FIELD OF THE INVENTION
The present invention relates to the novel crystalline form of Rabeprazole sodium. The present invention also relates to methods of making novel crystalline form of Rabeprazole sodium. BACK GROUND OF THE INVENTION
Achiphex ® (Rabeprazole sodium) is an inhibitor of the gastric proton pump. It causes dose-dependant inhibition of acid secretion and is useful as an antiulcer agent. The chemical designation of Rabeprazole sodium is 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-l//-benzimidazole sodium. It may be represented by Formula (1):

US Patent No. 5,045,552 incorporated herein by reference describes the synthesis of Rabeprazole and its sodium salt. Rabeprazole is prepared by oxidizing 2-[{4-(3-methoxypropoxy)-3 -methylpyridine-2-yl} methylthio] -1 H-benzimidazole with m-chloroperbenzoic acid to afford the Rabeprazole base, which is then converted to its sodium salt by aqueous sodium hydroxide solution.

Polymorphism is the occurrence of different crystalHne forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-Ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all soUd forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic fc|tni. Polymorphic forms of a compound can be distinguished in the laboratory by X-Ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
Crystal forms of Rabeprazole are mentioned in Japanese Patent 2001-39975 and designates them as crystal I and II, however does not identify crystal I by recognized methods of crystal structure identification such as X-Ray diffi-action and also the above patent disclosed amorphous form of Rabeprazole Sodium.
The crystal 11 of Rabeprazole sodium however is discussed in detail and characterized by its X-Ray diffraction spectroscopy. Infrared spectrometry and Differential Scanning Calorimetry.

The process for the preparation of crystal II as disclosed in the Japanese Patent specification comprises crystallization of amorphous Rabeprazole sodium or acetone complex of Rabeprazole sodium in one or more solvents selected from ethyl acetate, isopropyl acetate, isobutyl acetate, ethyl propionate, isobutyl propionate or ethyl butyrate. The X-ray diffractogram for crystal II as in Japanese Patent 2001-39975 is as follows:


Crystal forms of Rabeprazole Sodium are mentioned in Indian patent application 207
MAS 2002 and designate them as form X and form Y.
The form X and form-Y of Rabeprazole sodium however are discussed in detail and
characterized by its X-Ray diffraction spectroscopy, Lifrared spectrometry and
Differential Scanning Calorimetry.
The process for the preparation of form X as disclosed in the Indian patent application
207 MAS 2002 specification comprises
a) 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfmyl]-l// benzimidazole (prepared as per reference example 1) is dissolved in C1-C4 alkoanol and an alkali hydroxide such as methanolic sodium hydroxide, ethanolic sodium hydroxide or isopropanolic sodium hydroxide or mixtures in the ratio between 1:1-1.34 preferably in the ratio of 1:1.34 thereof, preferably methanolic sodium hydroxide, accompanied by distilling the solvent from the reaction solution;
b) chlorinated lower hydrocarbon solvents such as dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform or carbon tetrachloride, preferably dichloromethane is added to the residual mass obtained in step a)
c) the residual solvent of alcohol is distilled off azeotropically under reduced pressure from the reaction solution of step b)
d) chlorinated lower hydrocarbon solvents such as dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform or carbon tetrachloride, preferably dichloromethane and an Ci-Cio alkane solvent as

pentane, hexane, heptane, petether, octane, i-octane, nonane, decane or cyclic alkanes as cyclohexane, preferably petether; or mixtures thereof; such that the ratio of chlorinated lower hydrocarbon solvents to alkane solvent/ cyclic alkanes is in the range of 1:5-15 preferably 1:5-10 and more preferably 1:5 are added to the residue obtained in step c) and accompanied by stirring, e) the desired form X is isolated by conventional methods.
The X-ray diffractogram for form X as in Indian patent application 207 MAS 2002 is as follows


The Differential Scanning Calorimetry thermogram of crystalline form X exhibits
significant endo-exo pattern at 154.62*^0 and 214.65 C.
The melting range (capillary method) of crystalline form X is 140-150 ^C.
The process for the preparation of form Y as disclosed in the hidian patent specification
comprises
a) dissolving 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-l//-benzimidazole (prepared as per reference examplel) in CrC4 alcoholic solution of alkali hydroxide such as methanolic sodium hydroxide, ethanolic sodium hydroxide or isopropanolic sodium hydroxide or mixtures in the ratio between 1:1-1.34 preferably in the ratio l:1.34thereof, preferably methanolic sodium hydroxide, accompanied by distilling the solvent from the reaction solution;
b) adding of chlorinated lower hydrocarbon solvents such as dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform or carbon tetrachloride, preferably dichloromethane to the residual mass obtained in step a
c) distilling the residual solvent of alcohol azeotropically under reduced pressure from the reaction solution of b
d) adding to the residue obtained in step c) either C3-C5 straight or branched chain alcohols such as n-propanol, isopropanol, n-butanol, 2-butanol or tert.butanol, preferably n-butanol and an ether solvents selected from diethyl ether, diisopropyl ether, diisobutyl ether, ditert.butyl ether or tert.butyl methyl ether, preferably tert.butyl methyl ether; or mixtures thereof; such that the

