WO2011095984A1

WO2011095984A1 - A process for the preparation of amorphous esomeprazole

Info

Publication number: WO2011095984A1
Application number: PCT/IN2011/000042
Authority: WO
Inventors: Joseph Prabahar Koilpillai; Hemant Nimba Raundal; Nagan Nirmalan Kandasamy; Hiremath Veerabhadra Swamy; Milind Moreshwar Gharpure; Mubeen Ahmed Khan
Original assignee: Glenmark Generics Ltd
Current assignee: Glenmark Generics Ltd
Priority date: 2010-02-02
Filing date: 2011-01-20
Publication date: 2011-08-11
Anticipated expiration: 2012-08-02

Abstract

The present invention relates to a process for the preparation of esomeprazole in amorphous form by spray drying.

Description

A PROCESS FOR THE PREPARATION OF AMORPHOUS ESOMEPRAZOLE

PRIORITY

[0001] This application claims the benefit of IN 243/MUM/2010 filed on February

2, 2010, the content of which is incorporated herein by reference.

FIELD OF THE INVENTION

|0002] The present invention relates to a process for the preparation of esomeprazole in amorphous form by spray drying. The present invention also relates to a pharmaceutical composition comprising amorphous esomeprazole and a pharmaceutically acceptable carrier.

BACKGROUND OF THE INVENTION

[0003] Omeprazole is chemically known as 5-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl) methyl] sulfinyl]-l H-benzimidazole. The S-enantiomer, "esomeprazole", is chemically known as (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)-methyl]sulfinyl}-l H-benzimidazole. Esomeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and Zollinger-Ellison syndrome. Esomeprazole is marketed as LOSEC®/PRILOSEC®.

[0004] The magnesium salt of esomeprazole in the form of trihydrate is marketed under the brand name NEXIUM® and is represented by formula I.

(I)

[0005] U.S. Patent. No. 5,714,505 describes alkaline salts of the (-) enantiomer of

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazoles (i.e., esomeprazole) including the magnesium salt. [0006] U.S. Patent. No. 6,162,816 describes crystalline Form A and Form B of neutral esomeprazole, processes thereof and pharmaceutical compositions comprising the same.

[0007] U.S. PG Publication No. 20080269297 describes crystalline modifications C, E and G of neutral esomeprazole and processes thereof, and pharmaceutical

compositions comprising the same.

[0008] U.S. Patent. No. 7,563,812 describes amorphous esomeprazole hydrate and process thereof. U.S. PG publication No. 20060247277 describes crystalline esomeprazole Form I and II or hydrates and process thereof.

[0009] U.S. PG publication No. 20090082572 describes a process for preparation of amorphous esomeprazole by lyophilization.

[0010] The aforementioned processes for the preparation of amorphous

esomeprazole, inconsistently produce substantially amorphous form of esomeprazole.

[0011] Hence, there is need in the art to provide a process that is robust, cost effective, ecofriendly and commercially viable and can consistently produce esomeprazole substantially in amorphous form.

SUMMARY OF THE INVENTION

[0012] The present invention relates to a process for the preparation of amorphous esomeprazole.

[0013] In one aspect, the present invention relates to a process for the preparation of esomeprazole substantially in amorphous form comprising:

a) providing a solution of esomeprazole or salt thereof in a solvent or a mixture thereof; b) optionally treating the solution with an acid;

c) removing the solvent from the solution to provide the residue;

d) adding a suitable solvent to the residue to form a solution;

e) recovering the esomeprazole substantially in amorphous form by spray drying.

[0014] In another aspect, the present invention provides amorphous esomeprazole obtained by process herein described with an X-ray diffractogram, which is substantially in accordance with Fig. 1. [0015] In yet another aspect, the present invention provides amorphous esomeprazole obtained by process herein described with a differential scanning calorimetry (DSC) glass transition temperature curve, which is substantially in accordance with Fig. 2.

[0016] In yet another aspect, the present invention provides amorphous esomeprazole obtained by process herein described with a thermogravimetric analysis curve, which is substantially in accordance with Fig. 3.

[0017] In yet another embodiment, the present invention provides amorphous esomeprazole having purity at least about 99.8% as determined by chiral high performance liquid chromatography (HPLC).

[0018] In another embodiment, the present invention provides amorphous esomeprazole having less than about 0.15% area of (R)-isomer impurity as determined by chiral HPLC.

