in secondary Tripple laminated aluminium 1 mm thikness)
Related substance Impurity of Formula VII 0.226% 0.20% 0.19% 0.25%
Impurity of Formula IIB 0.825 % 0.81% 0.70% 0.59%
Hydroxy impurity of Formula IX 0.036% 1.53% 2.20% 0.09%
Impurity of formula V ND 0.01% 0.02% ND
Impurity of Formula XI ND 0.03% 0.06% ND
Impurity at RT 1.9 ND 0.11% 0.38% 0.01%
Moisture content Water content by KF 2.06% 2.4% 2.82% 2.26%
Assay Assay by HPLC 97.9% 84.39% 74.54% 101.5%
ND: below detection limit (detection limit is 0.02%)

It is surprisingly been found that there is no apparent change in impurity content of isomer of formula IIB and endo-isomer of formula VIII. But increase in Hydroxy-impurity of formula IX leads to sharp decline in assay of (7aS,2’S) -2-oxoclopidogrel indicating significant degradation of (7aS,2’S) -2-oxoclopidogrel. Hydroxy-impurity of formula IX when controlled in the finished oral dosage form, stability of (7aS,2’S) -2-oxoclopidogrel dosage form is achieved in conjunction with protective packing materials used as per the present invention described in this document.

According to the present invention, a substantially pure active ingredient (7aS,2’S) -2-oxoclopidogrel bisulphate stored over a period is shown to be stable if the Hydroxy impurity of formula IX is substantially below 0.5%, confirming that the hydroxy impurity progression adversely affects the stability of (7aS,2’S) -2-oxoclopidogrel.
Tests Specification PP2001 AURI 2001
AURI 2002
AURI 2003
AURI 2004
AURI
Related Substances
(By HPLC) Impurity VII
Impurity IX
Impurity IIB
Impurity V
Impurity XI
Total impurities : 0.11%
0.10%
0.09
0.01
0.08%
0.48% 0.19%
0.75%
0.14%
0.01%
0.53%
2.4% 0.23%
0.92%
0.18%
ND
0.65%
2.8% 0.13%
0.47%
0.13%
0.01%
0.32%
1.5% 0.11%
0.13%
0.11%
0.01%
0.05%
0.47%
Assay (By HPLC) 98.0 %-102.0% as is basis 98.10% 89.17% 88.80% 92.05% 98.51%

As shown in afore-mentioned description, the Hydroxy impurity formation on storage of (7aS,2’S) -2-oxoclopidogrel bisulphate triggers significant amount of side reactions of impurity as well as (7aS,2’S) -2-oxoclopidogrel bisulphate and when the impurity is controlled below 0.5%, most preferably below 0.2%, the compound is relatively stable with consistent assay value for (7aS,2’S) -2-oxoclopidogrel bisulphate.
It is therefore the object of this invention to provide a stable (7aS,2’S) -2-oxoclopidogrel bisulphate limited by virtue of control of impurity levels, specifically impurities of formula IX, X, & XI in the pure active ingredient.

Accordingly, the present invention provides (7aS,2’S)-2-oxoclopidogrel and/or its pharmaceutically acceptable salts consisting not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and contains less than 0.2% of a corresponding Hydroxy-impurity of Formula IX and wherein after storage for more than one year at 25 °C and 60% relative atmospheric humidity, the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel, where in the impurities of formula X & XI remain less than 0.2%.

[0055] The present invention thus provides processes to prepare pure and stable 7aS,2’S)-2-oxoclopidogrel and/or its pharmaceutically acceptable salts comprising the following steps:
Step 1) reacting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one HCl with a base such as sodium bicarbonate in a suitable solvent;
Step 2) reacting the reaction mass from step 1 with a solution of Methyl (7)-2-(4-nitrophenylsulfonyloxy)-2(2-chlorophenyl)acetate in a dry solvent at about 45-55oC under nitrogen atmosphere wherein the water content is less than 0.5%;
Step 3. Extracting the reaction residue obtained in step 2) in a suitable solvent such as ethyl acetate, and washing the organic layer with water in cold temperature such as temperature below 20 oC till the pH of washings is below 6 and concentrating organic layer to a an oily residue;
Step 4. Crystallizing the oily residue from a suitable solvent such as mixture of ethyl acetate & methanol under nitrogen atmosphere wherein the solvent moisture does not exceed 0.5% to yield Methyl (7aS,2'S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate;
Step 5). Optionally, converting the Methyl (7aS,2'S)/-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate to its bisulphate salt by treating Methyl (7aS,2'S)/-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate with concentrated suphuric acid in a suitable solvent such as dry acetone in an inert gas atmosphere. The moisture content in acetone is maintained well below 0.5%.

