FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR THE PREPARATION OF DEXLANSOPRAZOLE AND INTERMEDIATES THEREOF"
We, CADILA HEALTHCARE LIMITED, of Zydus Tower, Satellite Cross Road, Ahmedabad -380015, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to Dexlansoprazole (1) and its intermediates thereof. In particular, the present invention provides an improved process for preparation of intermediates in crystalline form with high purity. The present invention also relates to crystalline form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyI]sulfinyl]-lH-benzimidazole and methods for their preparation. The present application also relates to processes for the preparation of crystalline dexlansoprazole.
BACKGROUND AND PRIOR ART
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole, also known as Lansoprazole, is disclosed in Japanese patent application No. JP-A-61 -50978.
Lansoprazole is a well-known gastric acid secretion inhibitor and is useful as an anti-ulcer agent. Lansoprazole has a chiral sulfur within its molecular structure and hence occurs as two optical isomers, R-lansoprazole and S-lansoprazole.
(R)-(+)-lansoprazole "Dexlansoprazole" is know by its chemical names (R)- 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-IH-benzimidazole, or (+)-(2)-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole, and can be represented by structural formula (I).
Dexlansoprazole is available in the United States, in products sold by Takeda Pharmaceuticals America, Inc. using the trademark KAPIDEX, for the treatment of symptomatic non-erosive gastroesophageal reflux disease-heartburn associated with gastroesophageal reflux disease (GERD) and erosive esophagitis.
Dexlansoprazole was disclosed in Biochemical Pharmacology (1991), 42 (10), 1875-8 and is said to have antisecretory activity due to the inhibition of (H+-K+)-ATPase. U.S. Patent No. 6,462,058 discloses a crystal of (R)-2-[[[3-methyl-4-(2,2,2- trifIuoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole (dexlansoprazole), characterized by its X-ray powder diffraction pattern giving interplanar spacings (d) of 11.68, 6.77. 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41, and 3.11 Angstroms. The patent also discloses a crystal of dexlansoprazole 1.5-hydrate characterized by an X-ray powder diffraction pattern with interplanar spacings (d) of 13.22, 9.60, 8.87, 8.05, 6.61, 5.92, 5.65, 4.49, 3.50 and 3.00

Angstroms, and is described as more stable and preferable for use as a pharmaceutical than the amorphous form. The patent also discloses processes for the preparation of crystalline dexlansoprazole including, for example, crystallization from solution, crystallization from vapor and crystallization from molten form.
U.S. Patent No. 5,948,789 discloses a process for enantioselective synthesis of 2-(2-pyridinylmethylsulphinyl)-l H-benzimidazoles or an alkaline salt thereof, in the form of a single enantiomer or in an enantiomehcally enriched form, by oxidizing a pro-chiral sulfide with an oxidizing agent in the presence of a chiral titanium complex and a base in an organic solvent. .
U.S. Patent Application Publication No. 2005/0288334 A1 discloses a process for preparing an optically pure proton pump inhibitor (PPI) having a sulfinyl structure selected from the group consisting of (S)-or (R)-enantiomers of lansoprazole alongwith others proton pump inhibitor derivatives.
International (PCT) Publication WO 2005/054228 Al discloses a process for 2-(2-pyhdinylmethylsulphinyl)-lH-benzimidazoles, either as a single enantiomer or in an enantiomerically enriched form by asymmetric oxidation of the corresponding prochiral 4-chloro or 4-nitro analog of 2-(2-pyridinyImethyl-sulphinyl)-lH-benzimidazole with an oxidizing agent and a chiral titanium complex in an organic solvent, followed by reaction of 4-chloro or 4-nitro analog of 2-(2-pyhdinylmethylsulphanyl)-lH-benzimidazole with corresponding alkali metal or alkaline earth metal alkoxide. The only example provided in this document describes asymmetric oxidation of 5-methoxy-2-[[(3,5-dimethyl-4-nitro-2-pyridinyl) methyl]thio]-lH-benzimidazole (4-nitro analog of omeprazole) to provide (S)-5-methoxy-2-[[(3,5-dimethyl-4-nitro-2-pyhdinyl) methyl] su]finyl]-lH-benzimidazole and its subsequent reaction with sodium methoxide to get esomeprazole.
U.S. Patent Application Publication No. 2006/0057195 Al discloses stable solid dosage form comprising a non-toxic base and an amorphous dexlansoprazole. According to the application, amorphous dexlansoprazole stored with a base has a more stable color when compared to amorphous dexlansoprazole alone.
International (PCT) Publication WO 2009/087672 Al discloses a process for the preparation of stable amorphous R-Iansoprazole. International (PCT) Publication WO 2009/117489 A1 discloses a process for the preparation of Dexlansoprazole and polymorphs. In particular, the specification discloses the crystalline form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulflnyl]-lH-benzimidazole wherein water content is 5.66%, which corresponds to Monohydrate. Also, discloses various processes for the prepration of amorphous form of Dexlansoprazole.

International (PCT) Publication WO 2009/088857 Al discloses crystalline solvated
forms of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-IH-
benzimidazole. In particular, there is provided method for interconversion of various crystalline forms and amorphous form under different conditions. The specification provides various hydrates like 0.5 hydrate, 1.0 hydrate and 1.5 hydrate as well as alcoholate of methanol, ethanol, isopropanol and alcoholate hydrate. The various crystalline forms are designated as Form I, Form II, Form III, Form IV, Form V and Form IV.
U.S. Patent 6,723,852 B2 discloses methods for obtaining the derivatives of [[(pyridinyl-substituted)methyl]thio]benzimidazoIe. The process involves (a) reacting an N-oxide of a methylpyridine with an anhydride of activated carboxlyic acid or of sulfonic acid, and (b) reacting the intermediate formed in stage (a) with a corresponding mercaptobenzimidazole. The compounds thus obtained are useful in the synthesis of derivatives of [[(pyridinyl-substituted)methyl]thio]benzimidazole, such as omeprazole, lansoprazole, Rabeprazole or Pantoprazole.
ES 2 060 541 Bl discloses the process for the preparation of racemic 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole as per scheme-1.


