Field of the Invention:
The present invention relates to an improved process for the preparation of Dexlansoprazole and its pharmaceutically acceptable salts thereof The present invention also relates to an improved process for the preparation of polymorphic forms of dexlansoprazole. Dexlansoprazole is chemically known as 2-[(i?)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyi]methyI]sulfmyl]-l/f-benzimidazole represented by the following structural formula-1.

Dexlansoprazole is the R-enantiomer of lansoprazole. It belongs to benzimidazole type proton pump inhibitors which work by undergoing a rearrangement to form a thiophilic species which then conveniently bind to gastric H K-ATPase, the enzyme involved in the final step of proton production in parietal cells and there by inhibit the enzyme subsequently inhibiting the secretion of the gastric acid. Therefore they are useful in the treatment of diseases which include peptic ulcer, heartburn, non-ulcer dispepsia, reflux esophagitis, and erosive esophagitis. Dexlansoprazole is commercially available under the brand name of Kapidex®.
Background of the Invention:
Some of the benzimidazole compounds capable of inhibiting the gastric H K ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as lansoprazole (US Ft No: 4,628,098), omeprazole (US Ft No: 4,255,431 and US 5,693,818), pantoprazole (US Ft. No. 4,758,579) and rabeprazole (US Ft No: 5,045,552). These compounds are structurally related sulphoxides having stereogenic center at sulphur atom and thus exist as two optical isomers i.e. enantiomers. The synthesis of racemic mixtures of these compounds has been disclosed in the earlier years, the synthesis of single enantiomer has become prominent.
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us 5,948,789 disclose a process for enantioselective synthesis of single enantiomer of omeprazole and other structurally related compounds. The example-22 of this patent particularly disclosed the preparation of dexlansoprazole by asymmetric oxidation. The said process involves the oxidation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole using cumene hydro peroxide ( in 1 molar ratio with respect of benzimidazole compound) in presence of diethyl tartrate, titanium isopropoxide, water and diisopropylethylamine in toluene medium for the period of 16 hours at room temperature provides the dexlanoprazole as an oil with 13% of sulfide, 8% of sulfone and 76% of sulfoxide by achiral HPLC. The oil compound further purified using flash chromatography to provide the dexlansoprazole as oil with the optical purity of 99.6%ee. The said patent involves flash chromatography and the formation of sulfone is also high, hence this process is commercially not suitable.
US 6,982,275 disclose a process for optically active sulfoxide derivatives by employing kagan oxidation conditions. But the process involves the use of excess mole ratio of oxidizing agent (i.e. cumene hydroperoxide) in 2.5 to 10 molar equivalents relative to the benzimidazole starting material and the reaction is carried out at low temperatures between -20 to 20°C. The said application disclosed that the excess amount of oxidation agent used in the reaction helps to reduce the sulfone formation. However the usage of high amount of oxidation agent increases the over all cost of product and at the same time excess amount of base required for the decomposition of unreacted oxidizing agent substantially led to the increase in the formation of unwanted impurities. Moreover the oxidation reaction was carried out at low temperatures, which in general commercially not recommendable.
H.B.Kagan et.al in their resetirch publications, namely Tetrahedron Vol.43, No 21, pp 5135 to 5144, 1987 and J.Am.Chem. Soc, 1984, 106, 8188-8193, have disclosed the process for asymmetric oxidation of sulfides to sulfoxides using modified Sharpless reagent i.e. a combination of titanium isopropoxide, diethyl tartrate, and tertiary butyl hydroperoxide in the presence of water. But the reactions produced maximum yield while performed at -20° C, which is not preferred in large scale industrial process.
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wo 2008/18091 particularly disclosed a process for the preparation of omeprazole salts, by the asymmetric oxidation of 5-methyoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-lH-benzimidazole with a oxidizing agent in presence of chiral transition metal complex without using organic solvent and a base.
Anhydrous and hydrated crystalline forms of dexlansoprazole are disclosed in US 6462058. The said patent also disclosed a process for the preparation of both hydrated and anhydrous crystalline form. There is a need in the art for alternate process for the preparation of anhydrous dexlansoprazole.