The present invention further provides that the powder processing is carried out in area where the relative humidity is adjusted to less than 45% RH, most preferably less than 35% RH.
By following the process of the invention, a highly pure (7aS,2’S)-2-oxoclopidogrel and/or its pharmaceutical salt, for example (7aS,2’S)-2-oxoclopidogrel bisulphate salt, can be obtained. The impurity profiles of batches manufactured are:
Test Specification Batch 1 Batch 2 Batch 3 Batch 4 Batch 5
Related substance Impurity of Formula VII 0.245% 0.192% 0.259% 0.12% 0.11%
Impurity of Formula IIB 0.166% 0.110% 0.175% 0.11% 0.10%
Hydroxy impurity of Formula IX <0.02% <0.02% <0.02% <0.02% <0.02%
Impurity of formula V <0.02% <0.02% <0.02% <0.02% <0.02%
Impurity of Formula X <0.02% <0.02% <0.02% <0.02% <0.02%
Impurity of Formula XI <0.02% <0.02% <0.02% <0.02% <0.02%
Other unknowns <0.05% <0.05% <0.05% <0.05% <0.05%
Water Water content by KF 0.3% 0.13% 0.3% 0.15% 0.41%
Assay Assay by HPLC
ND: below detection limit (detection limit is 0.02%)

It has been found that the purity of (7aS,2’S)-2-oxoclopidogrel and its pharmaceutical salt can only be maintained under a selective packaging and conditions of storage conditions.

In another embodiment, the present invention provides moisture impervious barrier packing for (7aS,2’S)-2-oxoclopidogrel and/or a pharmaceutically acceptable salt containing not more than 0.2% of the impurity of formula X, not more than 0.2% of impurity of Formula XI and contains less than 0.5% of a corresponding Hydroxy-impurity of Formula IX and after storage for one year or more at 25°C±2°C and 60%±5% atmospheric humidity, which comprises at least 2 layered packing of moisture impervious HDPE or aluminium foil sheet layers with a gauge of 500 units or more, to arrest the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX that does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel, wherein, the impurities of formula X & XI remain less than 0.2%.

Accordingly, the present invention provide a suitable packing configuration and storage conditions for (7aS,2’S)-2-oxoclopidogrel and its pharmaceutical salt, but not limited to, comprising a three layered packaging wherein:

Primary packing is a moisture impervious material such as a clear HM HDPE polyethylene bag wherein the thickness is 500 gauge or more.,

Secondary packing is a black HM HDPE polyethylene bag wherein the thickness is 500 gauge or more and packed under positive inert gas pressure and a suitable desiccant is placed between primary and secondary pack. Suitable Desiccant quantity can be determined by skilled person based on the size of pack and material to be stored.

Tertiary packing is a PET/Aluminium/PET polyethylene bag of 500 guage or more and packed under inert positive gas pressure and having desiccants placed between tertiary and secondary pack. Suitable Desiccant quantity can be determined by skilled person based on the size of pack and material stored.

Nitrogen flushing of each packing layer is recommended. Notwithstanding above conditions, based on the teachings of the present invention, a skilled person can make modification or rudimentary/customary changes in packing materials or their configurations to make a stable packing for (7aS,2’S)-2-oxoclopidogrel and its pharmaceutical salt.

According to the present invention, it is preferred to store the active ingredient at a condition where the relative humidity is low and at cold temperatures. It is preferably to store below 20 oC, and most preferably at a temperature less than 10 oC.

Following the present invention, (7aS,2’S)-2-oxoclopidogrel and its pharmaceutical salt is found to be stable for a minimum of 24 months, and most preferably upto 48 months so that it permits to manufacture a solid oral dosage form yielding a minimum of 24 months shelf-life in normal storage conditions.

