Novel Crystalline Forms For Proton Pump Inhibitors and Processes Thereof

Field of Invention : The present invention relates to novel crystalline forms, Form I and Form II for Omeprazole sodium, Form III and Form IV for Pantoprazole sodium , and Form V and Form VI for Rabeprazole sodium. This invention further relates to the formation of proton pump inhibitors (PPFs) as freeze-dried ( lyophilized) active pharmaceuticals ingredients, comprising salts of benzimidazole compounds and bulking agents, available as sterile powder of PPFs which could be used for the oral , and injectable preparations by filing up in the glass vials in the acceptable doses.

Further, the present invention provides Form I and Form II for Omeprazole sodium, Form III and Form IV for Pantoprazole sodium , and Form V and Form VI for Rabeprazole sodium as novel crystalline forms with mannitol solid diluents as freeze-dried preparations in anhydrate forms with moisture contents of about 3% w/w ( i.e. free from bounded water or crystalline water).

Background of The Invention:

The acid - labile proton pump inhibitors (PPFs) are the anti-ulcer compounds used for the treatment of stomach and duodenal ulcers. PPFs are the benzimidazole class of compounds and are also effectively used to relieve symptoms of esophagitis and acute gastro - esophageal efflux and are also used to alleviate Helicobactor pylori infection which is considered to be the root cause of stomach ulcers. The PPFs block the production of stomach acids by inhibiting the system in the stomach known as proton pump, also referred to as hydrogen-potassium adenosine tri phosphate enzyme system. The acid - labile proton pump inhibitors are chiral compounds , and the term acid - labile proton pump inhibitors also

i

includes the pure enantiomers of the acid labile proton pump inhibitors and their mixtures in any mixing ratio. Pure enantiomers which may be mentioned by way of examples are 5-Methoxy - 2-[ (S)-[(4-methoxy-3,5-dimethyl-2- ρyridinyl)methyl] sulfinyl ] - lH-benzimidazole (INN: Esomeprazole).

WO 94 /02141 describes an injection comprising a 2-[(2-pyridyl)methyl sulfmyl]- benzimidazole and aqueous solvent added with non-aqueous solvent, wherein the pH of the injection is not less than 9.5 and not more than 11.5. It is mentioned that said injection does not cause hemolysis and causes less local irritations.

DE 4324014 describes the preparation of a lyophilisate of Pantoprazole sodium sesquihydrate in the presence of sucrose as an auxiliary at production temperature of — 25 to - 30 degree centigrade. It is disclose that lyophilisate is of improved storage stability and can be stored at room temperature for at least 18 months and is easily reconstituted in liquid form in suitable doses for use.

CN 1235018 describes a freeze-dried injection powder of pantoprazole sodium containing no crystallized water with PH value of 9-12.5 , which is composed of Pantoprazole sodium, freeze-dried powder supporting agent , metal ion complexing agent and pH regulator .

WO99/18959 describes aqueous pharmaceutical compositions , which are chemically and physically stable for intravenous injection which comprise anti- ulcerative compound and glycine as stabilizer in carrier.

WO02/41919 describes lyophilized pantoprazole preparations , which are obtainable by freeze-dried drying of an aqueous solution of pantoprazole, ethylendiamine tetra acetic acid and / or a suitable salt there of , and sodium hydroxide and /or sodium carbonate. The preparations have advantageous

properties when reconstituted for injections . Pantoprazole sodium for injection is commercially available as freeze-dried powder in a clear glass vial fitted with a rubber stopper and crimping seal .

Further , the injection for PPFs have recently been developed . Japnese Patent unexamined publication number JP 167587 / 1984 describes the process for preparation of injection for omeprazole. The process comprises dissolving sodium salt of omeprazole in sterilized water , filtering and lyophilizing the solution to give lyophilized product. This lyophilized product is dissolved in a mixture of polyethylene glycol 400 for injection , sodium hydrogen phosphate and sterilized water.

For Lansoprazole the lyophilized injection is prepared by dissolving lyophilized product of lansoprazole in a mixture of acid and at least one of ethanol , propylene glycol and polyethylene glycol as described in Japanese unexamined patent no. JP138213/1990.