The cited prior art discloses various crystalline forms of dexlansoprazole alongwith an amorphous form. There are various method provided for the preparation of stable amorphous form of dexlansoprazole. The racemic intermediate 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole reported in prior art doesn't provide any indication for water content. Further, the (R)-isomer with water content of 5,66% is reported.
Further, the prior art methods for the preparation of crystalline dexlansoprazole involves repeated crystallization wherein water is added. Dexlansoprazole is very sensitive product with repsect to hydrate formation. The intermediate with water content of about 5-6% may result in formation of crystalline dexlansoprazole with higher hydrates like 1.0 hydrate or 1.5 hydrate etc.
Hence, there remains a need to provide improved processes for the preparation of dexlansoprazole, crystalline intermediate 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methy!]sulfinyl]-1H-benzimidazole in anhydrous form and crystalline dexlansoprazole in anhydrous form with

high yield and high purity directly from the reaction mixture, or by converting dexlansoprazole hydrate to anhydrate, which is simple, cost-effective, eco-friendly and commercially viable. SUMMARY OF INVENTION
In first aspect, there is provided crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-]H-benzimidazole "Nitrosulfide" of formula (III)

According to the invention, the crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]- thio]-lH-benzimidazole "Nitrosulfide" of formula (III) which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.8, 15.3, 17.5, 20.7, 21.2, 22.5, 24.4, 27.1 and 29.3 degrees, and an IR spectrum having main bands at about 3074, 2958, 1930, 1618, 1492, 1222, 1153, 1072,898,850,671,634 and 596 cm-1.
In second aspect, there is provided a process for the preparation of crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-1 H-benzimidazole "Nitrosulfide" of formula (III),

the process comprising:
a) suspending nitrosulfide monohydrate in a first organic solvent;
b) concentrating the reaction mixture to remove the first organic solvent;
c) cool the residue;
d) treating residue with second organic solvent; and
e) isolating anhydrous nitrosulfide.
In further aspect, there is provided crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-l H-benzimidazole "Nitrosulfoxide" of formula (II)


According to the invention, the crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 29 at about 6.6, 13.7, 14.3, 16.1, 20.0, 21.4, 24.0, 28.5, and 32.9 degrees, and an IR spectrum having main bands at about 3282, 1926, 1612, 1598, 1438, 1271, 1247, 1074, 1051, 894, 881, 775, 759 and 572 cm-1.
In fourth aspect, there is provided a process for preparation of Crystalline anhydrous
form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfmyl3-lH-benzimidazole
"Nitrosulfoxide" of formula (II)

the process comprising: a) enantioselectively oxidizing nitrosulfide anhydrous of formula (III) with an oxidizing agent in the presence of a chiral auxiliary to provide Nitrosulfoxide (monohydrate) of formula (II) in the form of a single enantiomer or in an enantiomerically enriched form;

b) suspending crystalline Nitrosulfoxide (monohydrate) in suitable organic solvent;
c) adding base to the suspension;
d) treating the suspension with suitable acid to adjust the pH in the range of 7.5 to 10.0:
e) isolating crystalline Nitrosulfoxide (monohydrate);
f) purifying crystalline Nitrosulfoxide (monohydrate) in polar organic solvent; and
g) isolating crystalline Nitrosulfoxide anhydrous form of formula (II).
In another aspect, there is provided a process for preparing dexlansoprazole of formula (I), or a salt thereof


the process comprising:
a) suspending 2,2,2-triflouroethyl alcohol and a base in first organic solvent;
b) heating the reaction mixture at temperature Tl followed by cooling at an ambient temperature;
c) adding crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]-sulflnyl]-1 H-benzimidazole "Nitrosulfoxide" of formula (II)

to the reaction mixture;
d) heating the reaction mixture at temperature T2 followed by cooling to temperature Tl;
e) titurating reaction mixture with water followed by filtration;
f) treating aqueous filtrate with an second organic solvent and thereby adjusting the pH from about 7.5 to 10.0 with an acid; and
g) isolating dexlansoprazole (sesquihydrate) of formula (I), or a salt thereof
In further aspect, there is provided process for preparation of dexlansoprazole of formula (I), or a salt thereof

the process comprising:
a) suspending crystalline dexlansoprazole (Sesquihydrate) in suitable organic solvent;
b) partially concentrating the reaction mixture to remove organic solvent;
c) treating the residue with suitable anti-solvent;
d) filtering the reaction mixture followed by washing with anti-solvent: and
e) isolating dexlansoprazole (anhydrous) of formula (I), or a salt thereof.

In still further aspect, there is provided a process for the preparation of dexlansoprazole of formula (I) or a salt thereof

the process comprising:
a) suspending crystalline dexlansoprazole (Sesquihydrate) in a first organic solvent;
b) concentrating the reaction mixture to remove the first organic solvent;
c) cool the residue:
d) treating residue with second organic solvent; and
e) isolating anhydrous dexlansoprazole (anhydrous) of formula (I), or a salt thereof.
According to one of the aspect, crystalline dexlansoprazole Sesquihydrate is characterized by which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 29 at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees, and an JR spectrum having main bands at about 2978, 2816, 1643, 1581, 1473, 1313, 1111, 972, 858, 827, 802, 742 and 576 cm-1.
Accoryg to still one of the aspect, crystalline dexlansoprazole anhydrous is characterized by which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees, and an IR spectrum having main bands at about 2978, 2816, 1643, 1581, 1473. 1313, 1111, 972, 858, 827, 802, 742 and 576 cm"1.
In an aspect, the present application provides a compound of formula (II) and (III) having a HPLC purity of greater than about 95%, or greater than about 97%, or greater than about 99%, as determined using high performance liquid chromatography (HPLC).
In an embodiment, the present invention provides a compound of formula (II) having an chiral purity of greater than about 90%, or greater than about 95%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.8%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).
An aspect of the present invention provides compositions comprising dexlansoprazole substantially free of one or more of its corresponding impurities as measured by HPLC. BRIEF DESCRIPTION OF THE DRAWINGS
FIG.l illustrates a representative powder X-ray diffraction (PXRD) pattern for anhydrous 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III).