ratio of alcohol solvent to ether solvent is in the range of 1:10-20 preferably 1: 15-20 and more preferably 1:16; accompanied by stirring, e) Isolation of desired Polymorph form Y by conventional methods.
The X-ray diffractogram for form Y as in hidian patent application 207 MAS 2002 is as follows

The Differential Scanning Calorimetry thermogram of crystalline form Y exhibits a
significant endo-exo pattern respectively at 182.61^C and 215.57^C.
The melting range (capillary method) of crystalline form Y is 160-170 *^C.
It is an object of the present invention to provide novel crystalhne form of Rabeprazole
sodium designated as form Z for convenience.

Another object of the present invention is to provide a process for the preparation of novel crystalUne form Z of Rabeprazole sodium.
form Z of Rabeprazole sodium show better chemical stability such as thermo stability and light stability.
SUMMARY OF THE INVENTION
Accordingly, the present invention is directed to novel crystalline form of Rabeprazole
sodium. This crystalline form of Rabeprazole sodium is designated as form Z for
convenience.
The present invention further provides a process for the preparation of novel crystalline
form Z of Rabeprazole sodium, which is a commercially viable process and well suited
for industrial scale up.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
Fig. 1 is characteristic X ray powder diffractogram of form Z of Rabeprazole sodium. Fig. 2 is Differential Scanning Calorimetry thermogram of form Z of Rabeprazole sodium.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel crystalline form Z of Rabeprazole sodium. This solid-state form includes non-solvated and hydrated crystalline forms. The crystalline form Z of the present invention may be characterized by their X Ray powder diffraction. Thus the X-Ray diffraction pattem of form Z of Rabeprazole sodium was measured on a

Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source.
CrystaUine form Z has X-ray powder diffraction pattern essentially as shown in the Table 1. The X-ray powder diffraction pattern is expressed in terms of the 29, and relative intensities (cps).


The present invention also provides form Z of Rabeprazole sodium that is characterized
by its X Ray powder diffraction substantially as depicted in Figure 1.
The present invention also provides the Differential Scanning Calorimetry thermogram of
form Z of Rabeprazole sodium The Differential Scanning Calorimetry thermogram
exhibits a significant endo-exo pattern respectively at 106.5 C and 228.8 C.
The present invention also provides Differential Scanning Calorimetry thermogram of
form Z of Rabeprazole sodium substantially as depicted in Figure 2.
The present invention also provides melting range (capillary method) of crystalline form
Z at 224-230^C.
Accordingly the present invention also provides a process for the preparation of form Z
of Rabeprazole sodium, which comprises;
a) adding amorphous form or form-X or form Y of Rabeprazole Sodium having the chemical name sodium sah of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmyl]-l//-benzimidazole [prepared as per reference example 2 (amorphous) and Reference example 3 (form X) and reference example 4 (form Y)] to aromatic hydrocarbon solvents such as toluene and xylenes preferably toluene in the ratio between 1:3 to 1:20 preferably in the ratio of 1:4.
b) heating or reflux reaction mixture for 1-10 hrs azeotropically. Preferably 2-6 hrs.

reaction mixture to 0-40^C preferably to 25-35°C. d) isolation of desired form Z by conventional methods. The crystalline form Z of Rabeprazole sodium of the present invention is having high melting transition temperature in which residual solvents are within permissible limits and is very well suited for formulation.
DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWING
Fig-1 is characteristic X-ray powder diffraction pattem of form Z of 2-[[[4-(3-
methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmyl]-l//-benzimidazole sodium
(Rabeprazole sodium).
Vertical axis: hitensity (CPS); Horizontal axis: 29 (degrees). The significant 20 values
(in degrees) obtained are
4.694,9.070,9417J 1.254^4712^6.24147.264,18.52248.522^9320,19.626,19.920,20.
802.21.477,23.073,24.814.25.702,27.470,30.009,30.653,33.365and36.950.
Fig-2 is Differential Scanning Calorimetry thermogram of form Z of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmyl]-l//-benzimidazole sodium (Rabeprazole sodium). The Differential Scanning Calorimetry thermogram exhibits a significant endo-exo pattem respectively at 105-1 lO^C and 226-234^C.
The present invention is illustrated by the following examples, which are not intended to limit the effective scope of the claims.