WO 2005 / 065682 A2 discloses a novel drug delivery system for proton pump inhibitors comprising benzimidazole compounds or their salts, preferably rabeprazole or its salts, mannitol, alkaline compounds and water for injection, by a process dissolving sodium hydroxide in water for injection to adjust the pH 12.0, adding mannitol and rabeprazole sodium to the above said solution maintaining the pH of the said solution; filtering the said solution aseptically through 0.22 micron filter papers; filling the said solutions in previously sterilize 10 ml vials; maintaining the temperature of the injectable solution at 10 ± 2 degree centigrade through out the process; loading the vials into lyophilizer after partial bunging and lyophilizing the said solution to obtain the said powder form of drug delivery system which is reconstitutable in a parenterally acceptable solvent to form an injectable solution.

The lyophilized vials comprising freeze drying of the benzimidazole compounds or their salts, mannitol, alkaline compounds and water for injection is described in WO 2005 / 065682 A2 .

However, there is no sterile freeze dried (lyophilized) stabilized preparation as active pharmaceutical ingredient (API's) in powder form, readily available for the filling up. in injection vials, in particular, anhydrate forms i.e. free from bounded water (crystalline water).

The invention disclosed in patent No. WO 2005 / 065682 A2 also doesn't disclose the formation of crystalline forms and about the crystalline water

Because of the very low concentration of the active ingredient the lyophilization of PPFs alone in injection vials has some problems like filling up with the required dose, not producing the elegant cake structure, stability problem and crystalline water.

It is also observed or indicated in the literature that excessive moisture leads to the decrease in stability of the product and decrease in pH , formation of undesirable color. Thus, there is need for the sterile freeze dried (lyophilized) stabilized preparation of PPFs as active pharmaceutical ingredients (API's) in powder form, readily available for the filling up in injection vials, in particular, anhydrate forms i.e. free from bounded water (crystalline water).

The crystalline properties of any drug product leads to varying in physical properties like melting point, solubilities, stability etc. The physical properties of a drug can affect its bioavailability. Taking advantage of the difference in their physical properties, the crystalline behavior of drug can be differentiated by IR studies, Raman spectroscopy, thermo gravimetric analysis spectroscopy and X-ray diffraction spectroscopy. Since the crystalline properties of drug can affect its

bioavailability , discovery of new crystalline powder of proton pump inhibitors (PPI's) , provide a new opportunity to enhance the performance characteristics of a pharmaceutical products.

For pharmaceutical application of polymorphs please refer to G.M. Wall , Pharm Manuf.3,33(1986);J.K. Haleblian and W. Mc Crone, J. Pharm.ScL, 58,911(1969) and J.K. Haleblian, J.Pharm.Sci.64, 1269(1975).

Furthermore, it is economically desirable to develop sterile anhydrous crystalline powder forms of PPI's as active pharmaceutical ingredient (API's) having

, elegant cake structure , unique solubility and reconstitution stability studies behavior/properties, and are readily available for the filling up in injection vials, in particular, anhydrate forms i.e. tree from bounded water (crystalline water) without the need for specialized storage conditions.

Surprisingly , the inventors have found novel crystalline forms of PPI's namely Pantoprazole sodium, Omeprazole sodium, Esomeprazole sodium , and

Rabeprazole sodium and the like , herein designated as Form I and Form II for

Omeprazole sodium, Form III and Form IV for Pantoprazole sodium , and Form V and Form VI for Rabeprazole sodium. The novel forms of the present invention are anhydrous with moisture content not more than 3.0% w/w. These forms are substantially free from crystalline water or bounded water used in its preparation process, and are readily available for the filling up in injection vials used for pharmaceutical preparations with good thermal and /or good solubility characteristics.

SUMMARY OF THE INVENTION:

In one of the embodiment, the present invention provides a novel crystalline form,

Form-I of 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-ρyridinyl]sulfmyl]- l-H- benzimidazole sodium. The .crystalline Form-I of omeprazole sodium is characterized by X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes peaks selected from the group consisting of 39.52+0.09,38.10+0.09, 36.47+0.09, 36.09+0.09, 35.46+0.09, 33.90+0.09, 33.03+0.09, 31.41+0.09,

30.31+0.09, 28.53+0.09, 28.03±0.09, 27.44+0.09, 26.88+0.09, 25.57±0.09,

25.04+0.09, 21.21±0.09, 20.30+0.09, 19.74+0.09, 18.59+0.09, 17.16+0.09,

13.50±0.09, 10.80+0.09, 9.35+0.09, 5.23+0.09. The crystalline Form-I of omeprazole sodium has substantially the same X-ray diffraction pattern as shown in Fig.1.

