HPLC\u00a0 METHOD<\/p>\n

Rabeprazole with more impurities, particularly at 2.12 RRT (393 mass), 3.51 RRT (491 mass), 4.47 RRT (457 mass), 4.85 RRT (684 mass) and 4.54 RRT (893 mass). The mass (molecular or formula weight) number of the impurities were identified using LCMS. Particularly, the obtained product contains unknown impurities of higher molecular weight in the range of 0.1-1.0 % at relative retention time (RRT) of 2.12, 3.51, 4.47, 4.85, and 4.54 RRT as measured by high performance liquid chromatography (HPLC) method provided below.<\/p>\n

The purity of the product obtained is determined by high performance liquid chromatography method under the conditions mentioned below.<\/p>\n

Column: Prontosil Kromabond 100-5-C18 (250 x 4.6 mm), 5\u03bc,<\/p>\n

Mobile phase A: 1.36g KH_{2<\/sub>PO4 to 1 litre water, 0.5ml OfEt3<\/sub>N, Mobile phase B: Methanol: ACN (95:5),<\/p>\n}

Diluent: Mobile phase A and ACN (70:30),<\/p>\n

Flow Rate: 1.0 mL\/min,<\/p>\n

Detection: UV at 280 nm,<\/p>\n

Injection Volume: 20 \u03bcL, Run Time: 60 min.<\/p>\n

Column oven temperature: 3O^{0<\/sup>C. Surprisingly the applicant identified a method in which, crude Rabeprazole was treated with diethylamine and optionally addition of TBAB (tetrabutylammmonium bromide) as catalyst, where the impurity level reduced. Though the reported amines like triethyl amine, ethanolamine, and ammonia are effectively used to minimize sulfone impurity, those are failed or unsatisfactory to remove the impurities at 2.12 RRT, 3.51 RRT, 4.47 RRT, 4.85 RRT and 4.54 RRT.<\/p>\n}

SPECTRAL DATA<\/p>\n

EP 1869015 B1 FOR RABEPRAZOLE SODIUM<\/p>\n

IR Spectra (KBr, cm^{-1<\/sup>): 3382, 2927, 1583, 1462, 1384, 1298, 1269, 1190, 1157, 1093, 1018, 745.<\/p>\n}

H NMR Spectra [200 M Hz, CD3OD] \u03b4 (ppm): 8.23 – 8.25 (1H, d, ArH); 7.57 – 7.62 (2H, m, ArH); 7.0 – 7.09 (2H, m, ArH); 6.87 – 6.90 (1H, d, ArH); 4.57 – 4.63 (2H, d, O=S-CH2-Ar); 4.0 – 4.1 (2H, t, -O-CH2-CH2-); 3.49 – 3.55 (2H, t, -CH2-O-CH3); 3.31 (3H, s, -OCH3); 2.1 (3H, s, Ar-CH3); 1.96 – 2.0 (2H, t, -CH2-CH2-CH2-).<\/p>\n

MP<\/p>\n

As per the process described and exemplified in the U. S. Patent No.<\/p>\n

5,045,552, rabeprazole sodium is prepared by oxidizing 2-[[4-(3- methoxyporpoxy)-3-methylpyridine-2-yl]rnethylthio]-1 H-benzimidazole with m- chloroperbenzoic acid to afford the rabeprazole base which is further converted to its sodium salt by using 0.1 N aqueous solution of sodium hydroxide, followed by addition of ethanol. The water is removed by azeotropic distillation and the product is precipitated by using ether as solvent such as diethyl ether, tert-butyl methyl ether. The melting point of the disclosed rabeprazole sodium salt is 140- 141^{0<\/sup>C. The isolation process described in the U. S. Patent No. 5,045,552 has numerous disadvantages such as large volume of solvents is required for azeotropic removal of water during which the product is exposed to high temperature and leads to certain impurities. Based on these drawbacks the isolation process finds to be unsuitable for preparation of amorphous rabeprazole sodium at commercial scale operations.<\/p>\n}

Japanese patent application JP 2001039975 indicates that the product obtained by example 33 of the U. S. Patent No. 5,045,552 with a melting point of<\/p>\n

140-141^{0<\/sup>C corresponds to amorphous rabeprazole sodium. In this application, the X-ray powder diffraction pattern of the amorphous rabeprazole sodium is shown.<\/p>\n}