Reference Example 1:
Preparation of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmyl]-
1/f-benzimidazole (Rabeprazole)
2-[[4-(3-methoxypropoxy)-3-methyl-2-pyridmyl]-methylthio]4//-benzimidazole
(Prepared as per example 90 of the Patent No. 5,045,552)(100grams, 0.29 moles) is added to a mixture of chloroform (9500 ml) and dimethylsulphoxide (200ml) and the reaction mixture is cooled to-10 to-15 degree c. 3-chloroperbenzoic acid (60grams,0.24 moles) is dissolved in chloroform (500ml), and added to the above solution at -10 to-15 for about 1- 2 hours and the reaction mixture is maintained at the temperature for 30 minutes. Thereafter 12.8%w/v aqueous sodium hydroxide solution (500ml) is added to the reaction mixture. The pH of the reaction mixture is adjusted to 9.5 to 10.0 with acetic acid. From the biphasic system thus obtained, the organic layer is separated and then extracted with 1.6%w/v aqueous sodium hydroxide solution (500ml). Further the sodium hydroxide extract is diluted with a mixture of chloroform (140ml) and methanol (100ml). Then the pH of the mass is again adjusted to 9.5 to 10.0 with acetic acid and the organic layer separated again. To the separated organic layer is now added tert. Butyl methyl ether (440ml).The reaction mixture is stirred for about 1-2 hours at a temperature of 0-5''C and subjected to filtration. The residue is dissolved in a mixture of 110% w/v aqueous sodium hydroxide solution (100ml) and methanol (65ml). The pH is adjusted to 9.0 to 9.5 with acetic acid at 10-15C and further stirred for 2 hours followed by

filteration . The wet material is then dissolved in dichloromethane (130ml) and the water layer separated where after solution is added to tert.butyl methy ether (260ml), stirred at a temperature of 0-5C for 1-2 hours. The 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmyl]-l//-benzimidazole thus obtained is filtered and dried.
Reference Example 2:
Preparation of amorphous form of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-
pyridinyl]-methyl] sulfinyl]-l/r-benzimidazole sodium (Rabeprazole sodium):
2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmylj-l/f-benzimidazole (obtained as per reference example) (50.0 grams, 0.139 moles) is dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml) and stirred at ambient temperature 25-35^C. The reaction solution is filtered through hi-flow and washed with methanol (50.0 ml). Then the solvent of the filtrate is distilled off under reduced pressure. The reaction mass is cooled to ambient temperature followed by addition of petroleum ether (400.0 ml) is then added to the residual mass, which is then stirred at 25-30^C for about 1-2 hours. The precipitated solid is filtered and washed with petroleum ether (100.0 ml) and dried at 50-60^C for 12 hours to afford the desired amorphous form of Rabeprazole sodium (Weight: 50.4 grams, 94.9%) Reference Example 3:
Preparation of Crystalline form X of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-ljy-benzimidazole sodium (Rabeprazole sodium): 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-l//-benzimidazole (obtained by reference example 1) (50,0 grams, 0.139 moles) is dissolved in a mixture of

sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml) and stirred at ambient temperature 25-35°C. The reaction solution is filtered through hi-flow and washed with methanol (50.0 ml). Then the solvent of the filtrate is distilled off under reduced pressure. The reacfion mass is cooled to ambient temperature followed by addition of dichloromethane (100.0 ml) accompanied by distillation to remove traces of methanol. Dichloromethane (50.0 ml) and petroleum ether (100.0 ml) is then added to the residual mass, which is then stirred at 25-30*^C for about 6-8 hours. The solid that obtained is further diluted with petroleum ether (150 ml) and stirred at 25-30''C for 1-2 hours. The precipitated soUd is filtered and washed with petroleum ether (100.0 ml) and dried at 50-60*^C for 12 hours to afford the desired form X of Rabeprazole sodium (Weight: 50.4 grams, 94.9%) Reference example 4:
Preparation of Crystalline form-Y of 2-[[[4-(3-niethoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-l/f-benzimidazole sodium (Rabeprazole sodium): 2 - [ [ [4-(3 -methoxypropoxy)-3 -methyl-2-pyridinyl] -methyl] sulfinyl] -1 //-benzimidazole (obtained as per reference example 1) (750.0 grams, 2.089 moles) is dissolved in a mixture of sodium hydroxide (112.5 grams, 2.8125 moles) and methanol (1500.0 ml) and stirred at ambient temperature 25-35°C. The reaction solution is filtered through hi-fiow and washed with methanol (750.0 ml). Then the solvent of the filtrate is distilled off completely under reduced pressure. The reaction mass is cooled to ambient temperature followed by addifion of dichloromethane (1500.0 ml) accompanied by distillafion to remove traces of methanol. The reaction mass is cooled to ambient temperature and n-butanol (375.0 ml) and tertiary butyl methyl ether (6.0 lit) is added to the residual mass