US 2006/57095 disclosed a process for the preparation of amorphous dexlansoprazole by heating the hydrated crystalline dexlansoprazole at high temperatures for longer hours. The process requires high temperature for longer hours for the conversion of crystalline into ainorp)hous form as well as the chemical purity of the obtained substance is not satisfactory. Hence this process is not suitable for the commercial scale up. There is a need in the art for the preparation of amorphous dexlansoprazole.
There is a demand and a need for an enantioselective process that can be used in the large scale for the manufacture of the enantiomers of pharmacologically active compounds. The present invention provides an efficient process for the preparation of dexlansoprazole using kagan conditions with the optimum amount of oxidation agent at ambient temperature, which provides high yields, purity with low levels of sulfones.
Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of dexlansoprazole compound of formula-1, which comprise of oxidizing 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1 H-benzimidazole with an oxidizing agent in presence of a chiral titanium complex and a base, characterized in that the oxidizing agent used in the ratio of 1.1 to 1.4 with respect to the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1 H-benzimidazole compound of formula-2.

The second aspect of the present invention is to provide an improved process for the preparation of amorphous dexlansoprazole compound of formula-1.
The third aspect of the present invention is to provide a process for the preparation of anhydrous crystalline form of dexlansoprazole compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation of sesquihydrate crystalline form of dexlansoprazole compound of formula-1.
Detailed description of the Invention:
The present invention provides an improved process for the preparation of Dexlansoprazole compound of formula-1 and its pharmaceutically acceptable salts thereof. Dexlansoprazole is chemically known as 2-[(i?)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl] -1 ^-benzimidazole

Accordingly, the first aspect of the present invention provides a cost effective and industrially feasible process for the preparation of dexlansoprazole compound of formula-1 and its pharmaceutically acceptable sahs, which comprises of asymmetrically oxidizing the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole compound of formula-2

with an optimum amoimt of oxidizing agent in presence of a chiral transition metal complex, an organic solvent and a base, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole compound of formula-2,
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optionally converting the obtained compound of formula-1 into its pharmaceutically acceptable salts.
According to the present invention, the oxidation is carried out in the presence of a suitable oxidizing agent selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, selenium dioxide, sodium hypochlorite, sodium metaperiodate and the like; Preferably, the oxidizing agent used in the process is cumene hydroperoxide.
As per the prior art, the asymmetric oxidation of sulfide derivative is carried out using either one equivalents (US 5948789) or more equivalents of oxidizing agent (US 6982275) with respect to sulfide, in presence of a base, organic solvent, chiral metal ligand to provide the corresponding sulfoxide compound. If less amount of oxidizing agent is used, the reaction is incomplete and the sulphide compound used as starting material remains unreacted and contaminates the sulfoxide product. If excess amount of oxidizing agent used leads to the increase in cost of over all production as well as the impurity formation due to over oxidation. Whereas the present invention utilizes the optimum amount of oxidizing agent for the said reaction avoids the prior art problems. In the International publication number WO 2008/018091, the above said asymmetric oxidation carried out using a suitable oxidizing agent without the use of organic solvent and a base, to endup with the alkali metal salt of sulfoxide compound. It specifically exemplified the preparation of omeprazole magnesium and potassium salts and not dexlansoprazole.
According to the present invention, the asymmetric oxidation is carried out in the presence of a chiral transition metal complex, which is prepared from a transition metal catalyst and a chiral ligand. The transhion metal is selected fi-om the group comprising titanium, vanadium, molybdenum and tungsten, preferably titanium and vanadium compound. Preferred transition metal compound is titanium (IV) isopropoxide, titanium (IV)propoxide, titanium(IV)ethoxide, titanium(IV)methoxide, vanadium oxy tripropoxide or vanadium oxy triisopropoxide and the like. The chiral ligand used is selected from

chiral diols which are esters of tartaric acid particularly (+)-diethyl L-tartarate or (-)-diethyl D-tartarate, (+)-dimethyl L- tiirtarate or (-)- dimethyl D-tartarate and the like.