In yet another embodiment, the present invention provides for novel crystalline form, Form-II of 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl]sulfinyl]- l- H-benzimidazole sodium. The crystalline Form-II of omeprazole sodium is characterized by X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes peaks selected from the group consisting of 44.98±0.09, 40.43+0.09, 36.15+0.09, 35.08+0.09, 33.20±0.09, 32.14+0.09, 27.94+0.09, 25.32+0.09, 24.68+0.09, 22.10+0.09, 21.17+0.09,20.41+0.09, 19.46+0.09, 17.28+0.09, 13.67+0.09, 9.75±0.09, 5.30+0.09. The crystalline Foπn-II of omeprazole sodium has substantially the same X-ray diffraction pattern as shown in Fig.2.

In yet another embodiment, the present invention provides for novel crystalline form, Form-Ill of 5-(Difmromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium .The crystalline Form-Ill of pantoprazole sodium is characterized by X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes peaks selected from the group consisting of 39.43+0.09,36.09±0.09, 34.96+0.09, 32.06+0.09, 29.37+0.09, 27.88±0.09, 25.19+0.09,24.64+0.09, 22.03+0.09, 21.03+0.09, 20.35+0.09,19.37+0.09,

17.26+0.09, 13.57+0.09, 9.72±0.09.The crystalline Form-Ill of pantoprazole sodium has substantially the same X-ray diffraction pattern as shown in Fig.3.

In yet another embodiment, the present invention provides for novel crystalline form, Form-IV of 5-(Difmromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium .The crystalline Form-IV of pantoprazole sodium is characterized by X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes peaks selected from the group consisting of 55.27+0.09,46.35+0.09, 44.89±0.09, 40.35+0.09, 36.08±0.09,34.92+0.09,27.83+0.09,25.25+0.09,24.62+0.09,22.0 5+0.09,21.19+0.0 9,20.34+0.09, 19.38+0.09,17.22±0.9,9.68+0.9.The crystalline Form-IV of pantoprazole sodium has substantially the same X-ray diffraction pattern as shown in Fig.4.

In yet another embodiment, the present invention provides for novel crystalline form, Form-V of 2-[[[4-(3-Methoxyρropxy)-3-methyl-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole.The crystalline Form-V of Rabeprazole sodium is characterized by X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes peaks selected from the group consisting of 55.28±0.09,44.94+0.09, 42.43+0.09, 40.41+0.09, 36.09+0.09,27.79+0.09, 25.29±0.09,24.63+0.09,, 22.09+0.09,21.22+0.09,

20.39±0.09,19.57+0.9,18.82+0.9,17.27+0.9,13.62+0.9, 10.67+0.9, 9.69±0.9. The crystalline Form-V of Rabeprazole sodium has substantially the same X-ray diffraction pattern as shown in Fig.5.

In yet another embodiment, the present invention provides for novel crystalline form, Form- VI of 2-[[[4-(3-Methoxypropxy)-3-methyl-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole.The crystalline Form-VI of

Rabeprazole sodium is characterized by X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes peaks selected from the group consisting of 55.71+0.09,44.91+0.09, 43.94+0.09, 40.40+0.09, 36.10+0.09, 33.90+0.09, 33.13±0.09, 27.95±0.09, 25.27+0.09,24.58+0.09, 22.03+0.09,21.18+0.09, 20.36+0.09,18.74+0.9,17.24±0.9,13.60±0.9, 10.94+0.9, 9.70+0.9, 5.43+0.09. The crystalline Form- VI of Rabeprazole sodium has substantially the same X-ray diffraction pattern as shown in Fig.6.

In another embodiment the present invention provides for the preparation of novel crystalline Forms of PPFs consisting steps of

a), making a solution of sodium salts of PPFs particularly benzimidazole compounds or their salts with mannitol in water for injection b). adjusting pH with base solution b) . filtering the solution obtained through 1.5 μ to 2.5μ , then through 0.2 μ filter. c) . transferring the solution into stain less steel trays at low temperature d). freeze-drying at cryogenic temperature e).maintaining the media temperature followed by , f). heating the media for product drying e). thereafter, mixing and blending the powder and finally transferring in aluminium container

BRIEF DESCRIPTION OF THE DRAWINGS:

FIG.l shows a sample X-ray powder diffractogram of the crystalline Form- I omeprazole sodium.