[0019] In yet another embodiment, the present invention provides amorphous esomeprazole having less than about 0.1% area of (R)-isomer impurity as determined by chiral HPLC.

[0020] In yet another embodiment, the present invention provides amorphous esomeprazole having a specific surface area from about 0.4 m 2 /g to about 1.5 m 2 /g as measured by Brunauer-Emmett-Teller (BET) method.

[0021] In yet another aspect, the present invention provides a pharmaceutical composition comprising amorphous esomeprazole obtained by the process of present invention and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Fig. 1 : is an X-ray powder diffractogram of amorphous esomeprazole obtained by the process of the present invention.

[0023] Fig. 2: is a glass transition temperature by Differential scanning calorimetry of amorphous esomeprazole obtained by the process of the present invention.

[0024] Fig. 3 : is a thermogravimetric analysis curve of amorphous esomeprazole obtained by the process of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0025] The term polymorphism includes different physical forms, crystal forms, crystalline/liquid crystalline/non-crystalline (amorphous) forms. It has been observed that one or more polymorphic forms of a given drug exhibit superior bioavailability and consequently show much higher activity compared to other polymorphs. Amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. Amorphous materials do not exhibit the three dimensional long range order found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random.

[0026] Generally, amorphous solids offer opportunities for solubility and bioavailability enhancement since these materials are more soluble than the crystalline form of the same compound. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.

[0027] Additionally, amorphous solids are not crystalline and therefore do not give a definitive X-ray diffraction pattern. Amorphous materials do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point.

[0028] Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient (API), can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

[0029] The present invention relates to a process for the preparation of amorphous esomeprazole.

[0030] In one aspect, the present invention relates to a process for the preparation of esomeprazole substantially in amorphous form comprising:

a) providing a solution of esomeprazole or salt thereof in a solvent or a mixture thereof; b) optionally treating the solution with an acid ;

c) evaporating the solvent(s) from the solution to provide the residue;

d) adding a suitable solvent to the residue to form a solution; and

e) recovering the esomeprazole substantially in amorphous form by spray drying. [0031] The solution of esomeprazole or its salt, used in the process directly described above, can be obtained by dissolving esomeprazole or a pharmaceutically acceptable salt thereof in a solvent or mixture of solvents.

[0032] As used herein, a solvent is any liquid substance capable of dissolving esomeprazole or its pharmaceutically acceptable salt.

[0033] As used herein, a mixture of solvents refers to a composition comprising more than one solvent and may include water.

[0034] In one embodiment the present invention provides a solution of esomeprazole in a solvent. Suitable solvent may be chlorinated solvents and the like: Suitable chlorinated solvents include, but are not limited to, chloroform, carbon tetrachloride, perchloroethylene, methylene dichloride, and mixtures thereof. Preferably, methylene dichloride is used.

[0035] In one embodiment, the present invention provides a process comprising obtaining the solution of esomeprazole in a solvent by dissolving the esomeprazole salt in a solvent or a mixture of solvent and water; treating with an acid; and separating the solvent containing esomeprazole. In one preferred embodiment, the present invention provides a process comprising dissolving esomeprazole salt in a mixture of water and chlorinated solvent and treating with an acid. Preferably the chlorinated solvent is methylene dichloride.

[0036] Suitable salts of esomeprazole include, but are not limited to, alkali or alkaline salts of esomeprazole, such as sodium, lithium, potassium, magnesium, strontium, barium, calcium or alkyl ammonium salts of esomeprazole known in the art. Preferably potassium salts of esomeprazole.

[0037] The volume of the solvent used to solubilize esomeprazole or a salt thereof may range from about 2 volumes to about 20 volumes to the weight of the esomeprazole or a pharmaceutically acceptable salt thereof taken. Preferably, from about 5 volumes to about 10 volumes.

[0038] Suitable acids may be selected from the group consisting of acetic acid, formic acid, succinic acid, hydrochloric acid, sulfuric acid and aqueous mixtures thereof. Preferably, acetic acid is used. [0039] The solution obtained is optionally filtered by using conventional filtration techniques known in the art, such as through celite or diatomaceous earth, to separate the extraneous matter present or formed in the solution.

[0040] The solution of esomeprazole in solvent is evaporated to provide a residue. Evaporation may be carried out by heating under reduced pressure For example, the chlorinated solvent may be removed by heating, preferably under reduced pressure. Preferably, the solution is heated from about 0°C to about 60°C, more preferably from about from about 20°C to about 40°C, and even more preferably from about 30°C to about 40°C.