Further, the asymmetric oxidation of the present invention is carried out in presence of catalytic amount of water. The oxidation reaction of the present invention is carried out at a temperature in the range of 20 to 30°C, preferably between 21-28°C more preferably between 21-25°C, for a period of about 1-6 hours, preferably between 1-3 hours.
According to the present invention, the base used in the oxidation reaction is selected from a group comprising of but not limited to tertiary butylamine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like preferably N,N-diisopropylethylamine.
The asymmetric oxidation in the present invention is carried out in a suitable solvent and the solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like; preferably toluene
The dexlansoprazole obtained after the asymmetric oxidation may be further converted into its pharmaceutically acceptable salts by the conventional methods. The starting material 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]thio]-lH-benzimidazole compound of formula-2 can be prepared as per the process known in the art.
The second aspect of the present invention provides a process for the preparation of amorphous dexlansoprazole compound of formula-1, which comprises of the following steps,
a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof,
b) treating the reaction mixture with aqueous ammonia,
c) subjecting the reaction mixture to carbon treatment,
d) filtering the reaction mixture through hyflow,
e) treating the filtrate with aqueous lammonia.

f) stirring the reaction mixture and filtering the solid,
g) adding suitable chloro solvents like methylene chloride or chloroform to the obtained solid,
h) separating water from the organic layer,
i) distilling off the solvent from the organic layer under reduced pressure,
j) adding a suitable ketone solvent selected from acetone or methyl isobutyl ketone to
obtained amorphous solid and co-distilling off the acetone from the reaction mixture
under reduced pressure to get the amorphous dexlansoprazole.
In a preferred embodiment of the present invention, the process for the preparation of amorphous dexlansoprazole compound of formula-1 comprises of the following steps;
a) dissolving dexlansoprazole in acetone at room temperature,
b) treating the reaction mixture with aqueous ammonia,
c) subjecting the reaction mixture to carbon treatment,
d) filtering the reaction mixture through hyflow,
e) treating the filtrate with aqueous ammonia,
f) stirring the reaction mixture for 30 minutes at 25-30°C and filtering the solid,
g) adding methylene chloride to the obtained solid, h) separating water from the organic layer,
i) distilling off methylene chloride from the organic layer under reduced pressure, j) adding acetone to the obtained solid and co-distilled off the solvent from the reaction mixture under reduced pressure to get the amorphous dexlansoprazole.
The third aspect of the present invention provides a process for the preparation of anhydrous crystalline form of dexlansoprazole compound of formula-1, which comprises of the following steps,
a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof,
b) adding the obtained solution to a suitable hydrocarbon solvent selected fi-om toluene, heptane, cyclohexane, hexane or mixtures thereof at a suitable temperature ranges from 0°C to reflux temperature of the solvent.
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c) stirring the reaction mixture at a suitable temperature,
d) filtering the solid, washing with suitable hydrocarbon solvent as defined above,
e) drying the solid to get the anhydrous form of dexlansoprazole.
The addition of hydrocarbon solvent in step b) of the present aspect of the invention can be done in either ways i.e., adding a suitable hydrocarbon solvent to a solution of dexlansoprazole or adding a solution of dexlansoprazole in suitable solvent to the hydrocarbon solvent at a suitable temperature.
In a preferred embodiment of the present invention, the anhydrous crystalline form of dexlansoprazole compound of formula-1 comprises of the following steps;
a) Dissolving the amorphous dexlansoprazole in acetone,
b) adding the obtained solution to heptane at 35-45°C,
c) stirring the reaction mixture for an hour at 35-45°C,
d) filtering the solid, washing with heptane,
e) drying the solid to get the anhydrous crystalline form of dexlansoprazole.