FIG. 2 shows a sample X-ray powder diffractogram of the crystalline Form- II omeprazole sodium.

FIG. 3 shows a sample X-ray powder diffractogram of the crystalline Form- III Pantoprazole sodium.

FIG. 4 shows a sample X-ray powder diffractogram of the crystalline Form- IV Pantoprazole sodium .

FIG. 5 shows a sample X-ray powder diffractogram of the crystalline Form- V Rabeprazole sodium .

FIG. 6 shows a sample X-ray powder diffractogram of the crystalline Form- VI Rabeprazole sodium .

The novel crystalline forms of PPFs have surprising and important advantages:

The invention of novel crystalline forms of sterile proton pump inhibitors (PPP s) as active pharmaceutical Ingredients (API's) are crystalline powder, particularly anhydrate forms i.e. free from bounded water with moisture contents of about 3% w/w, which solves the foregoing problems like decrease in pH resulted decrease in stability of the PPFs and formation of undesirable color due to the excessive moisture contents and product handling .

Novel crystalline forms of sterile proton pump inhibitors (PPFs) have a long shelf life when stored at room temperature.

These crystalline forms of sterile proton pump inhibitors (PPFs) have excellent solubility characterization which provide short reconstitution time in water for injection or 0.9 %w/v NaCl solution, and maintained the characteristics of the desired dosage form upon reconstitution including solution properties.

Novel crystalline forms of sterile proton pump inhibitors (PPFs) as active pharmaceutical Ingredients (API's) contain crystalline diluents as bulking agent to

provide an elegant cake structure with good mechanical properties and bulk to the formulation because of very low dose strength of the active ingredients(40 mg and 20mg) ^■

These novel crystalline forms sterile proton pump inhibitors (PPF s) as active pharmaceutical Ingredients (API's) are the readily available stable injectable dosage forms which could be reconstituted in a physiologically acceptable volume of parenterally acceptable solvent liquid, to form an injectable solution.

These novel crystalline forms sterile proton pump inhibitors (PPFs) used as active pharmaceutical Ingredients (API's) having good stability upon reconstitution during the parenterally preparations.

The processes for the preparations of novel forms is not to be limited only to Omeprazole sodium,Pantoprazole sodium , and Rabeprazole sodium , but is intended to include pharmaceutical accepted salts of other PPFs namely , Esomeprazole sodium lansoprazole sodium, laminoprazole , and nepaprazole with bulking agents as diluents particularly .

Detailed Description of The Invention:

The present invention describes to novel crystalline forms, Form I and Form II for Omeprazole sodium, Form III and Form IV for Pantoprazole sodium , and Form V and Form VI for Rabeprazole sodium. This invention further relates to the formation of . proton pump inhibitors (PPFs) as freeze-dried ( lyophilized) active pharmaceuticals ingredients comprising salts of benzimidazole compounds and bulking agents, available as sterile powder of PPFs which could be used for the oral , and injectable pharmaceutical preparations by filing up in the glass vials in the acceptable doses. These vials are reconstituted in a parenterally accepted

solvent, preferably an aqueous liquid i.e. water for injection ,to form an injectable solution or 0.9%w/v NaCl solution.

Further, the present invention provides Form I and Form II for Omeprazole sodium, Form III and Form IV for Pantoprazole sodium , and Form V and Form

VI for Rabeprazole sodium as novel crystalline forms with mannitol solid diluents as freeze-dried preparations in anhydrate forms ( i.e. free from bounded water or crystalline water) .The anhydrous novel crystalline forms of said salts of benzimidazole contains about 3.0% of water, suitable less than 2 % and preferably 1 % or less water.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary, any use of the words such as "comprising," "having," and the like, means "including without ^" limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.

The novel crystalline forms of proton pump inhibitors (PPFs) may be salts of benzimidazole compounds .The benzimidazole compounds may be Omeprazole, Pantoprazole,Esomeprazole,Rabeprazole ,Lansoprazol,Laminoprazole,and Nepaprazole. The said salts of benzimidazole compounds are alkaline metal salts of sodium or potassium.

Omeprazole sodium, Form-I is characterized by X-ray diffraction pattern as depicted in X-ray diffractogram (Fig. 1) and as tabulated in Table 1 below.