Stability data of (7aS,2’S)-2-oxoclopidogrel bisulphate stored at 2 to 8oC for 48 months.
Test Specification Batch 1 Batch 2 Batch 3
Related substance Impurity of Formula VII 0.25% 0.20% 0.27%
Impurity of Formula IIB 0.12% 0.06% 0.15%
Hydroxy impurity of Formula IX 0.12% 0.1% 0.14%
Impurity of formula V 0.05% 0.05% 0.03%
Impurity of Formula X 0.05% 0.03% 0.03%
Impurity of Formula XI 0.03 0.01 0.05
Other unknowns <0.05% <0.05% <0.05%
Water Water content by KF 0.3% 0.61% 0.44%
Assay Assay by HPLC 99.6% 99.9% 100.0%
ND: below detection limit (detection limit is 0.02%)

In another aspect, the present invention provides a solid oral pharmaceutical formulation containing (7aS,2’S)-2-oxoclopidogrel with not more than 0.2% of the impurity of formula X (RT at 1.9), not more than 0.2% of impurity of Formula XI and contains less than 0.2% of a corresponding Hydroxy-impurity of Formula IX and after storage for one year or more at 25°C±2°C and 60%±5% atmospheric humidity the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX does not exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel, where in impurities of formula X & XI remain less than 0.2%.
Moon et al, according to US 2010179184, discloses for similar compound prasugrel the final drug product to be packed under positive nitrogen pressure for long storage of prasugrel. Though, every molecule is different, and requires specific treatment, it is hard to follow in practice the teachings of Moon et al., because when the packing is open for use, the nitrogen gas will be lost and may yield instability during the in-use phase while patient is taking the medication. However, present invention provides a simple solution to add the stability in molecular level for enduring the compound for more periods of storage and better patient compliance.

According to the present invention, the solid oral dosage form is a tablet or a capsule. More preferably, it is a tablet for oral administration. According to the present invention, following adjuvants/excipients, but not limited to , are suitable for manufacture of long term stabilized formulations Microcrystalline cellulose (MCC), HPMC, Mannitol, Croscarmellose sodium, Colloidal silicon dioxide, Magnesium stearate (vegetable grade), Hypromellose, Polyethylene glycol, Talc, and Titanium Dioxide and Pollyvinyl pyrrolidone. Excipient with peroxide free and low moisture grades are preferred according to present invention so that trigger for acceleration of degradation is restricted. Nitrogen flushing with excipients to displace any oxygen may be preferred. The adjutants are preferably substantially free from peroxides or other oxidizing agents wherein their contents are below 100 ppm.

According to the present invention, a low moisture or humidity controlled area is suggested for the processing area, powder handling area and a nitrogen or an inert gas atmosphere is best suited during the unit operations of manufacture of pharmaceutical product for control of impurities levels in the final dosage form.

By following present invention, the level of increase in the impurity formation during the pharmaceutical dosage form preparation may be minimized and impart stability to (7aS,2’S)-2-oxoclopidogrel by limiting the Hydroxy-impurity of Formula IX . Preferably, the processing area, sample handling area, tablet compression or capsule filling area etc. are maintained at a atmospheric humidity less than 40% RH, and preferably below 35% RH, and still most preferably below 30 % RH.

Excipients or adjuvants and solvents for granulation or other unit operations are to be preferably dried or low moisture grade to be preferred. Moisture levels suggested to be between 0.5% to 2%, and not more than 2%. All excipients preferably is to be selected from peroxide free or less than 100 ppm content and also substantially free (Less than 100 ppm) from any other oxidizing agents or oxygen producing agents.

According to the present invention, it is often desirable to film-coat the tablet or granules for filling in capsule according to the target dosage form to provide a pharmaceutically acceptable appearance and to make said tablet for added protection. A moisture barrier coating composition is preferred and commercial suppliers such as, for example, Colorcon Inc. (USA), produce a variety of film coating systems containing polymers, plasticizers and pigments that can be mixed with water and sprayed onto the tablets in a side vented coating pan. A particularly preferred system is marketed as Opadry (Colorcon Inc). The Colorcon film coating system is especially useful in film coating debossed tablets.