The fourth aspect of the present invention provides a process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula-1, which comprises of the following steps,
a) dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof,
b) treating the reaction mixture with aqueous ammonia,
c) subjecting the reaction mixture to carbon treatment,
d) filtering the reaction mixture through hyflow,
e) treating the filtrate with aqueous ammonia,
f) stirring the reaction mixture and filtering the solid,
g) drying the solid to get the sesquihydrate of dexlansoprazole.
In a preferred embodiment of the present invention, the process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula-1 comprises of the following steps;

a) dissolving the dexlansoprazole in acetone at room temperature,
b) treating the reaction mixture with aqueous ammonia,
c) subjecting the reaction mixture to carbon treatment,
d) filtering the reaction mixture through hyflov^^,
e) treating the filtrate with aqueous ammonia,
f) stirring the reaction mixture for 30 minutes and filtering the solid,
g) drying the solid at less than 40°C to get the crystalline sesquihydrate of dexlansoprazole.
The dexlansoprazole which is used for the preparation of crystalline and amorphous form of the present invention may be in crude dexlansoprazole obtained directly from the reaction mixture or crystalline material or amorphous material or a mixture of crystalline and amorphous material.
The anhydrous and sesquihydrate crystalline dexlansoprazole as prepared by the present invention is characterized by its powder X-ray diffractogram values, which are similar to the PXRD values of anhydrous and sesquihydrate crystalline dexlansoprazole disclosed in US 6462058 respectively.
Dexlansoprazole prepared as per any aspect of the present invention can be micronized or milled to get the desired particle size. The particle size distribution (P.S.D) of dexlansoprazole can be measured using Malvern Mastersizer 2000 instrument.
The anhydrous crystalline dexlansoprazole particles prepared by the present invention having the mean particle size D[4,3] in the range from 2 to 35 microns and having D(0.9) in the range of 2 to 80 microns.
The crystalline sesquihydrate dexlansoprazole particles prepared by the present invention having the mean particle size D[4,3] in the range from 1 to 50 microns and having D(0.9) in the range of 2 to 120 microns.
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The related substance of dexlansoprazole were analyzed by HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: YMC-PAK ODS-A Flow rate: 1.0 ml/min; wavelength: 285 nm; Temperature: Ambient; Load: 10 \il; Run time: 50 min; Elution: Gradient; and using water and acetonitrile as a mobile phase.
The isomer content of dexlansoprazole were analyzed by chiral HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and intergrator Column: Chiralpak-lC, Flow rate: 1.0 ml/min; wavelength: 285 nm; Temperature: Ambient; Load: 10 ^il; Run time: 50 min; Elution: Gradient; and using a mixture of acetonitrile:TFA:DEA as a mobile phase and diluent.
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The process described in the present invention was demonstrated in examples illustrated below. These examples aie provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
ExampIe-1: Preparation of Dexlansoprazole:
Mixture of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole (50 grams) and toluene (400 ml) was heated to reflux temperature and water was removed by azeotropic distillation. The reaction mixture was cooled to room temperature under nitrogen atmosphere. Water (0.4 ml) and L(+)-diethyltatarate (22.4 grams) were added to the reaction mixture under nitrogen atmosphere. The reaction mixture was heated to 55-60°C and stirred for 15 minutes. Titanium isopropoxide (14.4 grams) was added to the reaction mixture, stirred for 60 minutes at 55-60°C and then cooled to 21-25°C. Diisopropyl ethyl amine (11.8 grams) and cvimene hydroperoxide (29.61 grams) were added to the reaction mixture and stirred for 2 hours at 20-25°C. The reaction mixture was quenched with sodium thiosulphate solution and the layers were separated. The organic layer washed with sodium thiosulphate solution and water (100 ml) was added to it. Methyl tertiary butyl ether (200 ml) followed by cyclohexane (1 L) was added to the organic layer and stirred for 2 hours at 25-35°C. The solid obtained was filtered and washed with methyl tertiary butyl ether. Acetone (250 ml) was added to the wet solid and stirred for 15 minutes at 25-35°C. Water (750 m) was added to reaction mixture at 25-30°C and stirred for 30 minutes. The solid was filtered washed with water. Yield: 75 grams Chiral Purity by HPLC: 99.00 %; other isomer: 0.34%; sulfone: 0.49%; sulfide: 0.07%