FIG.2 illustrates representative IR spectra for anhydrous 2-[[(4-nitro-3-methyl-2-
pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (IN).
FIG.3 illustrates a representative powder X-ray diffraction (PXRD) pattern for monohydrate 2-
[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-1 H-benzimidazole "Nitrosulfide" of formula (III).
FIG.4 illustrates a representative powder X-ray diffraction (PXRD) pattern anhydrous 2-[(R)-
[(4-nitro-3-methyl-2-pyridinyl)methyl]sulflnyl]-lH-benzimidazole "Nitrosulfoxide" of formula
(II).
FIG.5 illustrates representative IR spectra for anhydrous 2-[(R)-[(4-nitro-3-methyl-2-
pyridinyl)methyl]sulfinyl]-l H-benzimidazole "Nitrosulfoxide" of formula (II).
FIG.6 illustrates a representative powder X-ray diffraction (PXRD) pattern for crystalline
dexlansoprazole sesquihydrate.
FIG.7 illustrates representative IR spectra for crystalline dexlansoprazole sesquihydrate.
FIG.8 illustrates a representative powder X-ray diffraction (PXRD) pattern for crystalline
dexlansoprazole anhydrous.
FIG.9 illustrates representative IR spectra for crystalline dexlansoprazole anhydrous.
DETAILED DESCRIPTION OF THE INVENTION
As used here in the term "isolation" may include filtration, filtration under vacuum, centrifugation, and decantation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
As used herein, the terms "triturating", "slurrying" and "suspending" are interchangeable, and refer to a process carried out in a heterogeneous mixture where complete dissolution does not occur. Also, heating the suspension or slurry can result in a homogenous mixture where complete or partial dissolution occurs at an elevated temperature or ambient temperature.
The term "elevated temperature" used herein means, heating the reaction mixture either heterogeneous or homogeneous at a temperature from about 35°C to boiling point of solvent. More preferably from about 35°C to about 100°C. The term "ambient temperature" used herein means, slurrying the reaction mixture either heterogeneous or homogeneous at a temperature from about 10°C to about 35°C of solvent. "Suitable solvent" means a single or a combination of two or more solvents.

According to the first embodiment of the present invention, there is provided crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-l H-benzimidazole "Nitrosulfide" of formula (HI)

The crystalline anhydrous form of 2-[[(4-nitro-3-methyI-2-pyridinyI)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III) having water content less than about 0.5% by Karl Fisheer.
In second embodiment, the crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III) is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.8, 15.3, 17.5, 20.7, 21.2, 22.5, 24.4, 27.1 and 29.3 degrees, and an IR spectrum having main bands at about 3074, 2958, 1930, 1618,1492,1222, 1153, 1072, 898, 850, 671, 634 and 596 cm"'.
The embodiments of the invention further includes crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-1 H-benzimidazole "Nitrosulfide" of formula (III), which is further characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.8, 9.6, 15.3, 17.5, 20.7, 21.2, 22.5, 24.4, 25.7, 26.2, 27.1 and 29.3 degrees, and an IR spectrum having main bands at about 3074, 2958, 2804, 1930, 1888, 1809, 1768, 1618, 1595, 1535, 1529, 1492, 1359, 1346, 1222, 1153, 1072, 1012,983,962,929, 898, 850, 702, 671, 634, 617 and 596 cm-1.
In general, the crystalline anhydrous form of 2-[[(4-nitro-3-rnethyl-2-pyridinyl)methyl]thioj-lH-benzimidazole "Nitrosulfide" of formula (III), is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.l, and an IR spectrum substantially as depicted in FIG.2.
Further embodiments of the invention includes, crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III) is having purity greater than 99.9% when measured by area percentage of HPLC.
According to the third embodiment, there is provided a process for the preparation of crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-l H-benzimidazole "Nitrosulfide" of formula (III),


the process comprising:
a) suspending nitrosulfide monohydrate in a first organic solvent;
b) concentrating the reaction mixture to remove the first organic solvent;
c) cool the residue;
d) treating residue with second organic solvent; and
e) isolating anhydrous nitrosulfide.
According to the embodiments of the process, the first organic solvent is selected from polar organic solvent like methanol, ethanol, isopropanol, butanol, acetone, water, dimethylformamide, dimethylacetamide, THF, N-methylpyrrolidone etc, non-polar organic solvent selected from toluene, xylene, ethyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, methylethyl ketone, methylisobutyl ketone, diethylether, diisopropyl ether etc or a mixture of polar and non-polar organic solvent, preferably methanol and toluene.
The second organic solvent is selected from non-polar organic solvent like toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, diethylether, diisopropylether etc, preferably heptane.
In general, the reaction of nitrosulfide monohydrate in first organic solvent can be carried out at an ambient temperature i.e. below 35°C. The anhydrous nitrosulfide is isolated by filtration followed by washing and drying till moisture content is below 0.5%. The washing of wet-cake after filtration is done with heptane.
According to fourth embodiment, the present invention provides crystalline anhydrous
form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole
"Nitrosulfoxide" of formula (II).
The crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-
pyridinyl)methyl]sulfinyl]-IH-benzimidazole "Nitrosulfoxide" of formula (II) having water content less than about 1.0% by Karl Fishcer.
In an embodiment, crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 6.6, 13.7, 14.3, 16.1, 20.0, 21.4, 24.0, 28.5, and 32.9 degrees, and an IR spectrum having main

bands at about 3282, 1926, 1612, 1598, 1438, 1271, 1247, 1074, 1051, 894, 881, 775, 759 and 572 cm"'.
The embodiments of the invention further includes, crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) further characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed 3.3, 6.6, 11.1, 11.8, 13.7, 14.3, 16.1, 17.9, 20.0, 21.4, 22.5, 24.0, 27.0, 28.5, 29.7 and 32.9 degrees, and an IR spectrum having main bands at about 3282, 3072, 2899, 2872, 1961, 1926, 1803, 1703, 1680, 1612, 1598, 1562, 1529, 1438, 1392, 1355, 1271, 1247, 1193, 1157, 1074, 1051, 894, 881, 840, 800, 775, 759, 734, 702, 642, 601, and 572 cm"1.
In general, crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-IH-benzimidazole "Nitrosulfoxide" of formula (II), which is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.4, and an IR spectrum substantially as depicted in FIG.5.
Further embodiments of the invention includes crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) having purity of atleast 99% and chiral purity of atleast 98%, when measured by area percentage of HPLC.
According to fifth embodiment, the present invention provides a process for preparation of crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II)

the process comprising:
a) enantioselectively oxidizing nitrosulfide anhydrous of formula (III) with an oxidizing agent
in the presence of a chiral auxiliary to provide Nitrosulfoxide (monohydrate) of formula (II)
in the form of a single enantiomer or in an enantiomerically enriched form:

b) suspending crystalline Nitrosulfoxide (monohydrate) in suitable organic solvent;

