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 AMORPHOUS DEXLANSOPRAZOLE"
We, CADILA HEALTHCARE LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad - 380 015, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The invention relates to Dexlansoprazole and its intermediates thereof. In particular, it relates to an improved process for preparation of amorphous Dexlansoprazole. The invention relates pharmaceutical compositions that include amorphous dexlansoprazole substantially free from crystalline forms. BACKGROUND AND PRIOR ART
Lansoprazole is a well-known gastric acid secretion inhibitor and is useful as an anti ulcer agent. Lansoprazole can exists in its optical isomers like, R-lansoprazole and S-lansoprazole.
(R)-(+)-lansoprazole "Dexlansoprazole" is chemically, (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfmyl]-lH-benzimidazole, or (+)-(2)-[(R)-{[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl3suIfinyl]-IH-benzimidazole, and can be represented by structural formula (I).

U.S. Patent No. 6,462,058 discloses a crystal of (R)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole (dexlansoprazole) and process for the preparation thereof, 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. It 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.
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.
US Patent No. 7,737,282 B2 discloses an amorphous compound of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyI]sulfinyI]lH-benzimidazole or a salt thereof.
U.S. Patent Application No. 2006/0057195 A1 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 No. WO 2009/087672 A1 discloses a process for preparing amorphous R-(+)-lansoprazole comprising optically resolving racemic lansoprazole by the formation of host-guest inclusion complexes (with R-2,2'-dihydroxy-1,1-binaphthyl) by selectively and reversibly including chiral guest molecules in the lansoprazole. The amorphous dexlansoprazole is obtained by evaporation of solvent. The amorphous form is stabilized by addition of polyvinylpyrrolidone (polymer).
International (PCT) Publication No. WO 2009/117489 Al discloses a process for the preparation of amorphous Dexlansoprazole and solid dispersion thereof with pharmaceutically acceptable carriers.
International (PCT) Publication No. WO 2009/088857 Al discloses crystalline solvated
forms of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]methyl]sulfmyl]-lH-
benzimidazole.
International (PCT) Publication No. WO 2009/088857 Al discloses crystalline solvated forms of dexlansoprazole.
International (PCT) Publication No. WO 2011/004387 Al discloses the process for the isolation of amorphous dexlansoprazole by dissolving dexlansoprazole in solvent, cooling, isolating dexlansoprazole solvate, and drying the obtained compound under reduced pressure to get amorphous dexlansoprazole.
US Patent Application No. 2011/0020410 Al discloses stable solid dosage form comprising a non-toxic base and an amorphous dexlansoprazole having a proton pump inhibitor (PPI) activity. US Patent Application No. 2010/0125143 Al discloses the process for the preparation of dexlansoprazole by condensation of Nitrosulfoxide with (e.e. 96%) with trifluoroethanol in presence of strong base (K2CO3 is included as strong base).
The cited prior art discloses various crystalline forms of dexlansoprazole as well as an amorphous form. There are few approaches provided for the preparation of amorphous form of dexlansoprazole. However, none of the prior art reference discloses the method of obtaining stable dexlansoprazole substance as such. There is no disclosure for the stability in terms of purity or appearance of amorphous drug substance.
Hence, there remains a need to provide improved processes for the preparation of amorphous dexlansoprazole, which is atleast stable under ordinary stability conditions with respect to purity and change in appearance and is free flowing powder. The process is simple, cost-effective, eco-friendly and commercially viable. SUMMARY OF INVENTION
In one general aspect, there is provided a stable amorphous form of dexlansoprazole or a salt thereof of formula (I)