Example-2: Preparation of amorphous dexlansoprazole:
1% aqueous ammonia (100 ml) was added to a solution of dexlanosprazole (75 grams) obtained as per example-1 in acetone (200 ml) and the reaction mixture was subjected to carbon treatment. The reaction mixture was filtered through hyflow and the bed was washed with acetone. Aqueous ammonia (500 ml) solution was added to the
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filtrate and stirred for 45 minutes at room temperature. The solid obtained was filtered, washed with aqueous ammonia. Methylene chloride (400 ml) was added to the obtained wet solid and stirred. The organic layer was separated and dried over sodium sulphate. The dried organic layer was distilled off under reduced pressure at below 40°C, Acetone (100 ml) was added to the obtained amorphous solid and co-distilled off the reaction mixture completely under reduced pressure to get the amorphous dexlansoprazole. Yield: 20 grams;
Chiral Purity: 99.82%; other isomer: 0.04%; sulfone: 0.05%; sulfide: 0.01% Purity by HPLC: 99.75%
Example-3: Preparation of anhydrous dexlansoprazole
Amorphous dexlansoprazole (25 grams) was dissolved in acetone (50 ml) and filtered for particle free. The filtrate was added to the n-heptane (500 ml) at 38-42°C. The reaction mixture was stirred for an hour at 38-42°C. The solid was filtered and washed with n-heptane. The solid was dried at 38-42°C under reduced pressure until the water content to reach below 0.5% w/w to get the title compound Yield: 20.2 grams
Chiral Purity by HPLC: 99.90 %; other isomer: 0.01%; sulfone: 0.03%; sulfide: 0.06% Purity by HPLC: 99.80%; sulfone: 0.03%; sulfide: 0.06% Particle Size Distribution:
Before micronization: D(O.l): 2.26 ^im; D(0.5): 9.59 jim; D(0.9):56.12 ^im; D[4,3]: 20.46 \im; After micronization: D(O.l): 1.26 ^im; D(0.5):4.54 ^im; D(0.9):9.93; D[4,3]: 5.18 ^un;
£xample-3: Preparation of crystalline sesquihydrate of dexlansoprazole:
1% aqueous ammonia (100 ml) was added to a solution of dexlanosprazole (75 grams) obtained as per example-1 in acetone (200 ml) and the reaction mixture was subjected to carbon treatment. The reaction mixture was filtered through hyflow and the bed was washed with acetone. Aqueous ammonia (500 ml) solution was added to the filtrate and stirred for 45 minutes at room temperature. The solid obtained was filtered
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and washed with aqueous ammonia. The solid was dried at below 40°C under reduced
pressure until the water content to reach below 6-8% w/w to get the title compound.
Yield: 24 grams
Cliiral Purity by HPLC: 99.81 %; other isomer: 0.03%; sulfone: 0.04%; sulfide: 0.05%
Purity by HPLC: 99.77%; sulfone: 0.04%; sulfide: 0.05%
Particle Size Distribution:
Before micronization: D(O.l): 1.44 ^im; D(0.5): 8.90 urn; D(0.9):88.35 ^m; D[4,3]:
27.57 |im;
After micronization: D(O.l): 0.67 ^im; D(0.5):2.06 ^im; D(0.9):5.25; D[4,3]: 2.57 \im;
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We Claim:
1. An improved cost effective and commercially feasible process for the preparation of dexlansoprazole compound of formula-1 and its pharmaceutically acceptable salts, which comprises of asymmetrically oxidizing the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1 H-benzimidazole compound of formula-2

with an optimum amount of oxidizing agent in presence of a chiral transition metal complex, an organic solvent, a base and catalytic amount of water, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole compound of formula-2 and the oxidation is carried out at a temperature of 22 to 28°C.
