FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
SALTS OF S-ENANTIOMER OF 5-METHOXY-2-[(4-METHOXY-3,5-DIMETHYL-2-PYRIDINYLMETHYL) SULFINYL] -l#-BENZIMIDAZOLE SUBSTANTIALLY FREE
OF SULFONE IMPURITY
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

SALTS OF S-ENANTIOMER OF 5-METHOXY-2-[(4-METHOXY-3,5-DIMETHYL-2-PYRIDINYLMETHYL) SULFINYL] -1//-BENZIMIDAZOLE SUBSTANTIALLY FREE
OF SULFONE IMPURITY * * - "' ~ *
The present invention relates to the salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-
3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-l//-benzimidazole, a compound of formula 1,
substantially free of sulfone impurity and a process for preparation thereof. S-enantiomer
of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]- \H-
benzimidazole which is known as esomeprazole and its pharmaceutically acceptable salts are used as antiulcerative agents.

Formula 1
Prior art discloses the synthesis of S-enantiomer of 5-methoxy-2-[4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole comprising enantioselective oxidation of the prochiral sulfide, viz. 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)thio-lH-benzimidazole.
United States Patent No. 5948789 (equivalent of WO 96/02535, Indian reference not available) provides a process for enantioselective synthesis of a sulphoxide compound or an alkaline salt thereof in the form of a single enantiomer or in an enantiomerically enriched form comprising oxidizing a prochiral sulfide with an oxidizing agent and in presence of a chiral titanium complex and a base. The exemplified preparation of esoemprazole in this patent provides esomeprazole with sulfone impurity of 2.7% in example 5 and with sulfone impurity of 3.8% in Example 9.
2

The PCT application WO 03/008406 (Indian reference not available) relates to an improved process for the preparation of benzimidazole-type proton pump inhibitors prepared by oxidation of corresponding sulphide wherein the sulfone impurity is removed by extraction with an aqueous alkaline solution at controlled pH. This process was applied on racemic benzimidazoles and not to S-omeprazole. When applied to the racemic compounds the % of sulfone was more than 0.2% in the final pure product.
The process of enantioselective oxidation, on increasing reaction scale, invariably leads to the formation of variable quantity (1 to 10%w/w) of an impurity, the sulfone derivative, an over oxidised product of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)thio-l//-benzimidazole. Formation of sulfone impurity in excess of 1% w/w, during the course of reaction, renders it difficult to purify and obtain high quality and quantity of the S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl) sulfinyl]-lH-benzimidazole and its pharmaceutically acceptable salts.
Thus there is need for a facile process for the preparation of pharmaceutically acceptable
salts of S-enantiomer of 5-methoxy-2-[4-methoxy-3,5-dimethyl-2-
pyridinylmethyl)sulfmyl]-lH-benzimidazole substantially free of sulfone impurity, wherein the salts are selected from alkaline earth metal and alkali metal.
The present invention provides alkali and alkaline earth metal salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole, substantially free of sulfone impurity, wherein the salts are selected from alkaline earth metal and alkali metal salts. More specifically the alkali metal salts may be sodium, potassium or lithium; and the alkaline earth metal salts may be magnesium, calcium or barium.
The pharmaceutically acceptable salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-l//-benzimidazole of the present invention are substantially free of sulfone impurity which does not exceed 0.5% w/w of the salt.
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In most preferred embodiments the sulfone impurity does not exceed 0.2% w/w of the salt.
In another preferred embodiments the sulfone impurity is absent or not detected by analytical methods such as HPLC.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole, substantially free of sulfone impurity, wherein the salts are selected from alkaline earth metal and alkali metal, said process comprising
a) enantioselective oxidation of the prochiral sulfide, 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylthio-lH-benzimidazole to form S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole;
b) reacting the S-enantiomer formed in step 'a' with basic salts of alkali or alkaline earth metals to form the salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl] -1H-benzimidazole;
c) removing the sulfone impurity from the alkali or alkaline earth metal salt formed in step 'b' by treatment with a solvent system, said solvent system comprising an organic solvent selected from ketone and nitrile,
d) and isolating the alkali or alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]-lH-benzimidazole which is substantially free of sulfone impurity, by conventional means.
In another aspect the present invention provides the alkali and alkaline earth metal salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole, substantially free of the sulfone impurity.
4

Preferably the present invention provides the alkali and alkaline earth metal salts of S-enantiomerof 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole wherein the sulfone impurity is less than 0.5 %w/w.
More preferably the present invention provides the alkali and alkaline earth metal salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]- \H-benzimidazole wherein the sulfone impurity is less than 0.2 %w/w.
DETAILED DESCRIPTION OF THE PROCESS
In step 'a' of the process the enantioselective oxidation of the prochiral sulfide, 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylthio-lH-benzimidazole to form S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]-l//-benzimidazole may be carried out by any process known in the art. Then it may be converted to basic salts of alkali or alkaline earth metals thereof to form the salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole in step 'b' of the process.
The salt of the S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]-l//-benzimidazole formed in step (b) of the process of the present invention has sulfone impurity, a compound of formula 2.