In a further aspect, there is provided stable amorphous form of dexlansoprazoie or a salt thereof of formula (I) having water content from about 0.2% to about 5% wt/wt.
According to yet another general aspect, any form of dexlansoprazoie can be spray dried by dissolving or suspending or slurring in suitable solvent or solvent-water system to get amorphous form. In the present invention feed stock of dexlansoprazoie in water, solvent or aqueous solvent system is spray-dried. Thus obtain spry-dried compound is in amorphous form, this fact is again confirmed by the X-ray powder diffractogram of spray-dried dexlansoprazoie.
One another aspect of the invention, there is provided a process for manufacturing amorphous form of dexlansoprazoie or salts thereof, which comprising:
(a) suspending dexlansoprazoie or its salts in suitable organic solvent;
(b) adding suitable amine to said suspension to prepare a feedstock in suitable organic solvent or a mixture thereof;
(c) spray drying of feed stock, and;
(d) isolating dexlansoprazoie or its salts in amorphous form.
In a preferred feature, the feedstock for spray drying is either a clear solution or in suspension form.
In another preferred feature, the spray drying of dexlansoprazoie is performed by a) maintaining the feed rate of the feed stock at 50 - 250 ml/hr, particularly 100-200 ml/hr; b) maintaining the inlet temperature in the range of 35°C-80°C, particularly, 50°C-70°C; c) maintaining the aspirator rate between 1000-1500 rpm, particularly 1200-1400 rpm; d) maintaining the outlet temperature in the range of 30°C to 60° C, particularly, 40°C to 50°C; e) maintaining air flow at 2-4 Kg/cm, particularly 2 Kg/cm; f) maintaining Atomizer speed between 20,000-100,000 rpm, particularly, 40,000-50,000 rpm, and; g) maintaining the vacuum at 30-120 mm of Hg, particularly 50-80 mm of Hg.
According to more general aspect, there is provided a process for preparation of amorphous dexlansoprazoie or salt thereof, the process comprising,
(a) suspending dexlansoprazoie. nH2O (wherein n is 0.1 to 1.5) in a suitable organic solvent;
(b) adding suitable amine to said suspension to prepare a feed stock in suitable organic solvent or a mixture thereof;
(c) spray drying of feed stock, and;

(d) isolating dexlansoprazole in amorphous form.
In one more general aspect, there is provided a process for preparation of amorphous dexlansoprazole or salt thereof, the process comprising,
(a) suspending dexlansoprazole.nH2O (wherein n is 0.1 to 1.5) in a suitable organic solvent;
(b) adding suitable amine to said suspension;
(c) removing organic solvent; and
(d) isolating amorphous dexlansoprazole or salt thereof.
In an aspect, the present invention provides dexlansoprazole amorphous of formula (I) 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.
An aspect of the present invention provides pharmaceutical compositions comprising dexlansoprazole substantially free from crystalline forms. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
FIG 1. shows the X-ray diffractogram (XRD) of the amorphous dexlansoprazole of the present invention obtained by spray drying technique.
FIG 2. shows the differential scanning calorimetry (DSC) of the amorphous dexlansoprazole of the present invention obtained by spray drying technique.
FIG.3 shows the Thermogravimetric analysis (TGA) of the amorphous dexlansoprazole of the present invention obtained by spray drying technique. DETAILED DESCRIPTION OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention, which leads to greater stability of amorphous dexlansoprazole. The invention also provides an improved process of spray drying the solution dexlansoprazole in a suitable organic solvent optionally in presence of suitable amines.
The invention provides stabilization of dexlansoprazole amorphous by spray drying a solution of dexlansoprazole.nH2O (wherein n is 0.1 to 1.5) in an organic solvent in presence of amine to obtain stable amorphous form of dexlansoprazole.
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 at a temperature from about 40°C to 50°C.