which is stirred at 25-30^C for 6-8 hours. The reaction mixture is further cooled to 5-15^C and then stirred for another 3-5 hours. The soUd thus obtained is filtered and washed with tertiary butyl methyl ether (1500.0 ml) and dried at 50-60*^C for 7 hours to afford the desired crystalline Form Y of Rabeprazole sodium (Weight: 725.0 grams, 91.1%) Example 1:
Preparation of Crystalline form Z of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-l^-benzimidazole sodium (Rabeprazole sodium) from 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-lfl^ benzimi da-zole (Rabeprazole):
2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmyl]-l//-benzimidazole (obtained by reference example 1) (50.0 grams, 0.139 moles) is dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml) then stirred at ambient temperature 25-35°C for about one hour. The reaction solution is filtered through hi-flow and washed with methanol (50.0 ml). Then the solvent of the filtrate is distilled off under reduced pressure. The reaction mass is cooled to ambient temperature followed by addition of Toulene (200.0 ml) to the residual mass, which is then refluxed for about 2-6 hours. The precipitated sohd is filtered, washed with Toluene (100.0 ml) and dried at 90-100*^C for 12 hours to afford the desired form Z of Rabeprazole sodium (Weight: 50.4 grams, 94.9%)

Example 2: Preparation of Crystalline form Z of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfmyl]-l/f-benzimidazole sodium (Rabeprazole
sodium):
Amorphous form or form-X or form Y of Rabeprazole Sodium having the chemical
name Sodium salt of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]
sulfmyl]-l//-benzimidazole [prepared as per reference example 2 (amorphous) and Reference example 3 (Form X) and reference example 4 (form Y)] (50.0 grams, 0.131 moles) is charged in to toluene (200.0 ml) and the mixture is heated to reflux temperature, then it is maintained at reflux temperature for 8-10 hrs. The reaction mixture is then cooled to 25-35°C. The precipitated solid is filtered off, washed with toluene (100.0 ml) and dried at 90-lOO^C for 6-8 hours to afford the desired form Z of Rabeprazole sodium (Weight: 45 grams, 90%)
The X-ray Diffraction Pattern, Differential Scanning Calorimetry thermogram of form Z of Rabeprazole sodium obtained in above example is in accordance to Figure 1 and 2 respectively.

We claim:
1. A crystalline form Z of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-l//-benzimidazole sodium (Rabeprazole sodium)
2. The crystalline form Z of Rabeprazole sodium of claim 1 having X-ray powder diffraction pattern with peaks at about
4.694,9.070,9417J1.254J4.712,16.241,17.264,18.522,18.522,19.320,19.626,19. 920,20.802.21.477,23.073,24.814.25.702,27.470,30.009,30.653,33.365,and 36.950 degrees 2 theta.

The crystalline form Z of Rabeprazole sodium of claim 1 having an X-ray powder diffraction pattern substantially as depicted in Figure 1.
The crystalline form Z of Rabeprazole sodium of claim 1 having a differential scanning calorimetery thermogram which exhibits a significant endo-exo pattern respectively at 105-llO^C and 226-234^C.
The crystalline form Z of Rabeprazole sodium of claim 1 having characteristic Differential Scanning Calorimeter thermogram as depicted in Figure 2. The crystalline form Z of Rabeprazole sodium of claim 1 having melting range of 220-230 ^C.
A process for preparing form Z of Rabeprazole sodium from Rabeprazole, A process for preparing form Z of Rabeprazole sodium from amorphous Rabeprazole sodium.
A process for preparing form Z of Rabeprazole sodium from form X of Rabeprazole Sodium.
A process for preparing form Z of Rabeprazole sodium from form Y of Rabeprazole Sodium.
A process for preparing form Z of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-
pyridinyl]-methyl] sulfmylj-l/f-benzimidazole sodium (form Z of Rabeprazole
sodium) using aromatic hydrocarbon solvents such as toluene and xylenes.
Novel crystalline form-Z of 2-[[[4-3-methoxypropoxy)-3-methyl-2-pyridinyl]-
methyl]sulfmyl]-lH-benzimidazole sodium(Rabeprazole sodium) and process for
the preparation thereof, which is herein described and exemplified.