OCH3
,CH3
According to the process of the present invention, in step 'c' the sulfone impurity is removed from salt of the S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-
5

pyridinylmethyl)sulfmyl]-lH-benzimidazole by treatment with a solvent system comprising an organic solvent selected from ketone and nitrile. Preferably the solvent could be a ketone or a nitrile having C2 to C10 carbon chain, which could be linear, branched or cyclic. The preferred solvents are acetone, acetonitrile, methylisobutyl ketone, methylethyl ketone and the like. The most preferred solvent is acetone.
According to the process of the present invention the solvent system further comprises an aqueous salt solution of a neutral salt of alkali or alkaline earth metal.
Any neutral salt of alkali or alkaline earth metal may be used in the solvent system used for removal of sulfone impurity. Examples of neutral salt of alkali or alkaline earth metal include sodium chloride (NaCl), potassium chloride (KC1), barium chloride, calcium chloride and the like. The preferred neutral salt is NaCl.
The solvent system used for removal of sulfone impurity in the process of the present invention may comprise the organic solvent and an aqueous salt solution of a neutral salt of alkali or alkaline earth metal in the ratio of 99.9:0.1 to 99.3:0.7 v/v.
In the solvent system of the present invention, the concentration of the aqueous solution of the neutral salt of alkali or alkaline earth metal is in the range between 0.5 to 5 %w/v., preferably in the range between 0.5 to 1 %w/v. The preferred neutral salt is NaCl.
In a preferred embodiment, in step 'c' of the process the solvent system comprises acetone.
In another preferred embodiment, in step 'c' of the process the solvent system comprises acetone and aqueous solution of NaCl.
The ratio of organic solvent and aqueous salt solution of neutral alkali or alkaline earth metal salt may be selected so as to maximise the sulfone impurity in soluble state. This specific combination helps in ensuring elimination of the sulfone impurity to the desired
6

level and providing the pure S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole salt as an insoluble filterable mass. The optimum ratio may be appropriately selected by one skilled in the art based on the sulfone content present in the product. The sulfone content of up to 4% can be effectively removed by the process of the present invention.
In yet another preferred embodiment the solvent system comprises acetone:aqueous salt solution of NaCl in the ratio of between the range from 99.9:0.1 to 99.3:0.7, preferably 99.3:0.7.
According to the process of the present invention the treatment with the solvent system may be carried out for example, by refluxing with the solvent system for a period of about 1 to about 8 hours, preferably about 1 to about 2 hours.
The reaction may be monitored for the levels of sulfone impurity by standard analytical techniques like TLC, HPLC. Alkali metal or alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-l//-benzimidazole substantially free of sulfone impurity is then isolated by conventional means such as filtration and drying.
The alkali metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole substantially free of sulfone impurity obtained by following the process of the present invention can be converted to alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole substantially free of sulfone impurity by reacting with an alkaline earth metal source. The alkaline earth metal source that may be used may be calcium, magnesium or barium salts like chlorides. For example, magnesium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-l//-benzimidazole substantially free of sulfone impurity may be prepared from sodium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-
7

dimethyl-2-pyridinylmethyl)sulfmyl]-lH-benzimidazole substantially free of sulfone impurity prepared by following the process of the present invention.
The present invention provides alkali or alkaline earth metal salts of "S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole substantially free of sulfone impurity.
In a preferred embodiment the present invention provides alkali or alkaline earth metal
salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-
pyridinylmethyl)sulfmyl]-l//-benzimidazole, wherein the sulfone impurity is less than
0.5%w/w.
In a more preferred embodiment the present invention provides alkali or alkaline earth metal salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole, wherein the sulfone impurity is less than 0.2%w/w.
In yet another preferred embodiment the present invention provides alkali or alkaline earth metal salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-l//-benzimidazole, wherein the sulfone impurity is absent or not detected by analytical methods such as High Performance Liquid Chromatograph (HPLC).
In a preferred embodiment the present invention provides sodium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-l//-benzimidazole substantially free of sulfone impurity.
In another preferred embodiment the present invention provides sodium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-\H-benzimidazole wherein the sulfone impurity is less than 0.5%w/w.
8

