The present invention relates to an improved process for the preparation of rabeprazole sodium in an amorphous form.
Rabeprazole sodium, a substituted benzimidazole that inhibits gastric acid secretion and can be used for the prevention or treatment of peptic ulcers. Chemically rabeprazole sodium is 2-[[[4-(3-methoxypropoxy) -3-methyl-2-pyridinyl]-methyl] sulfmyl] -1H-benzimidazole sodium salt and is known from U. S. Patent No. 5,045,552. It is represented by Formula I,
(Formula 1Removed)
Formula I
U. S. Patent No. 5,045,552, WO01/04109 and recent published application WO 06/024890 disclose the process for the preparation of rabeprazole sodium in an amorphous form by conventional methods, such as dissolution of the rabeprazole base in a mixture of aqueous sodium hydroxide and ethanol, evaporation of the solvent to remove water as an azeotropic mixture, drying the residue at low pressure and then crystallization of the residue with scantly polar solvent such as diethyl ether, tert-butyl methyl ether etc.
The above procedures of preparing rabeprazole sodium salt have numerous disadvantages such as large volume of solvents is required to azeotropically remove water and to crystallize out the product, which are difficult to recycle or dispose of in an environmentally acceptable manner. A further disadvantage of these processes is the presence of higher residual solvent content in the product resulting in lower potency. These methods are not suitable for industrial scale preparation of rabeprazole sodium.
U. S. Patent No. 6,545,024 and WO 03/101452 disclose the process for the preparation of rabeprazole sodium in an amorphous form by lyophilization technique. Lyophilization technique is an expensive technique as it involves the use of expensive cryogenic equipment and the production scale is also restricted due to plant-capacity or ability. Therefore it is not suitable for industrial scale preparation of rabeprazole sodium due to requirement of large-scale plant.
WO 04/085424 discloses the process for the preparation of rabeprazole sodium in an amorphous form by heat drying process, which involves lengthy steps of drying and therefore not suitable for industrial scale preparation of rabeprazole sodium.
Therefore, there has been an ongoing search for new technique, which is capable of producing rabeprazole sodium in an amorphous form. In the endeavor to find a simple, efficient, cost-effective technique for the preparation of rabeprazole sodium in an amorphous form, the present inventors have found a commercially viable process i.e spray-drying technique for the preparation of rabeprazole sodium in an amorphous form, which is well suited for industrial scale up.
The present invention provides a process for the preparation of amorphous rabeprazole sodium, which comprises the steps of:
a) providing a solution of rabeprazole sodium.
b) recovering amorphous form of rabeprazole sodium by spray drying technique.
The solution of rabeprazole sodium may be obtained by adding 2-[[[4-(3-methoxypropoxy) -3-methyl-2-pyridinyl]-methyl] sulfinyl] -1H-benzimidazole i.e rabeprazole base in an aqueous or alcoholic solution of sodium hydroxide.
Rabeprazole base may be obtained by methods known in the art including US 5045552, US 6545024, US 6313303, US 6603009, US 6723852, WO 00/027841 Al, WO 01/04109 Al, WO 02/062786 Al, WO 03/008406 Al and WO 04/056803 Al, which are incorporated herein by reference.
The aqueous solution of sodium hydroxide may be obtained by dissolving sodium hydroxide in water.
The alcoholic solution of sodium hydroxide may be obtained by dissolving sodium hydroxide in C1-C4 alkanol solvent.
The C1-C4 alkanol solvent may be selected from the group comprising of methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol or mixture(s) thereof.
Rabeprazole base may be added to the solution of sodium hydroxide at a temperature of about 15-30°C. Preferably it may be added at about 20°C.
The solution of rabeprazole sodium may be treated with activated charcoal. The solution of rabeprazole sodium may be concentrated under reduced pressure to obtain a residue.
A suitable solvent may be added to the residue to obtain a solution of rabeprazole sodium. Suitable solvent includes any solvent or solvent mixture in which rabeprazole sodium is soluble. Example of suitable solvent includes chlorinated hydrocarbons, alcohols, alkyl acetates and/or mixtures thereof.
The chlorinated hydrocarbons may be selected from the group comprising of dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, dichloropropane, chloroform, carbon tetrachloride or mixture(s) thereof.
The alcohols may be selected from the group comprising of methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol or mixture(s) thereof.
The alkyl acetates may be selected from the group comprising of ethyl acetate, isopropyl acetate or mixtures thereof.
Rabeprazole salt is recovered from the solution in an amorphous form using spray-drying technique. The Mini-Spray Dryer (Model: Hemraj Enterprises; PSD 01), which has been used, operates on the principle of nozzle spraying product and the drying gas flows in the same direction. The drying gas can be air or inert gases such as nitrogen, argon, and carbon dioxide. Preferably Nitrogen gas is used.
The inlet temperature to the spray drier may range from about 40°C to 125°C. The outlet temperature to the spray drier may range from about 25°C to 110°C.
In spray drying technique, the liquid food is introduced as a fine spray or mist into a tower or chamber with heated air. As the small droplets make intimate contact with the heated air, they flash off their moisture, become small particles, and drop to the bottom of the tower and are removed. The advantages of spray drying include a low heat and short time combination, which leads to a better quality product.
The amorphous form of rabeprazole sodium obtained by the method of present invention results in better purity and yield with absence of residual solvent impurity.
The amorphous form of rabeprazole sodium may be characterized by its FTIR spectrum and X-ray powder diffraction pattern as depicted in Figure 1 and 2 respectively.
METHODS
Powder XRD
X-Ray Difractometer, Rigaku Coorperation, RU-H3R
Goniometer CN2155A3
X-Ray tube with Cu target anode
Divergence slits 10, Receiving slit 0.15mm, Scatter slit 1 0
Power: 40 KV, 100mA
Scanning speed: 2 deg/min step: 0.02 deg
Wave length: 1.5406 A
FT-IR
Instrument: Perkin Elmer, 16 PC
SCAN: 16scans, 4.0 cm"1
According to the USP 25, general test methods page 1920, infrared absorption spectrum by
potassium bromide pellet method.
Figure 1 represents the FTIR spectrum of the amorphous form of rabeprazole sodium.
Figure 2 represents the X-ray powder diffraction pattern of the amorphous form of rabeprazole
sodium.
In the following section preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
Example 1: Preparation of amorphous rabeprazole sodium
Sodium hydroxide (6.6g, 0.167mol.) was dissolved in ethanol and rabeprazole base (60g, 0.167 mol) was added to this solution at 20°C. The reaction mixture was stirred for 30 minutes to get a clear solution. The resulting solution was treated with activated carbon and concentrated under
reduced pressure up to maximum extent below 35°C. The resulting residue was dissolved in
methylene chloride (900 ml). The clear solution thus obtained was subjected to spray drying in a
mini-spray dryer (Model: Hemraj Enterprises; PSD 01) at an inlet temperature of 52°C with a
feed rate of 15ml per minute. Rabeprazole sodium in an amorphous form was thus isolated.
Yield: 56.4gm
HPLC PURITY = 99.86 %
Example 2: Preparation of amorphous rabeprazole sodium
Sodium hydroxide (3.9g, 0.097 mol) was suspended in ethanol (175 ml) and stirred for 30 minutes to get a solution. The solution was cooled to 20°C and rabeprazole base (35 g, 0.097 mol) was added accompanied by stirring for 30 minutes. The clear solution thus obtained was subjected to spray drying in a mini-spray dryer (Model: Hemraj Enterprises; PSD 01) at an inlet temperature of 95°C with a feed rate of 15ml per minute. Rabeprazole sodium in an amorphous form was thus isolated. Yield: 31.5 gm HPLC PURITY = 99.83%
Example 3: Preparation of amorphous rabeprazole sodium
Rabeprazole base (50 g) was added to aqueous sodium hydroxide solution (5.5 g sodium
hydroxide dissolved in 250 ml water). The clear solution thus obtained was subjected to spray
drying in a mini-spray dryer (Model: Hemraj Enterprises; PSD 01) at an inlet temperature of
110°C with a feed rate of 15ml per minute. Rabeprazole sodium in an amorphous form was thus
isolated.
Yield: 40gm
HPLC PURITY = 99.76%
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