c) adding base to the suspension;
d) treating the suspension with suitable acid to adjust the pH in the range of 7.5 to 10.0;
e) isolating crystalline Nitrosulfoxide (monohydrate);
f) purifying crystalline Nitrosulfoxide (monohydrate) in polar organic solvent; and
g) isolating crystalline Nitrosulfoxide anhydrous form of formula (II).
In general, the enantioselectively oxidation of nitrosulfide anhydrous of formula (III) is performed with suitable oxidizing agent selected from hydroperoxide reagents such as t-butylhydroperoxide, cumene hydroperoxide, hydrogen peroxide and the like, peracids such as peracetic acid, m-chloroperbenzoic acid, perphthalic acid, and the like, sodium perborate and the like, and any other suitable oxidizing agents, preferably cumene hydroperoxide.
The oxidation is preferbably performed in presnce of chiral auxiliaries selected from transition metal complexes such as chiral titanium complexes, chiral zironium complexes, chiral vanadium complexes, chiral hafnium complexes, and the like and any other suitable chiral metal complexes, prerferably chiral titanium complexes like titanium isopropoxide with (+)-diethyl tartarte.
According to the embodiments, the oxidation is performed in suitable organic solvent can be selected from polar organic solvents like methanol, ethanol, isopropanol, butanol, acetonitrile, acetone, THF, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, dimethylsufoxide and water or mixture thereof with water, preferably a mixture of dimethylforamide, acetonitrile and water.
The ratio of organic solvent is selected based on the suitability of the reaction, preferably dimethylformamide, acetonitrile and water are taken in the ratio of 2:1:4, respectively.
The suspension of crystalline Nitrosulfoxide (monohydrate) in dimethylformamide, acetonitrile and water in the ratio of 2:1:4 is treated with a base selected from akali or akaline earth metal carbonate, bicarobate, hydroxide, hydride etc.
In general, the base is selected from sodium carbonate, potassium carbonate, sodium bicaronate, potassium bicaronate, sodium hydroxide, potassium hyrdroxide, lithium hydroxide, barium hydroxide, sodium hydride, lithium aluminum hydride etc, preferably potassium carbonate.
The reaction mixture is further treated with acid selected from mineral acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or organic acid like acetic acid etc., preferably acetic acid thereby adjusting the pH from about 7.5 to 10.0, preferably from about 8.5 to 9.0.
According to the important embodiment, the crystalline Nitrosulfoxide (monohydrate) is isolated by filtration followed by washing and drying. The isolated Nitrosulfoxide monohydrate

is purified in suitable polar organic solvent can be selected from methanol, ethanol, isopropanol, butanol, acetonitrile, acetone. THF, dimethylformamide. dimethylacetamide. N-methyl pyrrolidone, dimethylsufoxide and water or mixture thereof with water, preferably acetone.
The purification of crystalline Nitrosulfoxide (monohydrate) in acetone is performed at about 40°C to 80°C, preferably at about 50°C to 55°C under heating. The suspension of Nitrosulfoxide (monohydrate) in acetone is further cooled to 5°C to 10°C. The crystalline Nitrosulfoxide anhydrous form is isolated by filtration followed by washing and dyring till water content is less than 1%.
According to most important embodiments of the invention, there is provided a process for preparing dexlansoprazole of formula (I), or a salt thereof

the process comprising:
a) suspending 2,2,2-triflouroethyl alcohol and a base in first organic solvent:
b) heating the reaction mixture at temperature Tl followed by cooling at an ambient temperature;
c) adding crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]-sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II)

to the reaction mixture;
d) heating the reaction mixture at temperature T2 followed by cooling to temperature Tl;
e) titurating reaction mixture with water followed by filtration:
f) treating aqueous filtrate with an second organic solvent and thereby adjusting the pH from about 7.5 to 10.0 with an acid: and
g) isolating dex lansoprazole (sesqui hydrate) of formula (1), or a salt thereof.
In general, 2,2,2-triflouroethyl alcohol and a base are suspended in first organic solvent wherein first organic solvent is selected from polar orgaic solvent like methanol, ethanol, isopropanol, butanol, isobutanol, decanol, dodecanol, acetone, dimethylformamide,

dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, THF, acetonitrile and the like, preferbaly dimethylformamide.
The base for said reaction is selected from sodium carbonate, potassium carbonate, sodium bicaronate. potassium bicaronate, sodium hydroxide, potassium hyrdroxide, lithium hydroxide, barium hydroxide, sodium hydride, lithium aluminum hydride etc, preferably potassium carbonate.
The suspension of 2,2,2-triflouroethyl alcohol and a base is heated at temperature Tl. which is from about 40°C to about 120°C, preferably from about 40°C to about 7Q°C, most preferably from about 50°C to about 60°C. This suspension is cooled to an ambient temperature whereupon it is treated with crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]-sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) is added in the form of solution in dimethylformamide.
The reaction mixture after addition crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]-sulfmyl]-lH-benzimidazoIe "Nitrosulfoxide" of formula (II) is heated to temperature T2, which is from about 70°C to about 130°C, preferably from about 90°C to about 95°C. After maintaing the reaction for 6-8 hours at temperature T2, the reaction mixture is cooled to temperature Tl whereup it is titurated with water and filtered.
The aqueous filtrate obtained after filtration is further treated with second organic solvent is selected from acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, THF, 2-methyl THF or mixture thereof with water, preferably acetonitrile. The reactoin mixture in acetonitrile is further treated with acid can be selected from mineral acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or organic acid like acetic acid etc., preferably acetic acid thereby adjusting the pH from about 7.5 to 10.0, preferbaly from about 8.5 to 9.0.
The precipitated product, crystalline dexlansoprazole sesquihydrate is isolated by filtration followed by washing and drying.
In a most important embodiment, the present invention provides a process for preparation of dexlansoprazole of formula (I), or a salt thereof

the process comprising:
a) suspending crystalline dexlansoprazole (Sesquihydrate) in suitable organic solvent;
b) partially concentrating the reaction mixture to remove organic solvent;

c) treating the residue with suitable anti-solvent;
d) filtering the reaction mixture followed by washing with anti-solvent; and
e) isolating dexlansoprazole (anhydrous) of formula (I), or a salt thereof.
In general, the embodiments of the process includes, suspending crystalline dex lansoprazole sesquihydrate in suitable organic solvent is selected from polar organic solvent like like methanol, ethanol, isopropanol. butanol, isobutanol, decanol, dodecanol, acetone, dimethylformamide, dimethylacetamide. N-methylpyrrolidone, dimethylsulfoxide, THF, acetonitrile and the like, preferbaly acetone. The suspension is stirred for 15-30 minutes in acetone below 35°C.
The suspension is further subjected to partial distillation for removal of organic solvent till about 1 to 1.5 times of organic solvent remains in the suspension, whereupon it is treated with suitable antisolvent selected from non-polar organic solvent like toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, diethylether, diisopropylether etc, preferably diisopropylether.
The residue obtained after concentrating the suspension is treated with diisopropylether at about 25°C to about 40°C and filtered at about 25°C to about 35°C. The crystalline dex lansoprazole anhydrous of formula (I) or a salt thereof is isolated by washing and drying the wet-cake obtained by filtration.
In yet another embodiment, there is provided a process for the preparation of dexlansoprazole of formula (I) or a salt thereof