In yet another preferred embodiment the present invention provides sodium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-\H-benzimidazole wherein the sulfone impurity is less than 0.2%w/w. In a preferred embodiment the present invention provides magnesium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-\H-benzimidazole substantially free of sulfone impurity.
In another preferred embodiment the present invention provides magnesium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]-l//-benzimidazole wherein the sulfone impurity is less than 0.5%w/w.
In yet another preferred embodiment the present invention provides magnesium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]-lH-benzimidazole wherein the sulfone impurity is less than 0.2%w/w.
In preferred process of the present invention the sulfone impurity in the alkali or alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole obtained does not exceed 0.2%, thus rendering it pharmaceutically acceptable as per ICH guidelines.
The invention is illustrated but not restricted by the description in the following examples.
9

EXAMPLES
Example 1- Purification of esomeprazole salt by purification process of the present invention
Suspend lOOg of esomeprazole sodium (moisture content about 1% & sulfone content about 0.8 %) in a 1 L Acetone. Heat the above contents for a period of 1 hour at reflux temperature, then cool it to 35-38 °C and filter the product at 35-38 °C. The % of sulfone in the product is less than 0.2 %. The yield of isolated product is 85 g.
Example 2- Purification of esomeprazole salt by purification process of the present invention
Suspend l00g of esomeprazole sodium (moisture content about 1% & sulfone content
about 4 %) in a mix of 1 L Acetone and aqueous NaCl (the ratio of Acetone: aqueous
NaCl is 99.3:0.7 and the concentration of NaCl in water is about 5 %). Heat the above
contents for a period of 1 hour at reflux temperature, then cool it to 35-38°C and filter the
product at 35-38 °C.
The % of sulfone in the product is less than 0.2%.
The yield of isolated product is 65 g.
Example 3
Preparation of 5-methoxy-2-[(S)-(4-methoxy-3.5-dimethyl-2-pyridinylmethvl)sulphinyl]"j-lH-benzimidazole magnesium (esomprazole magnesium)
Mix 30 g of esomeprazole sodium prepared in Example 1, and 300 ml of distilled water,
into a 500 ml R.B.flask Add a solution Magnesium chloride, 16.7 g in Distilled water,
60 ml, slowly through addition funnel in 30 minutes at 25-30°C. Stir the reaction
mixture for 1.0 hr. Filter the product and wash the cake with Distilled Water, 60 ml. Dry
the product in vacuum at 50-55°C.
Yield of Esomeprazole magnesium = 26 g with an enantiomeric excess >98%.
HPLC purity: 99.76 % and Sulfone content: 0.07 %
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Example 4
(a) Preparation of sodium salt of 5-methoxv-2-[(S)-(4-methoxv-3,5-dimethyl-2-
pvridinvlmethvl)sulphinyl]-lH-benzimidazole (esomprazole sodium)
Mix, S-(+)-Methyl mandelate 60.6 g, Toluene 250 ml and Titanium isopropoxide 15 ml, into a 500 ml R.B.Flask assembly and stir to make a clear solution under Nitrogen atmosphere. Heat the reaction mixture to 40°C and maintain for 17 hr. Cool to 25-30°C and charge Omeprazole sulfide 50 g and Diisopropylethylamine 1.35 ml to it and stir for 10-15 minutes. Add Cumene hydroperoxide (~ 80 % solution in cumene) 28 ml slowly through addition funnel to the reaction mixture at 25-30°C. Stir the reaction mixture at 25-30°C for 2.0 hr. Filter the solid and wash with Toluene 50 ml. Collect the filtrate and charge 12.5 % ammonia solution 300 ml, to the filtrate and stir the mixture for 15 minutes. Back extract the Toluene layer with 12.5% Ammonia solution ; 200 ml and add Methyl isobutyl ketone 250 ml, to the combined aqueous layer. Adjust the pH of the solution to 7.3-7.6 by adding Glacial Acetic acid at 25- 30 °C. Stir the content for 30 min. Separate the organic layer and extract the aq. layer with Methyl isobutyl ketone ; 50 ml. Charge sodium hydroxide solution (50% w/v) 11 ml to combined organic layer and stir the mixture for 15 minutes. Distil off solvent completely under vacuum at 55-60 °C. Add Acetonitrile; 300 ml, to the residue and stir the content at 25-30°C. Filter the product under nitrogen atmosphere and wash the cake with Acetonitrile 50 ml. Dry the product in vacuum at 50-55°C. Yield of Esomeprazole sodium = 22.4 g.
(b) Preparation of 5-methoxv-2-F(S)-(4-methoxv-3,5-dimethyl-2-
pvridinvlmethvl)sulphinyl"j-lH-benzimidazole magnesium (esomprazole magnesium)