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.
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 particularly 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.
In a more preferred embodiment, the above dexlansoprazole amorphous is polymorphically pure; As used herein the term polymorphically pure amorphous form corresponds to composition containing dexlansoprazole amorphous form and not more than about 10% by weight, particularly, not more than 5%, and more particularly, not more than 1% by weight of
(a) dexlansoprazole characterized by a PXRD pattern having peaks at about 9.1, 9,9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees by X-ray powder diffraction analysis, designated as dexlansoprazole sesquihydrate or
(b) dexlansoprazole characterized by a PXRD pattern having peaks at about 7.4, 12.9, 15.1, 15.3, 19.9, 21.6, 23.9, and 26.0 degrees by X-ray.powder diffraction analysis, designated as dexlansoprazole anhydrous or
(c) mixture of (a) and (b).
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials. In the case of amorphous dexlansoprazole, "pure" also means about 99% of amorphous form free from any crystalline Form, as appropriate or in the case of crystalline solids.
As used herein, "stable dexlansoprazole" includes either: amorphous dexlansoprazole that after exposure to a relative humidity of 75% at 40°C, for a period of at least three months contains less than about 0.1% (wt/wt) sulfone or sulfide derivative by area percentage of HPLC, or amorphous dexlansoprazole that after exposure to a relative humidity of 75% at 40°C for a period of at least three months does not change its color or amorphous dexlansoprazole that after exposure to a relative humidity of 75% at 40°C for a period of at least three months does not show characteristic peaks at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees by X-ray powder diffraction analysis.

As used herein, "stable dexlansoprazole" also includes either: amorphous dexlansoprazole that after exposure to a relative humidity of 60% at 25°C, for a period of at least three months contains less than about 0.1% (wt/wt) sulfone or sulfide derivative by area percentage of HPLC, or amorphous dexlansoprazole that after exposure to a relative humidity of 60% at 25°C for a period of at least three months does not change its color or amorphous dexlansoprazole that after exposure to a relative humidity of 65% at 25°C for a period of at least three months does not show characteristic peaks at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees by X-ray powder diffraction analysis.
As used herein, "stable dexlansoprazole" may also includes either: amorphous dexlansoprazole that after exposure to a 2°C to 8°C, for a period of at least three months "contains less than about 0.1% (wt/wt) sulfone or sulfide derivative by area percentage of HPLC, or amorphous dexlansoprazole that after exposure to a 2°C to 8°C, for a period of at least three months does not change its color or amorphous dexlansoprazole that after exposure to a 2°C to 8°C, for a period of at least three months does not show characteristic peaks at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees by X-ray powder diffraction analysis.
"Suitable solvent" means a single or a combination of two or more solvents.
A preferred embodiment of the invention is spray drying a solution of dexlansoprazole and that involves the spray drying of feed stock, which is prepared as discussed below, wherein any crystalline form of dexlansoprazole is used. The feedstock is dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying is carried out under the following parameters.

Sr.No Parameters Conditions
a) Feed pump 10-50 rpm
b) Inlet temperature 35°-80°C
c) Outlet temperature 30°-60°C
d) Aspirator rate 1000-1500 rpm
e) Vacuum for conveying the dry product 30-120 mm of Hg
f) Hot air supply 2-4 Kg/cm2
g) Atomizer Speed: 40,000-100,000 rpm
Any known form of dexlansoprazole or the filtered cake that is obtained as an end result of the reaction or reaction mass comprising dexlansoprazole or solution comprising dexlansoprazole, can be used for the preparation of feed stock; most particularly dexlansoprazole.nH20 (wherein n is 0.1 to 1.5) which may include crystalline dexlansoprazole

anhydrous Form, crystalline dexlansoprazole sesquihydrate or crystalline dexlansoprazole monohydrate is used.
In the present invention, feed stock of dexlansoprazole is conveniently prepared by dissolving any known forms or wet cake of dexlansoprazole in the solvent selected from the group of solvents e.g. acetone, C1-4 alcohol, C2-6 acetate, acetonitrile, methylene dichloride, water or mixture thereof Most particularly water, methanol, ethanol, acetone, ethyl acetate, methylene dichloride, water-methanol or water-ethanol, water-acetone are suitable solvent used or such solvents that evaporate easily to afford dry product, most particularly acetone, methanol, ethanol or mixtures of the above.
In one general aspect, there is provided stable amorphous form of dexlansoprazole or a salt thereof of formula (I)