the process comprising:
a) suspending crystalline dexlansoprazole (Sesquihydrate) in a first organic solvent;
b) concentrating the reaction mixture to remove the first organic solvent;
c) cool the residue;
d) treating residue with second organic solvent and
e) isolating anhydrous dexlansoprazole (anhydrous) of formula (I), or a salt thereof.
The crystalline dexlansoprazole sesquihydrate is suspended in first organic solvent selected from polar organic solvent like methanol, ethanol, isopropanol, butanol, acetone, water, dimethylformamide, dimethylacetamide, THF, N-methylpyrrolidone etc, non-polar organic solvent selected from toluene, xylene, ethyl acetate, butyl acetate, methylene dichloride,

ethylene dichloride, methylethyl ketone, methylisobutyl ketone, diethyl ether, diisopropyl ether etc or a mixture of polar and non-polar organic solvent, preferably methanol and toluene. After that the suspension is subjected to distillation for removal of first organic solvent to obtain the residue.
The residue obtain after removal of first organic solvent is treated with second organic solvent selected from non-polar organic solvent like toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, diethylether, diisopropylether etc, preferably heptane.
In an embodiment, crystalline dexlansoprazole Sesquihydrate is characterized by which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 26 at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees, and an 1R spectrum having main bands at about 2978, 2816, 1643, 1581, 1473, 1313, 1111,972,858,827,802,742 and 576 cm" .
Crystalline dexlansoprazole Sesquihydrate is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.6, and an IR spectrum substantially as depicted in FIG.7.
In further embodiment, crystalline dexlansoprazole anhydrous is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees, and an IR spectrum having main bands at about 2978, 2816, 1643, 1581, 1473,1313, 1111, 972, 858, 827, 802, 742 and 576 cm-1.
Crystalline dexlansoprazole anhydrous is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.8, and an IR spectrum substantially as depicted in FIG.9.
In an embodiment, the present invention provides a compound of formula (II) and (III) having a HPLC purity of greater than about 95%, or greater than about 97%, or greater than about 99%, as determined using high performance liquid chromatography (HPLC).
In further embodiment, the present invention provides a compound of formula (II) having an chiral purity of greater than about 90%, or greater than about 95%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.8%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).
Powder X-ray Diffraction, and IR can characterize crystalline Nitrosulfide, crystalline Nitrosulfoxide, crystalline Dexlansoprazole sesquihydrate and crystalline Dexlansoprazole anhydrous form as follows: (i) Characterization by Powder X-ray Diffraction

The X-ray powder diffraction spectrum was measured under the following experimental conditions:
Instrument : X-Ray Diffractometer, D/Max-2200/PC Make: Rigaku, Japan.
X- Ray : Cu/40kv/40mA
Diverging : 1°
Scattering Slit : 1°
Receiving Slit : 0.15 mm
Monochromator RS : 0.8 mm
Counter : Scintillation Counter
Scan Mode : Continuous
Scan Speed : 3.000°/Min
Sampling Width : 0.020
Scan Axes : Two Theta / Theta
Scan Range : 2.000° to 40.000°
Theta Offset : 0.000°
The IR spectrum was measured by the KBr method.
According to further embodiment, the scope of the present invention can be illustrated by scheme-1 as shown below.

The invention also encompasses pharmaceutical compositions comprising dexlansoprazole or salts thereof of the invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" includes tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Pharmaceutical compositions containing the dexlansoprazole of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Any excipient commonly known and used widely in the art can be used in the pharmaceutical composition.
Carriers used include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like. Binders used include, but are not limited to, water, ethanol. propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethyl cellulose, shelac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like.
Disintegrating agents used include, but are not limited to, dried starch, sodium alginate, agar powder, laminalia powder, sodium hydrogen carbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium laurylsulfate, monoglyceride of stearic acid, starch, lactose, and the like.
Disintegration inhibitors used include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like. Absorption accelerators used include, but are not limited to, quaternary ammonium base, sodium lauryl sulfate, and the like.
Wetting agents used include, but are not limited to, glycerin, starch, and the like. Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like. Lubricants used include, but are not limited to, purified talc, stearates, boric acid powder, polyethylene glycol, and the like.
Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi- layered tablets.
When shaping the pharmaceutical composition into pill form, any commonly known excipient used in the art can be used. For example, carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, talc, and the /ike. Binders used include, but are not limited to, gum arabic powder, tragacanth gum powder, gelatin, ethanol, and the like. Disintegrating agents used include, but are not limited to, agar, laminalia, and the like.
For the purpose of shaping the pharmaceutical composition in the form of suppositories, any commonly known excipient used in the art can be used. For example, excipients include, but

are not limited to, polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, and semi synthesized glycerides.
When preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood. Injection preparations may use carriers commonly known in the art. For example, carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of ordinary skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make the injectable preparation isotonic.
Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents may be added. If necessary, coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also be added to the desired preparations.
The pharmaceutical compositions of the invention may be administered in a variety of methods depending on the age, sex, and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules may be orally administered. Injection preparations may be administered individually or mixed with injection transfusions such as glucose solutions and amino acid solutions intravenously.
If necessary, the injection preparations may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories may be administered into the rectum The dosage of a pharmaceutical composition for treating Parkinson's disease, Alzheimer disease and various types of dementia according to the invention will depend on the method of use, the age, sex, and condition of the patient.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification.
The process for preparation of nitrosulfide anhydrous (III) and Nitrosulfoxide (II) and crystalline forms thereof is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention. Example-1: Preparation of Nitrosulfide (Anhydrous)


