|Title of Invention||
A NOVEL PROCESS FOR THE PREPARATION OF HIGHLY PURE AMORPHOUS FORM OF RABEPRAZOLE SODIUM
|Abstract||A pure amorphous form of sodium salt of 2-[[[4-(3-methoxypropoxy)-3-methyl-pyridinyl] methyl] sulfinyl]-1H-benzimidazole (rabeprazole sodium) of greater than 99.5% purity determined by high-performance liquid chromatography and having less than 1000 parts per million per (p.p.m.) of residual toluene relative to rabeprazole sodium.|
|Full Text||COMPLETE AFTER PROVISIONAL LEFT ON 4 / 5 / 06
THE PATENTS ACT, 1970
(39 of 1970)
The Patent Rules, 2003
(See section. 10 and rule 13)
TITLE OF THE INVENTION
"A NOVEL PROCESS FOR THE PREPARATION OF HIGHLY PURE AMORPHOUS FORM OF RABEPRAZOLE SODIUM"
We, CADILA HEALTHCARE LTD., a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads., Ahmedabad - 380 015, Gujarat, India.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:
A novel process for the preparation of highly pure amorphous form of Rabeprazole sodium.
Background of the invention:
Rabeprazole is a substituted benzimidazole derivative that inhibits gastric acid secretion by specific inhibition of the H+/K+-ATPase enzyme system. It has been shown, Rabeprazole significantly decreases base!! acid output as well as meal-stimulated acid output and to increase mean gastric pH after oral administration.
The pharmacology of Rabeprazoli: sodium is also well described in Drugs of Future 16(1) 19 (1991) and J. Med. Chem., 35 1049 (1992).
Rabeprazole sodium is represented by structural Formula (I) while Rabeprazole is represented as Formula-(II).
Preparation of compounds of Formulae (I) and (II) are well disclosed in EP 0268956, US 5045552 and WO 01/04109. Preparation of Rabeprazole sodium (I) is described in 0268956 equivalent to US 5,045,552 in which it is obtained as white crystals with melting point of l40°C to l41°C.
Japanese Patent No. 2001-39975 discloses two crystalline forms, which are characterized as Crystal-I and Crystal-II. This patent describes obtaining these two forms by the crystallization of amorphous Rabeprazole sodium or an acetone clathrate of Rabeprazole sodium from the ester solvents such as ethyl acetate, isopropyl acetate, isobutyl acetate, etc.
JP 2001-39975 does not disclose the required scientific characterization data of polymorph Crystal-I, whereas X-ray powder diffractogram, IR-spectra and DSC data are provided for characterization for polymorph Crystal-II.
WO 03/082858 discloses two crystalline forms characterized as Form-X and Form-Y. The process for producing both the crystalline forms involves reacting free Rabeprazole of the Formula (II) with C1-C4 alcoholic sodium hydroxide followed by removal of solvent. Traces of alcohol are removed by azeotropic distillation with C1-C3 halogen substituted hydrocarbon solvent. When reaction mass thus obtained is treated with the mixture of halogenated hydrocarbon solvents having C1-C3 carbon atoms and linear or cyclic hydrocarbon solvent selected from C5-Q0 alkyl series Form-X crystallizes out. But when reaction mass is treated with the mixture of alcohol having C3-C5 straight or branched alkane chain and ether solvent, Form-Y crystallizes out.
X-ray powder diffractogram and IR-spectra are provided for both the Form-X and Form-Y. WO 03/082858 also teaches Form-X and Form-Y are non-solvated and hydrated compounds.
WO 03/101452 describes powder form of Rabeprazole sodium afforded by the process of lyophilization. X-ray powder diffractogram and IR spectrum are not mentioned. The technique of lyophilisation is time consuming and expensive due to high energy consumption, which reduces the efficiency of production and enhances the production cost. Summary of the invention:
The dissolution characteristics of an amorphous form is better than the crystalline compound, this nature is well described in Chem. Pharm. Bull. 38, 2003-2007 (1990), hence there is a constant need for the process which enables the preparation of Rabeprazole sodium in an amorphous form without simultaneous formation of crystalline forms or which will enable the conversion of crystalline forms into amorphous form.