TABLE 1

2θ (deg) d-spacing(A) Peak Intensity

39.52 2.27 108

38.105 2.35 34

36.47 2.46 77

36.09 2.48 169

35.46 2.52 117

33.90 2.64 137

33.03 2.70 172

31.41 2.84 92

30.31 2.94 71

28.53 3.12 55

28.03 3.18 219

27.44 3.24 190

26.88 3.31 130

25.57 3.48 74

25.04 3.55 161

21.21 4.18 666

20.30 4.37 888

19.74 4.49 756

18.59 4.76 231

17.16 5.16 1011

13.50 6.55 317

10.80 8.18 66

9.35 9.45 92

5.23 16.88 52

Omeprazole sodium, Form-II is characterized by X-ray diffraction pattern as depicted in X-ray diffractogram (Fig. 2) and as tabulated in Table 2 below.

TABLE 2

20 (deg) d-spacing(A) Peak Intensity

55.56 1.65 18

44.98 2.01 169

40.43 2.22 320

36.15 2.48 404

35.08 2.55 77

33.20 2.69 32

32.14 2.78 44

27.94 3.19 128

25.32 3.51 520

24.68 3.60 376

22.10 4.01 335

21.17 4.19 441

20.41 _. 4.34 924

19.46 4.55 193

17.28 5.12 159

13.67 6.47 38

9.75 9.06 610

5.30 16.64 52

Pantoprazole sodium, Form-Ill is characterized by X-ray diffraction pattern as depicted in X-ray diffractogram (Fig. 3) and as tabulated in Table 3 below.

TABLE 3

2θ (deg) d-spacing(A) Peak Intensity

39.43 2.28 69

36.09 2.48 404

34.96 2.56 86

32.06 2.78 49

29.37 3.03 32

27.88 3.19 219

25.19 3.53 424

24.64 3.61 692

22.03 4.03 590

21.03 4.22 306

20.35 , 4.35 1296

19.37 4.57 324

17.26 5.13 130

13.57 6.52 37

9.72 9.08 1056

Pantoprazole sodium, Form-IV is characterized by X-ray diffraction pattern as depicted in X-ray diffiactogram (Fig. 4) and as tabulated in Table 4 below.

TABLE 4

2θ (deg) d-spacing(A) Peak Intensity

55.27 1.66 24

46.35 1.95 17

44.89 2.01 132

40.35 2.23 ^■ 250

36.08 2.48 303

34.92 2.56 67

27.83 3.20 112

25.25 3.52 412

24.62 3.61 388

22.05 4.02 365

21.19 4.18 342

20.34 4.36 853

19.38 4.57 193

17.22 5.14 55

9.68 9.12 493

Rabeprazole sodium, Form-V is characterized by X-ray diffraction pattern as depicted in X-ray diffractogram (Fig. 5) and as tabulated in Table 5 below.

TABLE 5

2θ (deg) d-spacing(A) Peak Intensity

55.28 1.66 15

44.94 2.01 77

42.43 2.12 28

40.41 2.23 144

36.09 2.48 180

27.79 3.20 62

25.29 3.51 331

24.63 3.61 182

22.09 4.01 196

21.22 4.18 372

20.39 4.35 497

19.57 4.53 471

18.82 4.71 222

17.27 5.13 196

13.62 6.49 30

10.67 8.28 159

9.69 9.11 276

Rabeprazole sodium, Form- VI is characterized by X-ray diffraction pattern as depicted in X-ray diffractogram (Fig. 6) and as tabulated in Table 6 below.

TABLE 6

2θ (deg) d-spacing(A) Peak Intensity

55.71 1.64 8

44.91 2.01 102

43.94 2.05 55

40.40 2.23 159

36.10 2.48 253

33.90 2.64 28

33.13 2.70 . 38

27.95 3.18 86

25.27 3.52 313

24.58 3.61 193

22.03 4.03 172

21.18 4.19 346

20.36 4.35 524

18.74 4.73 142

17.24 5.13 262

13.60 6.50 69

10.94 8.08 45

9.70 9.10 400

5.43 16.24 64

The novel crystalline forms of PPFs under invention can be prepared by a method comprising the steps of a), making a solution of salts of PPI' s particularly benzimidazole compounds or their salts with bulking agent in water for injection b).adjusting pH with base solution c) . filtering the solution obtained through 1.5 μ to 2.5μ , then through 0.2 μ filter. d) . transferring the solution into stain less steel trays at low temperature e). freeze-drying at cryogenic temperature f).maintaining the media temperature followed by g). heating the media for product drying h). thereafter, mixing and blending the powder and finally transferring in aluminium container.