According to further general aspect, any form of dexlansoprazole can be spray dried by dissolving or suspending or slurring in suitable solvent or solvent-water system to get amorphous form. In the present invention feed stock of dexlansoprazole in water, solvent or aqueous solvent system is spray-dried. Thus obtain spry-dried compound is in amorphous form, this fact is again confirmed by the X-ray powder diffractogram of spray-dried dexlansoprazole.
According to preferred aspect, the present invention provides a process for manufacturing amorphous form of dexlansoprazole or salts thereof, which comprising:
(a) suspending dexlansoprazole in suitable organic solvent;
(b) adding suitable amine to said suspension to prepare a feed stock in suitable organic solvent or a mixture thereof;
(c) spray drying of feed stock, and;
(d) isolating dexlansoprazole in amorphous form.
The suspension of dexlansoprazole can be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable organic solvent selected from one or more of ketone, C1-4 alcohol, C2-6 acetate, nitrile, halogenated hydrocarbon, water or mixture thereof In particular acetone, methanol, ethanol, acetone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, methylene dichloride, water-methanol or water-ethanol, water-acetone or any combinations thereof
The suspension is treated with a suitable amines selected from ammonia, ammonium hydroxide, methylamine, diethylamine, triethylamine, diisopropylethylamine, trimethylamine,

diisopropylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine, 1,4-diazobicyclo-[2,2,2]octane (Dabco), l,5-diazabicyclo[[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and the like, particularly, ammonia.
In a specific preferred embodiment of the invention, weighed quantity of dexlansoprazole crystalline sesquihydrate is dissolved in 2-10 volumes of chosen solvent, particularly 4-5 volumes solvent at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercell, and filtrate is spray dried under following conditions. The obtained powder is further dried at 40°C for 12-16 hours under vacuum to afford stable form of dexlansoprazole amorphous.

Sr.No Parameters Conditions
a) Feed pump 10-50 rpm
b) Inlet temperature 35°-80°C
c) Outlet temperature 30°-60°C
d) Aspirator rate 1000-1500 rpm
e) Vacuum for conveying the dry product 50-120 mm of Hg
f) Hot air supply 2-4 Kg/cm2
g) Atomizer Speed: 40,000-100,000 rpm
In a preferred feature, the feedstock for spray drying is either a clear solution or in dispersion form.
In another preferred feature, the spray drying of dexlansoprazole is performed by a) maintaining the feed rate of the feed stock at 50 - 250 ml/hr, particularly 100-200 ml/hr; b) maintaining the inlet temperature in the range of 35°C - 80°C, particularly, 50°C-70 °C; c) maintaining the aspirator rate between 1000-1500 rpm, particularly 1200-1400 rpm; d) maintaining the outlet temperature in the range of 30°C to 60° C, particularly, 40°C to 50°C; e) maintaining air flow at 2-4 Kg/cm, particularly 2 Kg/cm; i) maintaining Atomizer speed between 20,000-100,000 rpm, particularly, 40,000-50,000 rpm, and; g) maintaining the vacuum at 30-120 mm of Hg, particularly 50-80 mm of Hg.
According to the another general aspect, there is provided process for preparation of amorphous dexlansoprazole or salt thereof, the process comprising of
(a) suspending dexlansoprazole.nH2O (wherein n is 0.1 to 1.5) in a suitable organic solvent;
(b) adding suitable amine to said suspension to prepare a feedstock in suitable organic solvent or a mixture thereof;
(c) spray drying of feed stock, and;