Since bioavailability of pharmaceutical compound differs from one polymorphic form to another, it is desirable to investigate all solid forms of a drug, for properties including of stability, dissolution and flow properties.
This invention relates to the preparation of amorphous form of Rabeprazole sodium, which is highly pure and stable and also matches economical aspects and is suitable to the plant operations. This process also overcomes the drawbacks of previous processes. Each step of the process disclosed in this invention is important since it removes the impurity and improves quality of the product.
Brief description of the accompanying drawings
Figs. 1 and 2 show X-ray powder diffractograms of rabeprazole sodium of the present invention. The diffractograms confirm that the product of the present invention is amorphous.
Disclosure of invention
The compound described herein representing Formula-(II), free Rabeprazole which is chemically known as 2-[[[4-(3-methoxypropoxy)-2-methyl-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole is dissolved in organic solvent, preferably hydrocarbons such as toluene, xylene etc. or alcohol containing lower alkyl chain C1-C4, preferably isopropyl alcohol (IPA) or mixtures thereof, at temperature 10°C to 20°C. A separately prepared alcoholic solution of sodium hydroxide, most preferably sodium hydroxide solution prepared in methanol or sodium hydroxide solution prepared in methanol-water mixture is then added to Rabeprazole solution in suitable organic solvent under cooling, along with stirring. The reaction mass is then filtered through fine filter bed. The solvents are removed under reduced pressure and traces of water are removed by azeotropic distillation.
Thus obtained technical grade Rabeprazole sodium is then purified by dissolving in toluene and subsequent distillation of toluene under reduced pressure. This exercise may be repeated till traces of water are removed. Finally Rabeprazole sodium is dissolved in toluene and added into straight or branched hydrocarbon solvent or mixture thereof. This affords precipitating out fine powder. The product thus obtained is then filtered and dried under reduced pressure to afford amorphous Rabeprazole sodium. This is confirmed by X-ray powder diffractograms [Figure-1 and Figure-2].
The process described as here in above consistently provides pure amorphous Rabeprazole sodium having individual related substances and unknown substances The scope of present invention is not limited by the description, examples and suggested uses described herein, and modifications can made without departing from the spirit of invention, for example, charcoalization can be done at any stage before filtration in hot condition or at ambient temperature at the purification stage, or intermediate stage may involve solvate formation herein this process for the purpose of preparing amorphous Rabeprazole sodium.
1) Rabeprazole(2-[[[4-(3-methoxypropoxy)-2-methyl-2-pyridinyl]methyl] sulfinyl]-l H-benzimidazole), 120.0 g. is suspended into reaction vessel containing 600.0 ml IPA, along with stirring and maintaining temperature at 25°C to 40°C.
2) Aqueous-methanolic sodium hydroxide solution is prepared separately by dissolving 13.82 g sodium hydroxide in mixture of 138.0 ml methanol and 2.76 ml water.
3) The reaction vessel is cooled to 10°C to 20°C and aqueous methanolic sodium hydroxide prepared in step 2) is added within 0.5 to 1.0 hour, maintaining the same temperature.
4) The solution obtained in step 3) is stirred for 1 hour by maintaining 10°C to 20°C followed by filtration through celite bed to afford clear solution.
5) The mixture of IPA, methanol and water is then distilled off under reduced pressure below 55°C temperature.
6) More 240.0 ml IPA is charged to the reaction mass obtained in step 5) and removed under vacuum below 55°C temperature.
7) Reaction mass obtained in step 6) is then added with 120.0 ml toluene and solvents removed completely under reduced pressure below 55°C.
8) More 360 ml toluene and 7.2 ml IPA are added to dissolve the reaction mass obtained in step 7) at temperature 50°C to 55°C, subsequent cooling is provided to the clear solution.
9) Then 2400.0 ml fine filtered n-heptane is charged in separate vessel and it is cooled to 5 to 10°C temperature.
10) The clear solution so obtained in step 8) is added slowly over a period of 1 -2 hours in the cooled solution of n-heptane by maintaining 5°C to 10°C temperature to precipitate out Rabeprazole sodium.
11) Suspension thus obtained in step 10) is stirred for 1 hour maintaining 5°C to 10°C temperature.