In the process of the invention the salts of PPFs are alkaline metal particularly sodium salts. Preferably the PPFs are sodium salts of benzimidazole compounds such as omeprazole sodium,pantoprazole sodium,rabeprazole sodium

,esomeprazole sodium lansoprazole sodium,laminoprazole and nepaprazole, especially omeprazole sodium,pantoprazole sodium,rabeprazole sodium .

Preferably the dissolution of salts of PPFs with in bulking agent is carried out in water for injection at ambient temperature, for example between 10-50° C, especially between 20-30 ° C .

Preferably the bulking agent is any one from the mannitol, anhydrous lactose, sucrose,D (+)-trehalose, dextran 40, 4-hydroxy propyl cellulose, lactose and povidone (PVP K24), and like, mixture thereof especially mannitol. Suitably the salts of PPFs and bulking agent may be dissolved in water for injection at a ratio weight of PPIrbulking agent ca.1:4-4:1 , for example typically 1 :1.76-1:2.968 , and this mixture is dissolved in water for injection at a ratio weight of mixture

of salts of PPI and bulking agent: water for injection 1:1-1 :40, for example typically 1:5-1:20.

The pH of said solution is adjusted between 8-12, preferably 9-12 . Suitably the pH adjustment is carried out with salts of alkaline metals , especially sodium hydroxide at ambient temperature, for example between 15-40° C, especially between 20-30 ° C .

The solution is filtered at 5-30 ° C, preferably at 5-10 ° C into stain less steel trays and freeze-dried at 0to-50°C ,most suitably at -40 to -5O ⁰ C and the same is maintained for 1-10 hours ,preferably for 1-4 hours.

The freeze-dried material is vacuumized and heated to -50 to 60°C , preferably -50 to 5O ⁰ C until 0.5-40 micron point is attained, suitably 0.5-4 micron. During drying the heating media temperature is also maintained for 2-10 hours at various temperature levels.

The crystalline material obtained in this way is mixed and blended and finally transferred in aluminium containers to provide as a readily available API to fill up in the glass vials.

Crystalline forms of the PPFs prepared by the process of invention may be used as a pharmaceutical anti-ulcerative compounds for the treatment of stomach and duodenal ulcers e.g. in injectable forms. For this it may be provided contained in sealed aluminium container as API's readily available to fill up in the glass vials. Alternatively these crystalline forms of PPFs prepared by the process of this invention may be used in formulations for oral administration e.g. in tablet, granules, syrup etc. formulations and for oral administration sterile formulation is not necessarily required.

The invention will now be illustrated by way of non-limiting examples. Example 1:

Preparation of Omiprazole sodium Form-I: Omiprazole sodium 2.155Kg was dissolved in 20 liter of water for injection . The mixture was stirred at ambient temperature until dissolution was complete . To this solution 3.53 kg of mannitol was added and stirred at ambient temperature. The pH of obtained solution was adjusted 10.5 to 12 with sodium hydroxide solution and filtered aseptically through 1.25 μand 0.2 μ cartridge at 0-5 ⁰ C of solution temperature, and 0±5°C of lyophilizer tray temperature . The filtered solution was filled in sterilized stainless steel trays equally with dosing pump at 0±5°C of lyophilizer tray temperature .After transferring, the trays containing the solution was chilled to -40 to-50° C and maintained the same for 2-4 hours. Then condenser is chilled to -40 to -45 ° C and vacuumized to less than 200 micron before opening the butterfly valve. After opening butterfly valve the product chamber vacuum was allowed to stabilize during one hour. Thereafter , heating media temperature was maintained as follow

1. -40to-20 °C 5 hours

2. -20 ⁰ C 10 hours 3. -10 ⁰ C 3 hours

4. 0 ⁰ C 3 hours

5. 05 ⁰ C 2 hours

6. 10 °C 2 hours

7. 15 ⁰ C 5 hours 8. 2O ⁰ C 5 hours

9. 50 ⁰ C until 2to 4 micron point condition was attained

After attaining 2 to 4 micron point condition butterfly valve was closed to break the vacuum. Moisture was checked and material unloaded into the SS drums ..milled , packed in aluminium containers and sealed.