100 g Nitrosuflide monohydrate, 400 mL methanol and 300 mL toluene were taken in round bottom flask at 25°C. The reaction mixture was stirred and concentrated under reduced pressure to remove solvent below 50°C to get thick slurry. Again 200 mL methanol and 100 mL of toluene were added at 25°C and stirred. The reaction mixture was concentrated under vacuum below 50°C to get thick slurry. The procedure was repeated twice and the thick slurry was cooled at 30°C. 100 mL heptane was added and the reaction mixture was further cooled to 20°C and stirred for 2 hours. The precipitated product was filtered and washed with heptane. The product was dried at 60°C till moisture content was below 0.2% to obtain 95 g (95%) crystalline nitrosulfide anhydrous. Moisture content 0.08%. HPLC Purity: 99.96%. The XRD spectrum of racemic crystalline nitrosulfide anhydrous is shown in FIG.l. IR spectrum of racemic crystalline nitrosulfide anhydrous is shown in FIG.2. The XRD spectrum of racemic crystalline nitrosulfide monohydrate is shown in FIG.3. Example-2: Preparation of Nitrosulfloxide (Anhydrous)

(A) Preparation of Nitrosulfoxide (Monohydrate)
100 g Nitrosuflide anhydrous and 1000 ml toluene were taken in the round bottom flask at 25°C. 15.7 g of (+)-Diethyl Tartrate was added and reaction mixture was heated to 60°C. 9.55 g of Titanium isopropoxide was added at same temperature and stirred for 30 minutes. The reaction mixture was cooled to 15°C. 14.6 g of diisopropylethyl amine was added and reaction mixture was further cooled to -10°C. 239.4 g of cumene hydrogen peroxide was slowly added within 3-4 hours at ~] 0°C and stirred for 14 hours. After the completion of the reaction by TLC, 158.8 g of sodium thiosulfate solution in 480 ml of water was added to the reaction mixture and slowly heated to 25°C. The reaction mixture was stirred for 2 hours and treated with 2000 ml piperidine solution in water with stirring. The separated organic layer was quenched with 2000 ml liq. ammonia solution and stirred for 30 minutes. The reaction mixture was filtered through hyflow bed and settled. The separated aqueous layer was washed with 300 ml of toluene followed by 600 ml of acetonitrile at 10°C. The reaction mixture was then treated with 680 ml conc, acetic acid to adjust the pH of 8.5 to 9.0 at 25° and stirred for 2 hours. The product thus obtained was filtered, washed with water and obtain 81 gm (78%) Nitrosulfoxide. Moisture content 4.92%. HPLC Purity: 96.82%, sulfone 3.05%. Chiral purity 95.40%.
(B) Purification of Nitrosulfoxide (Monohydrate):

100 g crystalline Nitrosulfoxide obtained by the process in step (A) wet-cake, 250 ml of DMF, 125 ml acetonitrile, 500 ml water and 52.4 g potassium carbonate solution in 700 ml water were taken in round bottom flask at 25°C. The reaction mixture was stirred for 15 minutes at 35°C and treated with 10 ml of charcoal. The reaction mixture was filtered and washed with water. The aqueous layer was cooled to 10°C and treated with 50% acetic acid to adjust the pH of 8.5 to 9.0. The product thus obtained was filtered and washed with 300 ml water and dried at 45°C for 8-12 hours to obtain 71g (71%) of Nitrosulfoxide in crystalline form having water content 5.23%, HPLC purity 96.11% and chiral purity 87.7%. (C) Purification of Nitrosulfoxide (anhydrous):
100 g crystalline Nitrosulfoxide obtained by the process in step (B) was treated with 1500 ml of acetone at 55°C followed by cooling to 10°C and stirred for 1 hour at same temperature. The product thus obtained for filtered, washed with acetone and dried at 40°C for 6-8 hours till the water content is less than 1% to obtain 86 gm (86%) of Nitrosulfoxide (anhydrous). Water content 0.73%, HPLC purity: 99.52%, Chiral purity: 98.98%. The XRD spectrum of crystalline Nitrosulfoxide (anhydrous) is shown in FIG.4.1R spectrum of crystalline Nitrosulfoxide (anhydrous) is shown in FIG.5. Example-3: Preparation of Dexlansoprazole Sesquihydrate

221.4 g of 2,2,2-trifluoroethanol and 600 ml of DMF were taken in round bottom flask at 25°C and cooled to 15°C. 305.4 g of potassium carbonate was added and heated to 55°C for 1 hour. The reaction mixture was cooled to 20°C. 100 g Nitrosulfoxide pure solution in 400 ml DMF was added to the reaction mixture and heated to 95°C for 6 hours. The reaction mixture was cooled to 60°C and treated with 3000 ml of water and 15 g charcoal and stirred for 30 minutes. The reaction mixture was filtered and washed with water. The filtrate was quenched with 500 ml acetonitrile and cooled to 15°C. The pH of the reaction mixture was adjusted to 8.5-9.0 by treating with dilute acetic acid and stirred for 2 hours. The precipitated product filtered and washed with water. The product was dried at 45°C for 10-12 hours to obtain 85 g (77%) of dexlansoprazole. Moisture content 7.07%, HPLC purity 99.57%, Sulfone 0.17, sulfide 0.02%, chiral purity 99.84%. The XRD spectrum of crystalline Dexlansoprazole (Sesquihydrate) is shown in FIG.6. IR spectrum of crystalline Dexlansoprazole (Sesquihydrate) is shown in FIG.7.
Example-4:

Preparation of Dexlansoprazole (Anhydrous)

100 g of Dexlansoprazole Sesquihydrate and 400 ml of acetone were taken in round bottom flask at 25°C and stirred for 15 minutes. Acetone was distilled under vacuum below 45°C. Further 300 ml of acetone was added to get clear solution. 10 g of activated charcoal was added and stirred for 30 minutes. The solution was filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum below 45°C till approx 120 ml acetone remains in the reaction mixture. 500 ml of diisopropyl ether was added to the reaction mixture and stirred for 2 hours at 40°C. The reaction mixture was filtered and washed with 100 ml of diisopropyl ether. The product was dried for 6-8 hours at 45°C to obtain 85 gm (85%) Dexlansoprazole anhydrous. Moisture content 0.08%. Chiral Purity: 99.98% and HPLC purity: 99.81%. The XRD spectrum of crystalline Dexlansoprazole (Sesquihydrate) is shown in FIG.8. IR spectrum of crystalline Dexlansoprazole (Sesquihydrate) is shown in FIG.9. Example-5: Preparation of Dexlansoprazole (Anhydrous)

100 g of dexlansoprazole sesquihydrate, 400 mL methanol and 300 mL toluene were taken in round bottom flask at 25°C. The reaction mixture was stirred and concentrated under reduced pressure to remove solvent below 50°C to get thick slurry. Again 200 mL methanol and 100 mL of toluene were added at 25°C and stirred. The reaction mixture was concentrated under vacuum below 50°C to get thick slurry. The procedure was repeated twice and the thick slurry was cooled at 30°C. 100 mL heptane was added and the reaction mixture was further cooled to 20°C and stirred for 2 hours. The precipitated product was filtered and washed with heptane. The product was dried at 60°C till moisture content was below 0.2% to obtain 95 g (95%) crystalline dexlansoprazole anhydrous. Moisture content 0.08%. HPLC Purity: 99.96%.