(d) isolating dexlansoprazole in amorphous form.
The suspension of dexlansoprazole.nH2O (wherein n is 0.1 to 1.5) can be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable organic solvent selected from the group consisting of ketone, C1-4 alcohol, C2-6 acetate, nitrile, halogenated hydrocarbon, water or mixture thereof. Most particularly pure acetone, methanol, ethanol, acetone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, methylene dichloride, water-methanol or water-ethanol, water-acetone and any combinations thereof.
The dexlansoprazole used as the starting material can be in different crystalline forms for example and not limited to anhydrous, monohydrate, sesquihydrate or mixture thereof. The suspension can be subjected to spray drying conditions as mentioned herein above to isolate amorphous dexlansoprazole.
The suspension is treated with a suitable amines selected from ammonia, ammonium hydroxide, methylamine, diethylamine, triethylamine, diisopropylethylamine, trimethylamine, diisopropylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine, 1,4-diazobicyclo-[2,2,2] octane (Dabco), l,5-diazabicyclo[[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and the like, particularly ammonia.
In an embodiment, there is provided the process for preparation of amorphous dexlansoprazole or salt thereof, the process comprising,
(a) suspending dexlansoprazole.nH2O (wherein n is 0.1 to 1.5) in a suitable organic solvent;
(b) adding suitable amine to said suspension;
(c) removing organic solvent; and
(d) isolating amorphous dexlansoprazole or salt thereof.
In general, the suspension of dexlansoprazole can be prepared in a suitable organic solvent as described-herein above. The suitable amine can be added to the suspension before the removal of organic solvent. The suitable amine can be selected from the amines described herein above in the specification.
The embodiments include removal of organic solvent for isolation of amorphous dexlansoprazole. The solvent can be removed by evaporation techniques includes using distillation under reduced pressure, rotational distillation device such as a Buchi Rotavapor, spary drying, agitated thin film drying or freeze drying and the like particularly by distillation under reduced pressure.
The addition of amine before the removal of solvent provides stable dexlansoprazole. The stable dexlansoprazole doesn't change its color upon stability. The product obtained is yellow to offwhite color instead of pink to dark brown color with prior art methods for removal of solvents. The product is free flowing and free from residual organic solvents. The stable

dexJansoprazole contains less than about 0.1% (wt/wt) sulfone or sulfide derivative by area percentage of HPLC.
In an embodiment, the present invention provides dexlansoprazole amorphous of formula (I) having 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).
The invention also provides the isolation of amorphous dexlansoprazole or salt -thereof after drying as described herein above. The suitable salts can be selected from alkali or alkaline earth metal salts of dexlansoprazole, particularly sodium, potassium, lithium, calcium, magnesium and the like, particularly sodium or potassium salt in amorphous form.
The invention includes converting amorphous dexlansoprazole obtained from spray drying to its alkali or alkaline earth metal salts thereof by treating with suitable inorganic base selected from sodium hydroxide, potassium hydroxide, calcium hydroxide or acetate, lithium hydroxide, magnesium methoxide etc.
An aspect of the present invention provides compositions comprising dexlansoprazole substantially free of one or more of its corresponding impurities as measured by HPLC.
An aspect of the present invention provides compositions comprising dexlansoprazole substantially free residual solvents as measured by GC.
An aspect of the present invention provides compositions comprising dexlansoprazole substantially free from crystalline forms.
Amorphous dexlansoprazole is characterized as substantially depicted in XRD (FIG.l), DSC (FIG.2) and TGA (FrG.3) as shown herein above.
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 : 10
Scattering Slit : 10
Receiving Slit : 0.15 mm
Monochromator RS : 0.8 mm

Counter : Scintillation Counter
Scan Mode : Continuous
Scan Speed : 3.0000 /Min
Sampling Width : 0.020
Scan Axes : Two Theta / Theta
Scan Range : 2.0000 to 40.0000
Theta Offset : 0.0000
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.
An embodiment of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous dexlansoprazole substantially free from crystalline sesquihydrate, and one or more pharmaceutically acceptable carriers, excipients or diluents.
An embodiment of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous dexlansoprazole substantially free from crystalline anhydrous, and one or more pharmaceutically acceptable carriers, excipients or diluents.

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 dexlansoprazole sesquihydrate and anhydrous form as starting material 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)

(A) Preparation of Nitrosulfoxide (Monohydrate)
100 g Nitrosulfide 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)


100 g Nitrosuflide anhydrous and 1000 ml toluene were taken in the round bottom flask at25°C 15.7 g of (+)-DiethyI 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 diisopropyiethyl amine was added and reaction mixture was further cooled to -I0°C. 239.4 g of cumene hydrogen peroxide was slowly added within 3-4 hours at -10°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 cone, 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 96.1 i% 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%. 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%. 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%. 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%. Example-6: Preparation of Amorphous dexlansoprazole
75.0 g of dexlansoprazole sesquihydrate is dissolved in 300.0 mL of acetone at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 3.8 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 75.0 mL acetone. The filtrate is concentrated under vacuum below 45°C till 100 mL acetone remains. 655 mL acetone was added and stirred to get clear solution. 2.2 mL liquor ammonia solution was added into the reaction mixture followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C ± 5°C under vacuum for 16 hours to get 17.0 g of stable amorphous dexlansoprazole.