Example 2:

Preparation of Omiprazole sodium Form-II: Omiprazole sodium 2.155Kg was dissolved in 20 liter of water for injection . The mixture was stirred at ambient temperature until dissolution was complete . To this solution 3.53 kg of mannitol was added and stirred at ambient temperature. The pH of obtained solution was adjusted 10.5 to 12 with sodium hydroxide solution and filtered aseptically throughl.25μand 0.2 μ cartridge at 0-5 ⁰ C of solution temperature, and 0±5°C of lyophilizer tray temperature . The filtered solution was filled in sterilized stainless steel trays equally with dosing pump at 0±5°C of lyophilizer tray temperature .After transferring, the trays containing the solution was chilled to -40 to-50° C and maintained the same for 2-4 hours. Then condenser is chilled to -40 to -45 ° C and vacuumized to less than 200 micron before opening the butterfly valve. After opening butterfly valve the product chamber vacuum was allowed to stabilize during one hour. Thereafter , heating media temperature was maintained as follow

1. -40 to-20 °C 5 hours

2. -20 ⁰ C 10 hours

3. -1O ⁰ C 3 hours

4. 0 ⁰ C 3 hours

5. 05 ⁰ C 2 hours 6. 10 ⁰ C 2 hours

7. 15 ⁰ C 5 hours

8. 20 ⁰ C 5 hours

9. 30 ⁰ C until 2to 4 micron point condition was attained

After attaining 2 to 4 micron point condition butterfly valve was closed to break the vacuum. Moisture was checked and material unloaded into the SS drums, milled, packed in aluminium containers and sealed. Example 3: Preparation of Pantoprazole sodium Form-Ill: Pantoprazole sodium 2.155Kg was dissolved in 20 liter of water for injection . The mixture was stirred at ambient temperature until dissolution was complete . To this solution 3.53 kg of mannitol was added and stirred at ambient temperature. The pH of obtained solution was adjusted 10.5 to 12 with sodium hydroxide solution and filtered aseptically through 1.25 μand 0.2 μ cartridge at 0-5 ⁰ C of solution temperature, and 0±5°C of lyophilizer tray temperature . The filtered solution was filled in sterilized stainless steel trays equally with dosing pump at 0±5°C of lyophilizer tray temperature .After transferring, the trays containing the solution was chilled to -40 to-50° C and maintained the same for 2-4 hours. Then condenser is chilled to -40 to -45 ° C and vacuumized to less than 200 micron before opening the butterfly valve. After opening butterfly valve the product chamber vacuum was allowed to stabilize during one hour. Thereafter , heating media temperature was maintained as follow

1. -40to-20 °C 5 hours

2. -10 ⁰ C 10 hours

3. - 5 ⁰ C 3 hours

4. 0 ⁰ C 3 hours

5. 05 ⁰ C 2 hours 6. 10 ⁰ C 2 hours

7. 15 ⁰ C 5 hours

8. 2O ⁰ C 5 hours

9. 50 ⁰ C until 2to 4 micron point condition was attained

After attaining 2 to 4 micron point condition butterfly valve was closed to break the vacuum. Moisture was checked and material unloaded into the SS drums, milled, packed in aluminium containers and sealed. Example 4: Preparation of Pantoprazole sodium Form-IV: Pantoprazole sodium 2.155Kg was dissolved in 20 liter of water for injection . The mixture was stirred at ambient temperature until dissolution was complete . To this solution 3.53 kg of mannitol was added and stirred at ambient temperature. The pH of obtained solution was adjusted 10.5 to 12 with sodium hydroxide solution and filtered aseptically throughl.25μand 0.2 μ cartridge at 0-5 ⁰ C of solution temperature, and 0±5°C of lyophilizer tray temperature . The filtered solution was filled in sterilized stainless steel trays equally with dosing pump at 0±5°C of lyophilizer tray temperature .After transferring, the trays containing the solution was chilled to -40 to-50° C and maintained the same for 2-4 hours. Then condenser is chilled to -40 to -45 ° C and vacuumized to less than 200 micron before opening the butterfly valve. After opening butterfly valve the product chamber vacuum was allowed to stabilize during one hour. Thereafter , heating media temperature was maintained as follow

1. -40to-20 °C 5 hours

2. -10 ⁰ C 10 hours

3. -5 ⁰ C 3 hours

4. 0 ⁰ C 3 hours

5. 05 ⁰ C 2 hours 6. 1O ⁰ C 2 hours

7. 15 ⁰ C 5 hours

8. 20 ⁰ C 5 hours

9. 30 ⁰ C until 2to 4 micron point condition was attained

After attaining 2 to 4 micron point condition butterfly valve was closed to break the vacuum. Moisture was checked and material unloaded into the SS drums ..milled , packed in aluminium containers and sealed.