Claims:
1. Crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyI)methyl]thio]-1H-benzimidazole "Nitrosulfide" of formula (III)
2. Crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyI)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III) having water content less than about 0.5% by Karl Fishcer.
3. Crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyI)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III), which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.8, 15.3, 17.5, 20.7, 21.2, 22.5, 24.4, 27.1 and 29.3 degrees, and an IR spectrum having main bands at about 3074, 2958, 1930, 1618, 1492, 1222, 1153, 1072, 898, 850, 671, 634 and 596 cm-1.
4. The crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III) as claimed in claim 3, which is further characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 29 at about 4.8, 9.6, 15.3, 17.5, 20.7, 21.2, 22.5, 24.4, 25.7, 26.2, 27.1 and 29.3 degrees, and an IR spectrum having main bands at about 3074, 2958, 2804, 1930, 1888, 1809, 1768, 1618, 1595,1535, 1529, 1492, 1359, 1346, 1222, 1153, 1072, 1012, 983, 962, 929, 898, 850, 702, 671, 634, 617 and 596 cm-1.
5. Crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III), which is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.l, and an IR spectrum substantially as depicted in FIG.2.
6. Crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III) of any preceeding claims having purity greater than 99.9% when measured by area percentage of HPLC.
7. A process for the preparation of crystalline anhydrous form of 2-[[(4-nitro-3-methyl-2-pyridinyl)methyl]thio]-lH-benzimidazole "Nitrosulfide" of formula (III),

the process comprising:
a) suspending nitrosulfide monohydrate in a first organic solvent;
b) concentrating the reaction mixture to remove the first organic solvent;

c) cool the residue;
d) treating residue with second organic solvent; and
e) isolating anhydrous nitrosulfide.

8. The process as claimed in claim 6, wherein first organic solvent can be selected from polar organic solvent like methanol, ethanol, isopropanol, butanol, acetone, water, dim ethyl formamide, dimethylacetamide, THF, N-methylpyrrolidone etc, non-polar organic solvent selected from toluene, xylene, ethyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, methylethyl ketone, methylisobutyl ketone, diethylether, diisopropyl ether etc or a mixture of polar and non-polar organic solvent.
9. The process as claimed in claim 7, wherein first organic solvent can be a mixture or polar and non-polar organic solvent preferably methanol and toluene.
10. The process as claimed in claim 6, wherein second organic solvent can be selected from non-polar organic solvent like toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, diethylether, diisopropylether etc.
11. The process as claimed in claim 9, wherein second organic solvent is heptane.
12. The process as claimed in claim 6, wherein nitrosulfide monohydrate is treated with first organic solvent at an ambient temperature.
13. The process as claimed in claim 6, residue is cooled below 35°C.
14. The process as claimed in claim 6, wherein anhydrous nitrosulfide is isolated by filtration followed by washing and drying till moisture content is below 0.5%.
15. The process as claimed in claim 6, wherein washing can be done with second organic solvent preferably, heptane.
16. Crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II).
17. Crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) having water content less than about 1.0% by Karl Fishcer.
18. Crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 29 at about 6.6, 13.7, 14.3, 16.1, 20.0, 21.4, 24.0, 28.5, and 32.9 degrees, and an IR spectrum having main bands at about 3282, 1926, 1612, 1598, 1438, 1271,1247,1074, 1051, 894, 881, 775, 759 and 572 cm-1.
19. The crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) as claimed in claim 18, which is further characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed

3.3, 6.6, 11.1, 11.8, 13.7, 14.3, 16.1, 17.9, 20.0, 21.4, 22.5, 24.0, 27.0, 28.5, 29.7 and 32.9 degrees, and an IR spectrum having main bands at about 3282, 3072, 2899, 2872, 1961, 1926, 1803, 1703, 1680, 1612, 1598, 1562, 1529, 1438, 1392, 1355, 1271, 1247, 1193, 1157, 1074, 1051, 894, 881, 840, 800, 775, 759, 734, 702, 642, 601, and 572 cm-1.
20. Crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide:' of formula (II), which is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.4, and an IR spectrum substantially as depicted in FIG.5.
21. Crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II) according to any preceeding claims having purity of atleast 99% and chiral purity of atleast 98%. when measured by area percentage of HPLC.
22. A process for preparation of crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II)

the process comprising:
a) enantioselectively oxidizing nitrosulflde anhydrous of formula (III) with an oxidizing agent
in the presence of a chiral auxiliary to provide Nitrosulfoxide (monohydrate) of formula (II)
in the form of a single enantiomer or in an enantiomerically enriched form;

b) suspending crystalline Nitrosulfoxide (monohydrate) in suitable organic solvent;
c) adding base to the suspension;
d) treating the suspension with suitable acid to adjust the pH in the range of 7.5 to 10.0;
e) isolating crystalline Nitrosulfoxide (monohydrate);
f) purifying crystalline Nitrosulfoxide (monohydrate) in polar organic solvent; and
g) isolating crystalline Nitrosulfoxide anhydrous form of formula (II).

23. The process as claimed in claim 22, wherin suitable oxidizing agent can be selected from hydroperoxide reagents such as t-butylhydroperoxide, cumene hydroperoxide, hydrogen peroxide and the like, peracids such as peracetic acid, m-chloroperbenzoic acid, perphthalic acid, and the like, sodium perborate and the like, and any other suitable oxidizing agents.
24. The process as claimed in claim 22, wherein chiral auxiliaries may be selected from transition metal complexes such as chiral titanium complexes, chiral zironium complexes, chiral vanadium complexes, chiral hafnium complexes, and the like and any other suitable chiral metal complexes.
25. The process as claimed in claim 22, wherein suitable organic solvent can be selected from polar organic solvents like methanol, ethanol, isopropanol, butanol, acetonitrile, acetone, THF, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, dimethylsufoxide and water or mixture thereof with water.
26. The process as claimed in claim 25, wherein suitable organic solvent is mixture of dimethylformamide, acetonitrile and water.
27. The process as claimed in claim 26. wherein dimethylformamide, acetonitrile and water are taken in the ratio of 2:1:4, respectively.
28. The process as claimed in claim 22, wherein base can be selected from akali or akaline earth metal carbonate, bicarobate, hydroxide, hydride etc.
29. The process as claimed in claim 28, wherein base is selected from sodium carbonate, potassium carbonate, sodium bicaronate, potassium bicaronate, sodium hydroxide, potassium hyrdroxide, lithium hydroxide, barium hydroxide, sodium hydride, lithium aluminum hydride etc.
30. The process as claimed in claim 22, wherein suitable acid can be selected from mineral acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or organic acid like acetic acid etc.
31. The process as claimed in claim 22, wherein pH is adjusted from about 8.5 to 9.0.
32. The process as claimed in claim 22, wherein crystalline Nitrosulfoxide (monohydrate) is isolated by filtration followed by washing and drying.
33. The process as claimed in claim 22, wherein suitable polar organic solvent can be selected from methanol, ethanol, isopropanol, butanol, acetonitrile, acetone, THF, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, dimethylsufoxide and water or mixture thereof with water.
34. The process as claimed in claim 22, wherein crystalline Nitrosulfoxide (monohydrate) is purified in acetone at about 40°C to 80°C.
35. A process for preparing dexlansoprazole of formula (I), or a salt thereof