Mix, esomeprazole sodium prepared above, 20 g and Distilled water, 200 ml, into a 500 ml R.B.flask Add a solution Magnesium chloride, 11 g in Distilled water, 50 ml, slowly through addition funnel in 30 minutes at 25-30°C. Stir the reaction mixture for 1.0 hr. Filter the product and wash the cake with Distilled Water, 60 ml. Dry the product in vacuum at 50-55°C. Yield of Esomeprazole magnesium = 15 g with an enantiomeric excess >98%.
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Example 5
Preparation of sodium salt of 5-methoxv-2-r(SV(4-methoxy-3,5-dimethvl-2-pyridinvlmethvl)sulphinvll-lH-benzimidazole (esomprazole sodium) -
Mix, Toluene 120 L, Omeprazole sulfide 30 Kg, followed by 204 ml Water, D-(-)-Diethyl tartrate 9.4 L and Titanium isopropoxide 7.98 Kg , into a 500 L reaction assembly and stir to make a homogenous suspension under Nitrogen atmosphere. Heat the reaction mixture to 50-52°C and maintain for 1 hour. Cool to 15-20°C and charge Diisopropylethylamine 3.56 Kg to it and stir for 10-15 minutes. Add Cumene hydroperoxide (~ 80 % solution in cumene) 16.37 Kg slowly through addition funnel to the reaction mixture at 0 to 5°C.
Stir the reaction mixture at 25-30°C for 2.0 hr. Charge 12.5 % ammonia solution 240 L, to it and stir for 10-15 minutes. Back extract the Toluene layer with 12.5% Ammonia solution ; 60 L and add Methyl isobutyl ketone 120 L, to the combined aqueous layer. Adjust the pH of the solution to 7.3-7.6 by adding Glacial Acetic acid at 25- 30 °C. Stir the content for 30 min. Separate the organic layer and extract the aq. layer with Methyl isobutyl ketone ; 30 L. Charge sodium methoxide solution (30% w/v) about 15 Kg to combined organic layer and stir the mixture for 15 minutes. Distil off solvent completely under vacuum at 55-60 °C. Add Acetonitrile; 90 L to the residue and stir the content at 25-30°C. Filter the product under nitrogen atmosphere and wash the cake with Acetonitrile 60 L. Dry the product in vacuum at 50-55°C. Yield of Esomeprazole sodium = about 18 Kg. Sulfone content: 4.0 %
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We claim
1. The alkali and alkaline earth metal salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole wherein the sulfone impurity is less thari 0.2%w/w.
2. The compound as claimed in claim 1 wherein the salt is sodium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl) sulfinyl]- \H-benzimidazole.
3. The compound as claimed in claim 1 wherein the salt is magnesium salt of S-enantiomer of 5-methoxy-2'[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl) sulfinyl]-lH-benzimidazole.
4. The alkali and alkaline eartli metal salts as claimed in 1 prepared by a process comprising
a) enantioselective oxidation of the prochiral sulfide, 5-methoxy-2-(4-methoxy-3,5-
dimethyl-2-pyridinylmethylthio-li/-benzimidazole to form S-enantiomer of 5-
methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]-l//-
benzimidazole;
b) reacting the S-enantiomer formed in step 'a' with basic salts of alkali or alkaline earth metals to form the salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfmyl]-l/f-benzimidazole;
c) removing the sulfone impurity from the alkali or alkaline earth metal salt formed in step 'b' by treatment with a solvent system, said solvent system comprising an organic solvent selected from ketone and nitrile,
d) and isolating the alkali or alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole which is substantially free of sulfone impurity, by conventional means.

5. The alkali and alkaline earth metal salts as claimed in 4 prepared by a process wherein the said solvent system further comprises an aqueous salt solution of a neutral salt of alkali or alkaline earth metal.
6. The alkali and alkaline earth metal salts as claimed in 4 prepared by a process further comprising reacting the alkali metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-li/-benzimidazole with an
13

alkaline earth metal source to yield the alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-1H-benzimidazole substantially free of sulfone impurity.
7. The magnesium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-l//-benzimidazole substantially free of sulfone impurity prepared by a process as claimed in claim 4, 5 or 6.
8. The compounds as claimed in claims 1 to 7 substantially as herein described and illustrated by examples 1 to 3.

>nd
Dated this 22n0 day of April, 2002.


DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LIMITED