Packing material preferred is high density polyethylene (HDPE) bottles or equivalent. High thickness HDPE bottles are more preferred or a moisture barrier coating inside the bottle wall is most suitable. Suitable quantities of dessicants and rayon may be placed inside the bottle to add more protection from moisture. 1-3 gm dessicants may be preferred to be placed inside the HDPE bottle. With the present invention, one may not need a costly filling under inert gas positive pressure to keep the drug product stable and with the advantage that the dosage form remain stable during the in-use phase of medication. It is obvious that inert gas pressure packing may be added to the present invention will keep further long periods of storage if need be.
Alumnium foil and aluminium-aluminium layered blister packing may be used for packing of solid oral dosage forms like tablet or capsules. Though aluminium foils withstand moisture, it is preferred to use grades exclusively used for zone IV climatic conditions. Thickness of aluminium foils in the range of 0.025 mm to 0.05 mm may be used. Pockets with dessicant loaded blister packing may be optionally considered for long term protection of solid dosage forms. Inert gas, like Nitrogen, may be purged at packing lines while filling the bottles or blister, may optionally be practiced. Any modification or addition/deletions in the suggested packing configurations are within the scope of skilled artisan and depends on the level of impurities in the final oral dosage form, especially the Hydroxy impurity of Formual IX and the endo-isomer of formula VII.

According to the present invention, it is possible to achieve a shelf-life of about 2 years for (7aS,2’S)-2-oxoclopidogrel bisulphate with the HDPE bottle packing configurations at 25°C±2°C and 60%±5% RH, as detailed below.
Packing: Multilayer HDPE bottle 60cc/33 mm Screw neck and 33 mm CR cap with heat sealed 123 liner and Rayon fiber coil without dessicant or nitrogen filling
Test Specification API Batch Purity 40 mg tablet (initial) 40 mg tablet (at 24 months) 10 mg tablet (initial) 10 mg tablet (at 24 months)
Related substance Impurity of Formula VII 0.259% 0.5% 0.4% 0.5% 0.4%
Impurity of Formula IIB 0.175% 1.04% 0.90% 1.0% 0.90%
Hydroxy impurity of Formula IX <0.02% 0.08% 0.20% 0.05% 0.12%
Impurity of formula V ND ND ND ND ND
Impurity at RT 1.9 ND 0.02% 0.06% 0.02% 0.04%
Impurity of Formula XI ND ND 0.04 ND 0.02
Water Water content by KF 0.3% 2.55% 2.63% 2.31% 2.49%
Assay Assay by HPLC 99.6% 95.9% 94.2% 96.8% 98.0%
ND: below detection limit (0.02%)

According to the present invention, oxygen scavengers are useful as an additional measure to reduce the level of oxygen induced degradation products. Oxygen scavengers packaged in the form of sachets, catridges or canisters are preferred. Examples of oxygen scavengers of various types are available commercially and may be used. One of skill in the art is able to determine an appropriate amount of oxygen scavenger necessary to effectively maintain oxygen levels below specified limits for the desired length of storage time and for the bottle size and number of tablets or capsules used.

Dessicants according to the invention are materials with the ability to control the relative humidity (RH) in the package. While a variety of desiccants are available for use with pharmaceutical products (silica gel, activated carbon, clays, molecular sieve, etc.), a desiccant material such as molecular sieve is especially preferred. One of skill in the art is able to determine with minimal experimentation an adequate quantity of desiccant for the number of tablets in the bottle and the specified shelf life.

According to present invention, a secondary packing over the primary packing of HDPE bottles or Blister packing is recommended for adding additional protection, especially for high humid zone IV climatic areas. The secondary packing may act as a pouch to prevent entry of moisture to cross the primary packing and material such as PVC, PVDC, and aluminium films may be considered for secondary pouch packing of primary packs in which the dosage forms are stored. Secondary packing option may be optionally used to extend the term of storage.

Exemplary embodiments illustrated above and in foregoing examples, the formulations of (7aS,2’S)-2-oxoclopidogrel containing varying amounts of Hydroxy impurity of formula IX, and all of which initially contain less than 0.20% of Hydroxy-impurity of Formula IX and after one year of storage at 25°C±2°C and 60%±5%humidity, the conversion of (7aS,2’S)-2-oxoclopidogrel to its corresponding Hydroxy-impurity of Formula IX is measured not to exceed 0.5% by weight of (7aS,2’S)-2-oxoclopidogrel are stable for end use. Any levels of Hydroxy-impurity of Formula IX greater than 0.5% indicates that the degradation trigger is initiated and the product is not in a condition for subsequent storage or medical use.

Examples.
Methyl (7aS,2'S)/(7aR,2'S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate.