2. The process as claimed in claim 1, where in the oxidizing agent used is cumene hydroperoxide in an amount of 1.1 to 1.4 molar equivalents with respect to 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole compound of formula-2.
3. The process as claimed in claim 1, wherein the organic solvent used is toluene and the base used is diisopropyl ethyl amine.
4. The process according to claim 1, where in the chiral transition metal complex comprises of titanium isopropoxide and L(+)-diethyl tartarate.
5. An improved cost effective process for the preparation of dexlansoprazole compound of formula-1 and its pharmaceutically acceptable sahs, which comprises of asymmetrically oxidizing the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-l H-benzimidazole compound of formula-2
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with cumene hydroperoxide in presence of a titanium isopropoxide, L(+)-diethyl tartarate, diisopropyl ethyl amine and a catalytic amount of water in toluene medium to provide the dexlansoprazole compound of formula-1, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole compound of formula-2 and the oxidation is carried out at a temperature of 22 to 28°C.
6. Process for the preparation of amorphous dexlansoprazole compound of formula-1,
which comprises of the following steps,
a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof,
b) treating the reaction mixture with aqueous ammonia,
c) subjecting the reaction mixture to carbon treatment,
d) filtering the reaction mixture tlirough hyflow,
e) treating the filtrate with aqueous ammonia,
f) stirring the reaction mixture and filtering the solid,
g) adding suitable chloro solvents like methylene chloride or chloroform to the obtained solid,
h) separating the water from organic layer,
i) distilling off the solvent from the organic layer under reduced pressure, j) adding a suitable ketone solvent selected from acetone or methyl isobutyl ketone to the obtained amorphous solid and co-distilling the solvent from the reaction mixture under reduced pressure to get the amorphous dexlansoprazole.
7. Process for the preparation of amorphous dexlansoprazole compound of formula-1,
which comprises of the following steps,
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a) Dissolving dexlansoprazole in acetone at room temperature,
b) treating the reaction mixture v/ith aqueous ammonia,
c) subjecting the reaction mixture to carbon treatment,
d) filtering the reaction mixture through hyflow,
e) treating the filtrate with aqueous ammonia,
f) stirring the reaction mixture for 30 minutes and filtering the solid,
g) adding methylene chloride to the obtained solid, h) separating water fi-om the organic layer,
i) distilling off the methylene chloride from the organic layer under reduced
pressure, j) adding acetone to the obtained amorphous solid and co-distilling the acetone from
the reaction mixture under reduced pressure to get the amorphous
dexlansoprazole.
8, Process for the preparation of anhydrous crystalline form of dexlansoprazole
compound of formula-1, which comprises of the following steps,
a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof,
b) adding above obtained solution to a suitable hydrocarbon solvent selected from toluene, heptane, cyclohexane., hexane or mixtures thereof at a temperature from 0°C to reflux temperature of the solvent,
c) stirring the reaction mixture at a suitable temperature
d) filtering the solid, washing with suitable hydrocarbon solvent as defined above,
e) drying the solid to get the anhydrous form of dexlansoprazole.
9. Process for the preparation of anhydrous crystalline form of dexlansoprazole
compound of formula-1, which comprises of the following steps,
a) Dissolving amorphous dexlansoprazole in acetone,
b) Adding the above obtained solution to heptane at 35-45°C,
c) stirring the reaction mixture for an hour at 35-45°C,
d) filtering the solid and washing with heptane,
e) drying the solid to get the anhydrous crystalline form of dexlansoprazole.

10. Process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula-1, which comprises of the following steps,
a) Dissolving the dexlansoprazole in acetone at room temperature,
b) treating the reaction mixture with aqueous ammonia,
c) subjecting the reaction mixture to carbon treatment,
d) filtering the reaction mixture through hyflow,
e) treating the filtrate with aqueous ammonia,
f) stirring the reaction mixture for 30 minutes and filtering the solid,
g) drying the solid at below 40°C to get the crystalline sesquihydrate of
dexlansoprazole having water content of 6-8 %w/w.