12) Suspension is then filtered maintaining 5°C to 10°C temperature, which provides suck-dried wet cake of Rabeprazole sodium.
13) The wet cake is then dried in two stages under vacuum between 50°C to 55°C temperature for 12 hours and between 70°C to 73°C till moisture of Rabeprazole sodium is constant below 6% and residual solvents observed under limit to afford 118.0 g of product.
1) Rabeprazole (2-[[[4-(3-methoxypropoxy)-2-methyl-2-pyridinyl]methyl] sulfinyl]-lH-benzimidazole) 120.0 g. is suspended into reaction vessel containing 360.0 ml toluene, along with stirring and maintaining temperature 25°C to 35°C.
2) Methanolic sodium hydroxide solution is prepared separately by dissolving 13.82 g sodium hydroxide in 138.0 ml methanol.
3) The reaction vessel is cooled to 10°C to 20°C and methanolic sodium hydroxide prepared in step 2) is added within 1 to 2 hour, maintaining the same temperature.
4) The solution obtained in step 3) is stirred for 1 hour by maintaining 10°C to 20°C temperature.
5) To the above solution 12.0 g of activated charcoal is added and temperature raised to 25°C to 35°C and stirred for 0.5 to 1.0 hour at that temperature.
6) The reaction mass is filtered through celite bed and the bed washed with a mixture of 60.0 ml toluene and 12.0 ml methanol.
7) The mixture of toluene and methanol is then distilled off under reduced pressure below 55°C temperature.
8) More 120.0 ml toluene is charged to the reaction mass obtained in step 7) and removed under vacuum below 55°C temperature.
9) Reaction mass obtained in step 8) is then added with 300.0 ml toluene and 18.0 ml IPA and the contents heated to 60°C and stirred to clear solution.
10) The clear solution is filtered through celite bed and the bed washed with mixture of hot (55°C to 60°C) toluene (60 ml) and IPA (12 ml).
11) 1800.0 ml of fine filtered n-heptane is taken and cooled to 5°C to 10°C temperature
12) The clear solution obtained in step 1(1) is added to n-heptane through an addition funnel over a period of 1 to 2 hours at 5°C to 10°C temperature.
13) The reaction mass is stirred for 1 hour at 5°C to 10°C temperature.
14) The product filtered at 5°C to 10°C and washed with two 60 ml portions of chilled n-heptane and the cake is sucked dry.
15) The wet cake of Rabeprazole sodium is dried under vacuum at 25°C to 35°C for 12 hours and then dried under vacuum at 50°C to 55°C for 12 hours and finally dried under vacuum at 70°C to 75°C for 20 - 24 hours.
16) The vacuum oven is cooled to 25°C to 35°C and the product weighed to afford 119.0 g of amorphous Rabeprazole sodium.
Method of HPLC analysis:
HPLC Operating Parameters
High-performance liquid chromatography was performed using a YMC ODS-AM (Type LI) Column (4.6 mm x 250 mm, 5/um, or equivalent particle size) with the following parameters:
Mobile Phase : Transfer 550 mL of Methanol, 450 mL of
Deionized water and 1 mL of Triethylamine to a suitable container. Adjust pH to 7.5 ±0.10 using Orthophosphoric acid. Filter through 0.45 um
Wavelength Flow Rate Temperature Injection Volume Auxiliary range Attenuation
Nylon 6,6 membrane filter and degas prior to use by sonication.
Set appropriate attenuation to obtain 50% of full
scale response (For chromtopac C-R7Ae Plus, Class vp or
Not less than 60 minutes for Related Substances
Preparation of standard solution
Weigh accurately 50 mg of Rabeprazole Sodium in-house reference standard and transfer it in to a 50 mL volumetric flask. Add about 25 mL of methanol and sonicate to dissolve the solids with occasional shaking. Dilute to volume with methanol and mix well. This solution contains about 1000 μg/mL of Rabeprazole Sodium. Designate it as stock standard solution S. Transfer 5.0 mL of stock standard solution S to 50 mL volumetric flask and dilute upto volume with methanol and mix well. Designate it as diluted stock standard solution. This solution contains about 100 u.g/mL of Rabeprazole Sodium. Note: Rabeprazole sodium is unstable in event, therefore sample and standard preparation should be done prior to injection.