Example 5:

Preparation of Rabeprazole sodium Form-V: Rabeprazole sodium 1.260Kg was dissolved in 20 liter of water for injection . The mixture was stirred at ambient temperature until dissolution was complete . To this solution 3.74 kg of mannitol was added and stirred at ambient temperature. The pH of obtained solution was adjusted 10.5 to 12 with sodium hydroxide solution and filtered aseptically through 1.25 μand 0.2 μ cartridge at 0-5 ⁰ C of solution temperature, and 0±5°C of lyophilizer tray temperature . The filtered solution was filled in sterilized stainless steel trays equally with dosing pump at 0±5°C of lyophilizer tray temperature .After transferring, the trays containing the solution was chilled to -40 to-50° C and maintained the same for 2-4 hours. Then condenser is chilled to -40 to -45 ° C and vacuumized to less than 200 micron before opening the butterfly valve. After opening butterfly valve the product chamber vacuum was allowed to stabilize during one hour. Thereafter , heating media temperature was maintained as follow

1. -40to-20 °C 5 hours

2. -10 ⁰ C 10 hours

3. -5 ⁰ C 3 hours

4. 0 ⁰ C 3 hours

5. 05 ⁰ C 2 hours 6. 10 ⁰ C 2 hours

7. 15 ⁰ C 5 hours

8. 20 ⁰ C 5 hours

9. 30 ⁰ C until 2to 4 micron point condition was attained

After attaining 2 to 4 micron point condition butterfly valve was closed to break the vacuum. Moisture was checked and material unloaded into the SS drums ,milled , packed in aluminium containers and sealed.

Example 6:

Preparation of Rabeprazole sodium Form- VI: Rabeprazole sodium 0.6Kg was dissolved in 13 liter of water for injection . The mixture was stirred at ambient temperature until dissolution was complete . To this solution 1.094 kg of mannitol was added and stirred at ambient temperature. The pH of obtained solution was adjusted 10.5 to 12 with sodium hydroxide solution and filtered aseptically through 1.25 μand 0.2 μ cartridge at 0-5 ⁰ C of solution temperature, and 0±5°C of lyophilizer tray temperature . The filtered solution was filled in sterilized stainless steel trays equally with dosing pump at 0±5°C of lyophilizer tray temperature .After transferring, the trays containing the solution was chilled to -40 to-50° C and maintained the same for 2-4 hours. Then condenser is chilled to -40 to -45 ° C and vacuumized to less than 200 micron before opening the butterfly valve. After opening butterfly valve the product chamber vacuum was allowed to stabilize during one hour. Thereafter , heating media temperature was maintained as follow

1. -40to-20 °C 5 hours

2. -10 ⁰ C 10 hours

3. -5 ⁰ C 3 hours

4. 0 ⁰ C 3 hours

5. 05 ⁰ C 2 hours 6. 10 ⁰ C 2 hours

7. 15 ⁰ C 5 hours

8. 20 ⁰ C 5 hours

9. 30 ⁰ C until 2to 4 micron point condition was attained

After attaining 2 to 4 micron point condition butterfly valve was closed to break the vacuum. Moisture was checked and material unloaded into the SS drums, milled, packed in aluminium containers and sealed.

The examples described above for Omeprazole sodium,Pantoprazole sodium and Rabeprazoe sodium and the lyophilization processes thereof are also applicable for the preparations of novel crystalline forms for Esomeprazole sodium lansoprazole sodium,Laminoprazole sodium and Nepoprazole sodium in a similar manner .

The accelerated stability studies carried out as per ICH guidelines were satisfactory. The reconstitution solubility as well as stability studies were carried out in water for injections and 0.9%w/v NaCl solution. The solubility for all the forms were excellent in lml,2ml,3ml,4ml and 5ml. All the forms also showed good stability upon reconstitution in water for injection as well as in 0.9%w/v NaCL solution.

It is to be understood while at the invention has been described in conjunctions with the details description thereof, the foregoing description is intended to illustrate and not to limit the scope of the invention which is defined by the scope of the appended claims. The other aspects like advantages and modifications are within the scope of the following claims.