Sr.No Parameters Conditions
a) Feed pump 30 rpm
b) Inlet temperature 60°C
c) Outlet temperature 40°C
d) Aspirator rate 1300 rpm
e) Vacuum for conveying the dry product 80 mm of Hg
h) Hot air supply 2 Kg/cm"
The spray-dried dexlansoprazole is amorphous in nature. The obtained product contains residual solvent well within ICH limit. Example-7: Preparation of Amorphous dexlansoprazole

75.0 g of dexlansoprazoie sesquihydrate is dissolved in 325.0 mL of ethyl acetate at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 3.8 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 75.0 mL ethyl acetate. The filtrate is concentrated under vacuum below 45°C till 100 mL ethyl acetate remains. 650 mL ethyl acetate was added and stirred to get clear solution. 2.2 mL liquor ammonia solution was added into the reaction mixture followed by spray drying in J1SL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C ± 5°C under vacuum for 16 hours to get 20.0 g of stable amorphous dexlansoprazoie.

Sr.No Parameters Conditions
a) Feed pump 30rpm
b) Inlet temperature 60°C
c) Outlet temperature 40°C
d) Aspirator rate 1300 rpm
e) Vacuum for conveying the dry product 80 mm of Hg
h) Hot air supply 2 Kg/cm2
The spray-dried dexlansoprazoie is amorphous in nature. The obtained product contains residual solvent well within ICH limit. Melting point: 76.5-79°C, optical purity > 99% and water content by TGA<1%. Example-8: Preparation of Amorphous dexlansoprazoie
75.0 g of dexlansoprazoie anhydrous is dissolved in 300.0 mL of methanol at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C To this, 3.8 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 75.0 mL methanol. The filtrate is concentrated under vacuum below 45°C till 100 mL methanol remains. 600 mL methanol was added and stirred to get clear solution. 2.3 mL liquor ammonia solution was added into the reaction mixture followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C ± 5°C under vacuum for 16 hours to get 20.0 g of stable amorphous dexlansoprazoie.

Sr.No Parameters Conditions
a) Feed pump 30 rpm

b) Inlet temperature 60°C
c) Outlet temperature 40°C
d) Aspirator rate 1300 rpm
e) Vacuum for conveying the dry product 80 mm of Hg
h) Hot air supply 2 Kg/cm2
The spray-dried dexlansoprazole is amorphous in nature. The obtained product contains residual solvent well within ICH limit. Example-9: Preparation of Amorphous dexlansoprazole
75.0 g of dexlansoprazole sesquihydrate is dissolved in 350.0 mL of methylene dichloride at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 3.8 g charcoal was added and stirred for 30 minutes at 25°C to 30CC. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 75.0 mL methylene dichloride. The filtrate is concentrated under vacuum below 45°C till 100 mL methylene dichloride. 600 mL methanol was added and stirred to get clear solution. 2.5 mL liquor ammonia solution was added into the reaction mixture followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C ± 5°C under vacuum for 16 hours to get 20.0 g of stable amorphous dexlansoprazole.

Sr.No Parameters Conditions
a) Feed pump 30 rpm
b) Inlet temperature 60°C
c) Outlet temperature 40°C
d) Aspirator rate 1300 rpm
e) Vacuum for conveying the dry product 80 mm of Hg
h) Hot air supply 2 Kg/cm2
The spray-dried dexlansoprazole is amorphous in nature. The obtained product contains residual solvent well within ICH limit. Melting point: 76.5-79°C, optical purity > 99%. Example-10: Preparation of Amorphous dexlansoprazole
75.0 g of dexlansoprazole sesquihydrate is dissolved in 300.0 mL of ethyl acetate at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 3.8 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel,