In a reactor, under nitrogen atmosphere, 28.8 liter acetonitrile, 1.58kg of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one HCl, 1.76kg of sodium carbonate were added and stirred for 1 hour. To this mixture, 3.2kg of Methyl (7)-2-(4-nitrophenylsulfonyloxy)-2(2-chlorophenyl)acetate was added and the mixture was heated to about 50° C. After reaction, reaction mass was filtered, filtrate was concentrated and the concentrated mass was taken in 48 liter ethyl acetate, washed with water four times (100 liter) till pH of washing is below 6.
Organic layer was concentrated under reduced pressure at below 40°C under nitrogen atmosphere, concentrated mass taken in 2.4 liter dry ethyl acetate (moisture below 0.25%), stirred at 25-30°C and filtered.
Wet product dried under vacuum at 35-40°C and 1.2 kg product obtained. Hydroxy impurity of formula IX as measured through HPLC was <0.06%.

Example 2. Purification of Methyl (7aS,2'S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydro thieno[3,2-c]-5-pyridin-2-one)acetate
Under nitrogen atmosphere, 21.6 liter of ethyl acetate (moisture below 0.25%) and 1.2 kg of Methyl (7aS,2'S)/(7aR,2'S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate were stirred at 25-30°C,charcolised and filtered. Distilled out filtrate under reduced pressure at below 40°C. The concentrated mass was taken in 3.6 liter methanol, stirred at 25-30°C and filtered. Wet product dried under vacuum at 35-40°C to obtain 1.1 kg pure crystalline product.

Example 3 Preparation of Methyl (7aS,2'S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate hydrogen sulfate
In a reactor, under nitrogen atmosphere, 24.2 Liter of Anhydrous acetone (moisture content 0.5%) and 1.1 Kg of Methyl(S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate were added. It was cooled to around 5° C. and 3.3 liter of sulfuric acid was added slowly under nitrogen atmosphere without increasing temperature above 10 oC.
After Sulfuric acid addition, the mass was stirred at about 20-30° C temperature and filtered under nitrogen atmosphere.

The wet product was further stirred in anhydrous acetone ,filtered under nitrogen atmosphere and dried under reduced pressure to obtain pure 1.1kg of Methyl (7aS,2'S)-2(2-chlorophenyl)-2(2,4,5,6,7,7a-hexahydrothieno pyridin-2-one)acetate hydrogen sulfate. Yield=77%; Purity by HPLC=99.5%, Ratio of isomers by Chiral HPLC ee 99.8%.

Hydroxy impurity of formula IX as measured through HPLC was below detection limit of <0.02%.

Impurity of formula X as measured through HPLC was below detection limit of 0.02%.
Impurity of formula XI as measured through HPLC was below detection limit of 0.02%.

Comparative example 1.
In a four necked round bottomed flask, under nitrogen atmosphere, 1000 ml acetonitrile, 49.5 gm of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one HCl, 55 gm of sodium carbonate and 100 gm of Methyl (7)-2-(4-nitrophenylsulfonyloxy)-2(2-chlorophenyl)acetate were added and the mixture was heated to about 50° C. After reaction, reaction mass was filtered, filtrate concentrated and concentrated mass was taken in dichloromethane, washed with water and concentrated under reduced pressure. The oily residue was treated with IPA.HCl solution in isopropanol (IPA) and filtered to obtain the mixture of isomers as hydrochloride salt. To it sodium bicarbonate solution was added till pH turned alkaline. The product was then extracted in dichloromethane (MDC). The MDC layer was washed with water (pH of washing is 7), dried and distilled to obtain the product as an oily residue.
Hydroxy impurity of formula IX as measured through HPLC was 0.49%
Comparative example 2 Methyl (7aS,2'S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydro thieno[3,2-c]-5-pyridin-2-one)acetate
In a four necked round bottomed flask, under nitrogen atmosphere, 150 ml of ethyl acetate-methanol (water content 2%) and 70 gm of mixture or isomers was taken and warmed to dissolve, and stirred for under room temperature, crystals obtained were filtered and the solid was dried to obtain 52 gm Methyl (S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate. Hydroxy impurity of formula IX as measured through HPLC was 0.43%.

Foregoing exemplary embodiments show that, contrary to Ashok Kumar's disclosure, the presence of Hydroxy impurity of formula IX in an amount greater than 0.5% does adversely affect the stability of (7aS,2’S)-2-oxoclopidogrel when stored for one year at 25°C±2°C and 60%±5%. The examples also show that the (7aS,2’S)-2-oxoclopidogrel formulations prepared in accordance with the invention showed adequate stability with the controls of elements that were used.