The PCT patent publication No. WO 03\/101452 discloses a method for the preparation of rabeprazole sodium comprising dissolving rabeprazole base in aqueous sodium hydroxide and then subjecting to lyophilization. U.S. Patent No. 6,180,652 B1 (the ‘652 patent) describes acetone complex of rabeprazole sodium, process for its production and characterizes it by powder X-ray diffraction, infra-red spectroscopy and\u00a0^{1<\/sup>H-NMR spectroscopy. The ‘652 patent further reports a process for preparation of amorphous rabeprazole sodium by lyophilizing (freeze-drying) an aqueous solution of rabeprazole sodium acetone complex.<\/p>\n}

However, lyophilization is a technique, which is not suitable for production at industrial scale because this process presents serious limitations on cost, time, equipment capability and environmental protection.<\/p>\n

According to PCT patent publication No. WO 2004\/085424A1 , amorphous rabeprazole sodium is obtained by heating the rabeprazole sodium acetone complex at elevated temperature, preferably between 100 and 110^{0<\/sup>C. It is well known that exposing rabeprazole-type compounds to high temperatures increases the risk of decomposition to form impurities and as such, heat treatment of rabeprazole sodium acetone complex into amorphous rabeprazole sodium is not adequate for the production of a rabeprazole which is suitable for pharmaceutical use.<\/p>\n}

PCT patent publication No. WO 2007\/023393 A2 reports a process for preparation of amorphous rabeprazole sodium, the said process comprises: i) contacting rabeprazole sodium acetone complex with a first solvent system which includes a hydrocarbon solvent or an ether solvent or an alcohol solvent or mixtures thereof; ii) filtering the solid from the solvent system used in step i) or distilling the solvent system used in step i) under reduced or atmospheric pressure, to thereby obtain a residue; iii) contacting the wet solid or the residue of step ii) with a second solvent system which includes a hydrocarbon solvent or an ether solvent; and iv) filtering to obtain a wet solid from the solvent system used in step iii) to obtain a wet solid.<\/p>\n

The methods for preparation of amorphous rabeprazole sodium as described in the patents U.S. Patent No. 6,180,652 B1 , PCT patent publication No. WO 2004\/085424A1 and PCT patent publication No. WO 2007\/023393 A2 involves lengthy process i.e., proceeds via rabeprazole sodium acetone complex intermediate and also the yields obtained in these processes are very low.<\/p>\n

U.S. Patent Application No. US2004\/0180935A1 teaches a process for production of amorphous rabeprazole sodium by dissolving rabeprazole acid in a mixture of sodium hydroxide and methanol at 25-35^{0<\/sup>C, removing the solvent by evaporation and precipitating the product by adding petroleum ether.<\/p>\n}

PCT patent publication No. WO 2006\/120701 A1 teaches a process for manufacture of amorphous rabeprazole sodium with mean particle diameter between 10 to 55 \u03bcm, the said process comprises, addition of rabeprazole to aqueous sodium hydroxide; addition of ethyl alcohol to the solution; distillation of solvents from the solution thus obtained till thick mass is obtained; addition of an organic solvent selected from ethyl acetate, dichloromethane, chloroform, butyl acetate, ethanol, isopropyl alcohol, methanol, tetrahydrofuran, to the residue to obtain a clear solution; addition of this clear solution to an anti-solvent includes diisopropyl ether, diethyl ether, methyl tert-butyl ether, under agitation and isolation of the product.<\/p>\n

Since a solvent may play an important role in increasing the yield rate or in determination of physical properties of drug substance such as crystal form, purity, solubility, etc., even if such a solvent is known to be toxic, there may be many cases that the use thereof in the preparation of drug substance cannot be avoided in terms of risk benefits. In such cases, this guideline (ICH guidelines Q3C(R3)) decrees that a concentration of a residual solvent in drug substance should be not more than a specified value, which is toxicologically acceptable. The methods for preparation of amorphous rabeprazole sodium as described in the patents, U.S. Patent Application No. US2004\/0180935A1 and PCT patent publication No. WO 2006\/120701 A1 suffers with residual solvent problem and thereby commercially not viable. These methods utilize the solvents like diisopropyl ether and petroleum ether as precipitating solvents. These solvents are difficult to remove completely by practical manufacturing techniques. According to the ICH guidelines Q3C(R3), there is no adequate toxicological data for the solvents like diisopropyl ether and petroleum ether on which to base a PDE was found. However, a need still remains for an improved and commercially viable process of preparing pure amorphous rabeprazole sodium that would solve the aforesaid problems associated with processes described in the prior art, which will be suitable for largr-scale preparation, in terms of simplicity, chemical yield and purity of the product, and which would carry out with comparatively smaller volume of solvent<\/p>\n","protected":false},"excerpt":{"rendered":"