and the Hyflosupercel pad is washed with 75.0 mL ethyl acetate. The filtrate is concentrated
under vacuum below 45°C till 100 mL ethyl acetate remains. 655 mL ethyl acetate was added
and stirred to get clear solution. The solution is dried over anhydrous magnesium sulfate and 2.2
mL liquor ammonia solution was added into the reaction mixture followed by concentrating
under reduced pressure, to obtain amorphous dexlansoprazole.
Example-11:
Preparation of Amorphous dexlansoprazole
75.0 g of dexlansoprazole sesquihydrate is dissolved in 300.0 mL of acetone at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 3.8 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 50.0 mL acetone. The filtrate is concentrated under vacuum below 45°C till 80 mL acetone remains. 600 mL acetone was added and stirred to get clear solution. The solution is dried over anhydrous magnesium sulfate and 2.5 mL liquor ammonia solution was added into the reaction mixture followed by concentrating under reduced pressure, to obtain amorphous dexlansoprazole. Example-12: Preparation of Amorphous dexlansoprazole sodium:
75.0 g of amorphous dexlansoprazole is dissolved in 350.0 mL of acetone at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 75.0 mL acetone. The filtrate is treated with 10% sodium hydroxide solution (40 g). The reaction mixture is heated to 45°C for 2-4 hours. The reaction mixture is concentrated under vacuum till removal of solvent to obtain amorphous dexlansoprazole sodium.

Claims
1. A stable amorphous dexlansoprazole compound.
2. The compound as claimed in claim 1, which is substantially free from crystalline dexlansoprazole sesquihydrate.
3. The compound as claimed in claim 1, which is substantially free from crystalline dexlansoprazole anhydrous.
4. A process for stabilization of amorphous dexlansoprazole by spray drying a solution of dexIansoprazole.nH2O (wherein n is 0.1 to 1.5) in an organic solvent in presence of amine to obtain stable amorphous form of dexlansoprazole.
5. The process as claimed in claim 4 wherein spray drying a solution of dexlansoprazole involves the spray drying of feed stock into JISL Mini Spray-dried LSD-48 instrument.
6. The process as claimed in claim 4 wherein feed stock of dexlansoprazole is prepared by dissolving any known forms or wet cake of dexlansoprazole in the solvent.
7. The process as claimed in claim 6 wherein solvent can be selected from acetone, C1-4 alcohol, C2-6 acetate, acetonitrile, methylene dichloride, water or mixture thereof.
8. A process for manufacturing amorphous form of dexlansoprazole, which comprising:

(a) suspending dexlansoprazole in suitable organic solvent;
(b) adding suitable amine to said suspension to prepare a feed stock in suitable organic solvent or a mixture thereof;
(c) spray drying of feed stock, and;
(d) isolating dexlansoprazole in amorphous form.

9. The process as claimed in claim 8, wherein suspension can be. a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable organic solvent.
10. The process as claimed in claim 9, wherein suitable organic solvent can be selected from one or more of ketone, C1-4 alcohol, C2-6 acetate, nitrile, halogenated hydrocarbon, water or mixture thereof.
11. The process as claimed in claim 10, wherein suitable organic solvent can be selected from acetone, methanol, ethanol, acetone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, methylene dichloride, water-methanol or water-ethanol, water-acetone or any combinations thereof.
12. The process as claimed in claim 8, wherein amine is selected from ammonia, ammonium hydroxide, methylamine, diethylamine, triethylamine, diisopropylethylamine, trimethylamine, diisopropylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-

methylmorpholine, l,4-diazobicyclo-[2,2,2]octane (Dabco), l,5-diazabicyclo[[4.3.0]non-5-ene (DBN) and I,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and the like. 13. The process as claimed in claim 8, the spray drying of the feed stock can be done under following conditions,

Sr.No Parameters Conditions
a) Feed pump 10-50 rpm
b) Inlet temperature 35°-80°C
c) Outlet temperature 30°-60°C
d) Aspirator rate 1000-1500 rpm .
e) Vacuum for conveying the dry product 50-120 mm of Hg
f) Hot air supply 2-4 Kg/cm2
g) Atomizer Speed: 40,000-100,000 rpm
14. A process for preparation of amorphous dexlansoprazole or salt thereof, the process
comprising:
(a) suspending dexlansoprazole.nH2O (wherein n is 0.1 to 1.5) in a suitable organic solvent;
(b) adding suitable amine to said suspension to prepare a feedstock in suitable organic solvent or a mixture thereof;
(c) spray drying of feed stock, and;
(d) isolating dex lansoprazole in amorphous form.