WE CLAIM:
1. A process for the preparation of amorphous rabeprazole sodium, which comprises the steps
of:
a) providing a solution of rabeprazole sodium.
b) recovering amorphous form of rabeprazole sodium by spray drying technique.

2. The process according to claim 1, wherein solution of rabeprazole sodium may be
obtained by adding 2-[[[4-(3-methoxypropoxy) -3-methyl-2-pyridinyl]-methyl] sulfinyl]
-IH-benzimidazole i.e rabeprazole base in an aqueous or alcoholic solution of sodium
hydroxide.
3. The process according to claim 2, wherein alcoholic solution of sodium hydroxide may
be obtained by dissolving sodium hydroxide in C1-C4 alkanol solvent.
4. The process according to claim 3, wherein C1-C4 alkanol solvent may be selected from
the group comprising of methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol
or mixture(s) thereof.
5. The process according to claim 2, wherein rabeprazole base may be added to the solution
of sodium hydroxide at a temperature of about 15-30°C.
6. The process according to claim 1, wherein the solution of rabeprazole sodium may be
concentrated under reduced pressure to obtain a residue.
7. The process according to claim 1, wherein a suitable solvent may be added to the residue
to obtain a solution of rabeprazole sodium.
8. The process according to claim 7, wherein suitable solvent includes chlorinated
hydrocarbons, alcohols and alkyl acetates.
9. The process according to claim 8, wherein chlorinated hydrocarbons may be selected
from the group comprising of dichloromethane, dichloroethane, trichloroethane,
tetrachloroethane, dichloropropane, dichloropropane, chloroform, carbon tetrachloride or
mixture(s) thereof.

10. The process according to claim 8, wherein alcohols may be selected from the group
comprising of methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol or
mixture(s) thereof.
11. The process according to claim 8, wherein alkyl acetates may be selected from the group
comprising of ethyl acetate, isopropyl acetate or mixtures thereof.
12. The process according to claim 1, wherein inlet temperature to the spray drier ranges
from 40°Ctol25°C.
13. The process according to claim 1, wherein outlet temperature to the spray drier ranges
from25°C to ll0°C.
14. A process for the preparation of amorphous rabeprazole sodium as herein described and
illustrated by the examples.