Preparation of sample solution for related substance:
Weigh accurately 100 mg Rabeprazole Sodium sample and transfer into a 50 mL volumetric flask. Add about 25 mL of methanol and sonicate to dissolve the solids by occasional shaking. Dilute to volume with methanol and mix well.
The Rabeprazole sodium so obtained in the above examples is amorphous, which can be confirmed by the X-ray powder diffractograms, Figure-1 and Figure-2. Purity of the amorphous Rabeprazole sodium is 99.5 % Total known and unknown impurities are not more than 0.5 %.
1. A pure amorphous form of sodium salt of 2-[[[4-(3-methoxypropoxy)-3-methyl-pyridinyl]methyl]sulfinyl]-lH-benzimidazole (rabeprazole sodium) of greater than 99.5% purity determined by high-performance liquid chromatography and having less than 1000 parts per million (p.p.m,) of residual toluene relative to rabeprazole sodium.
2. Rabeprazole sodium according to claim 1 having not more than 890 p.p.m of residual toluene relative to rabeprazole sodium.
3. Rabeprazole sodium according to claim 1 wherein total known and unknown impurity is not more than 0.5%.
4. Rabeprazole sodium according to claim 3 wherein the known impurities 2-[[[4-(3-methoxypropoxy)-3-methyl-pyridinyl]methyl]sulfonyl]-lH-benzimidazole; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]- methyl]thio]-lH-benzimidazole; 4-(3-methoxypropoxy)-2-chloromethyl-'3-methylpyridine hydrochloride; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole N-oxide; 2-mercepto benzimidazole and other unknown impurities are present to an extent not more than 0.5%.
5. Rabeprazole sodium according to claim 1 having not more than 600 p.p.m. of residual methylene dichloride relative to rabeprazole sodium.
6. Rabeprazole sodium according to claim 1 having not more than 500 p.p.m. of residual acetonitrile relative to rabeprazole sodium.
7. A process of preparing highly pure amorphous form of Sodium salt of 2-[[[4-(3-methoxypropoxy)-3-methyl-pyridiayl]methyl]sulfinyl]-lH-benzimidazole (rabeprazole) sodium of formula (I),
from rabeprazole of formula (II)
8. A process according to claim 7 comprising of
a) dissolving rabeprazole in suitable volume of solvent at appropriate temperature.
b) adding aqueous-methanolic sodium hydroxide at appropriate temperature.
c) filtration and drying the solid so obtained at suitable temperature.
9. A process as claimed in claim $ wherein said suitable solvent is selected from the group of IPA, Toluene, Xylene et;, preferably mixture of IP A and Toluene.
10. A process as claimed in claim 8 wherein the volume of suitable solvent is 1-10, preferably, 1- 5 times that of rabeprazole.
11. A process as claimed in claim 8 wherein said rabeprazole is dissolved in said solvent at temperature in the range of 20 to 60°C, preferably, 25 to 40°C .
12. A process as claimed in claim 8, wherein aqueous-methanolic sodium hydroxide solution is prepared in methanol or methanol/water mixture.
13. A process as claimed in claim 8 wherein aqueous-methanolic sodium hydroxide is added at a temperature in the range of 5 to 30°C, preferably, 10 to 20°C.
14. The process as claimed in claim 8, wherein the amorphous form of rabeprazole sodium is obtained by filtration and drying.
15. A process for preparing amorphous form of rabeprazole sodium of formula (I) such as herein described substantially as described herein with reference to the^ accompanying drawings and foregoing examples.
A pure amorphous form of sodium salt of 2-[[[4-(3-methoxypropoxy)-3-methyl-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (rabeprazole sodium) of greater than 99.5% purity determined by high-performance liquid chromatography and having less than 1000 parts per million per (p.p.m.) of residual toluene relative to rabeprazole sodium.
|Indian Patent Application Number||559/MUM/2005|
|PG Journal Number||03/2012|
|Date of Filing||05-May-2005|
|Name of Patentee||CADILA HEALTHCARE LIMITED|
|Applicant Address||Zydus Tower, Satellite Cross Roads, Ahmedabad|
|PCT International Classification Number||C07D401/12 C07D401/00|
|PCT International Application Number||N/A|
|PCT International Filing date|