15. The process as claimed in claim 14, wherein dexlansoprazole.nH2O can be selected from anhydrous, monohydrate, sesquihydrate and the like.
16. A process for preparation of amorphous dex lansoprazole or salt thereof, the process comprising:

(a) suspending dexlansoprazole.nH2O (wherein n is 0.1 to 1.5) in a suitable organic solvent;
(b) adding suitable amine to said suspension;
(c) removing organic solvent; and
(d) isolating amorphous dexlansoprazole or salt thereof.

17. The process as claimed in claim 16, wherein suitable organic solvent can be selected from one or more acetone, methanol, ethanol, acetone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, methylene dichloride, water-methanol or water-ethanol, water-acetone or any combinations thereof.
18. The process as claimed in claim 16, wherein suitable amine can be selected from one or more of amines ammonia, ammonium hydroxide, methylamine, diethylamine, triethylamine, diisopropylethylamine, tri methylamine, diisopropylamine, pyridine, 4-

dimethylaminopyridine (DMAP), N-methylmorpholine, 1,4-diazobicyclo-[2,2,2]octane (Dabco), l,5-diazabicyclo[4.3.0]non-5-ene(DBN) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and the like.
19.The process as claimed in claim 16, wherein sovlent can be removed by evaporation techniques includes using distillation under reduced pressure, rotational distillation device such as a Buchi Rotavapor, spary drying, agitated thin film drying or freeze drying and the like.
20. An amorphous dexlansoprazole prepared according to process of any preceding claims having chiral purity of greater than about 96% as determined by HPLC.
21. The process according to any preceding claims wherein amorphous dexlansoprazole isolated can be converted to its salts.
22. The process as claimed in claim 21, wherein suitable salts can be selected from alkali or alkaline earth metal salts of dexlansoprazole like sodium, potassium, lithium, calcium, magnesium, and the like.
23. A polymorphically pure amorphous dexlansoprazole.
24. The polymorphically pure amorphous dexlansoprazole as claimed in claim 23, wherein
composition containing dexlansoprazole amorphous formdoesn't have more than about 10%
by weight, particularly, not more than 5%, and more particularly, not more than 1% by
weight of
(a) dexlansoprazole characterized by a PXRD pattern having peaks at about 9.1, 9.9, 10.9, 13.3, 15.6, 17.6, 19.6, 20.6 and 21.5 degrees by X-ray powder diffraction analysis, designated as dexlansoprazole sesquihydrate or
(b) dexlansoprazole characterized by a PXRD pattern having peaks at about 7.4, 12.9, 15.1, 15.3, 19.9, 21.6, 23.9, and 26.0 degrees by X-ray powder diffraction analysis, designated as dexlansoprazole anhydrous or
(c) mixture of (a) and (b).

25. A pharmaceutical composition comprising amorphous dexlansoprazole substantially free from one or more of its corresponding impurities as measured by HPLC.
26. A pharmaceutical composition comprising amorphous dexlansoprazole substantially free from residual solvents as measured by GC.
27. A pharmaceutical composition comprising amorphous dexlansoprazole substantially free from crystalline forms.
28. A pharmaceutical composition comprising a therapeutically effective amount of amorphous dexlansoprazole substantially free from crystalline sesquihydrate, and one or more pharmaceutically acceptable carriers, excipients or diluents.

29. A pharmaceutical composition comprising a therapeutically effective amount of amorphous dexlansoprazole substantially free from crystalline anhydrous, and one or more pharmaceutically acceptable carriers, excipients or diluents.