the process comprising:
a) suspending 2,2,2-trifIouroethyI alcohol and a base in first organic solvent;
b) heating the reaction mixture at temperature Tl followed by cooling at an ambient temperature;
c) adding crystalline anhydrous form of 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]-sulfinyl]-lH-benzimidazole "Nitrosulfoxide" of formula (II)

to the reaction mixture;
d) heating the reaction mixture at temperature T2 followed by cooling to temperature Tl;
e) titurating reaction mixture with water followed by filtration;
f) treating aqueous filtrate with an second organic solvent and thereby adjusting the pH from about 7.5 to 10.0 with an acid; and
g) isolating dexlansoprazole (sesquihydrate) of formula (I), or a salt thereof.

36. The process as claimed in claim 35, wherein first organic solvent can be selected from polar orgaic solvent like methanol, ethanol, isopropanol, butanol, isobutanol, decanol, dodecanol, acetone, dimethylformamide, dimethylaceiamide, N-methylpyrrolidone, dimethylsulfoxide, THF, acetonitrile and the like.
37. The process as claimed in claim 35, wherein base is selected from sodium carbonate, potassium carbonate, sodium bicaronate, potassium bicaronate, sodium hydroxide, potassium hyrdroxide, lithium hydroxide, barium hydroxide, sodium hydride, lithium aluminum hydride etc.
38. The process as claimed in claim 35, wherein temperature Tl is from about 40°C to about 120°C.
39. The process as claimed in claim 35, wherein ambient temperature is less than about 35°C.
40. The process as claimed in claim 35, wherein temperature T2 is from about 70°C to about 130°C.

41. The process as claimed in claim 35, wherein second organic solvent is selected from acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, THF, 2-methyl THF or mixture thereof with water.
42. The process as claimed in claim 35. wherein acid can be selected from mineral acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or organic acid like acetic acid etc., preferably acetic acid.
43. The process as claimed in claim 35, wherein pH is adjusted from about 8.5 to 9.0.
44. A process for preparation of dexlansoprazole of formula (I), or a salt thereof

the process comprising:
a) suspending crystalline dexlansoprazole (Sesquihydrate) in suitable organic solvent;
b) partially concentrating the reaction mixture to remove organic solvent:
c) treating the residue with suitable anti-solvent;
d) filtering the reaction mixture followed by washing with anti-solvent; and
e) isolating dexlansoprazole (anhydrous) of formula (1), or a salt thereof.

45. The process as claimed in claim 44, wherein suitable organic solvent is selected from polar organic solvent like like methanol, ethanol, isopropanol, butanol, isobutanol, decanol, dodecanol, acetone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, THF, acetonitrile and the like.
46. The process as claimed in claim 44, wherein crystalline dexlansoprazole (Sesquihydrate) is treated with acetone below 35°C.
47. The process as claimed in claim 46, antisolvent can be selected from non-polar organic solvent like toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, diethylether, diisopropylether etc.
48. The process as claimed in claim 44. wherein reaction mixture is filtered at about 25°C to about 35°C.
49. A process for the preparation of dexlansoprazole of formula (I) or a salt thereof


which comprises of:
a) suspending crystalline dexlansoprazole (Sesquihydrate) in a first organic solvent:
b) concentrating the reaction mixture to remove the first organic solvent;
c) cool the residue;
d) treating residue with second organic solvent; and
e) isolating anhydrous dexlansoprazole (anhydrous) of formula (I), or a salt thereof.

50. The process as claimed in claim 50, wherein first organic solvent can be selected from polar organic solvent like methanol, ethanol, isopropanol, butanol, acetone, water, dimethylformamide, dimethylacetamide, THF, N-methylpyrrolidone etc, non-polar organic solvent selected from toluene, xylene, ethyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, methylethyl ketone, methylisobutyl ketone, diethylether. diisopropyl ether etc or a mixture of polar and non-polar organic solvent.
51. The process as claimed in claim 50, wherein first organic solvent can be a mixture or polar and non-polar organic solvent preferably methanol and toluene.
52. The process as claimed in claim 50, wherein second organic solvent can be selected from non-polar organic solvent like toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, diethylether, diisopropylether etc.
53. The process as claimed in claim 50, wherein nitrosulfide monohydrate is treated with first organic solvent at an ambient temperature.
54. The process as claimed in claim 50, residue is cooled below 35°C.
55. The process as claimed in claim 50, wherein washing can be done with second organic solvent preferably, heptane.
56. Crystalline dexlansoprazole sesquihydrate as claimed in claim 50, is characterized by which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 29 at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees, and an IR spectrum having main bands at about 2978, 2816, 1643, 1581, 1473, 1313, 1111, 972, 858, 827, 802, 742 and 576 cm-1.
57. Crystalline dexlansoprazole sesquihydrate as claimed in claim 56, which is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.6, and an IR spectrum substantially as depicted in FIG.7.
58. Crystalline dexlansoprazole anhydrous as claimed in claim 49, is characterized by which is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as 20 at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees, and an IR

spectrum having main bands at about 2978, 2816, 1643, 1581, 1473, 1313, 1111, 972, 858, 827, 802, 742 and 576 cm-1. 59. Crystalline dexlansoprazole anhydrous as claimed in claim 58, which is characterized by atleast one of an x-ray powder diffraction spectrum substantially as depicted in FIG.8, and an IR spectrum substantially as depicted in FIG.9.