[0041] In one embodiment, the present invention provides a process comprising dissolving esomeprazole potassium in a mixture of water and methylene dichloride; treating with acetic acid; separating the methylene dichloride layer containing esomeprazole from the aqueous layer; and evaporating the methylene dichloride layer under reduced pressure to obtain a residue.

[0042] A suitable solvent may be added to the residue to form a solution from which the esomeprazole can be recovered substantially in amorphous form by spray drying.

[0043] The solvent to be added to the residue may be selected from the group consisting of C₃-C₅ aliphatic ketones; C C₆ chlorinated hydrocarbons; Cj-C₆ aliphatic alcohols; C₃-C₆ aliphatic esters; C₂-C₅ aliphatic nitriles; ethers.

[0044] The solvent that may be used for adding to the residue may include C3-C5 aliphatic ketones such as acetone and the like; C|-C₆ chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride and the like ; C|-C₆ aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butyl alcohol and the like; C3-C10 aliphatic esters such as ethyl acetate, isopropyl acetate and the like; C₂-C₅ aliphatic nitriles such as acetonitrile, propionitrile and the like; ethers such as tetrahydrofuran and the like. Preferably acetone is used as a solvent.

[0045] The solution of esomeprazole may be added dropwise or continuously to the drying chamber. The speed of the addition of the solution will depend on the solvent used, the viscosity of the mixture, and the height of the chamber. These and other parameters are well known to a person skilled in the art of drying. The concentration, solvent type, temperature, vacuum and feeding rate are set to combinations where the esomeprazole coming from the inlet precipitates essentially instantly. Otherwise, crystalline material can also form.

[0046] In the spray drying technique, a solution of esomeprazole is sprayed into the spray drier at the flow rate ranging from about 10 ml/hr to about 300 ml/hr. Preferably at flow rate of about 100 ml/hr to about 200ml/hr.

[0047] The air inlet temperature to the spray drier used may range from about 25 °C to about 100°C. In one embodiment, the air inlet temperature is in the range from about 30 °C to about 80°C. Preferably from about 35°C to about 55°C.

[0048] The air outlet temperature used may range from about 30°C to about 90°C. Preferably, from about 35°C to about 50°C.

[0049] The process frequently is carried out at lower temperatures of about 35°C to about 50°C under reduced pressures of about 600mmHg to about 700mmHg. These dryers are indirectly heated and therefore air does not come in contact with the product.

[0050] The esomeprazole product produced by spray-drying may be recovered by techniques commonly used in the art, such as using a cyclone or a filter.

[0051] Illustratively, in a non-limiting example a typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber. Examples of such apparatuses include Niro® Models PSD-I, PSD-2 and PSD-4 (Niro A/S, Soeborg, Denmark). Typically, the product collection means includes a cyclone connected to the drying apparatus. In the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent^ allowing the particles to be collected. A filter may also be used to separate and collect the particles produced by spray drying. Spray- drying may be performed in a conventional manner in the processes of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 19th ed., vol. II, pg. 1627, 2006 herein incorporated by reference). The drying gas used in the invention may be any suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are preferred. Nitrogen gas is a particularly preferred drying gas for use in the process of the invention. [0052] In one embodiment the residue obtained after removal of methylene dichloride solution containing esomeprazole is dissolved in acetone and is subjected to spray drying at a flow rate ranging from about lOOml/hr to 200ml/hr. The air inlet temperature to the spray drier used may range from about 35°C to about 50°C, preferably about 40°C to 45°C and the outlet air temperature used may range from about 30°C to about 60°C, preferably, about 35°C to about 40°C to obtain esomeprazole substantially in amorphous form by spray drying.

[0053] It has been observed that when the inlet temperature goes beyond about

60°C, there may be a minor contamination of crystalline product formation. While at an inlet temperature of about 80°C, the observed material may be a gummy mass. It is found that the inlet temperature should be maintained below about 60°C to afford the desired substantially pure amorphous esomeprazole.

[0054] The esomeprazole substantially in an amorphous form obtained by the above process may be further dried in, for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents. When implemented, the preferred instrument is a vacuum tray dryer.

[0055] The temperature for drying can range from about 25°C to about 75°C under vacuum. Preferably, from about 25°C to about 35°C, under vacuum. The drying can be carried out for any desired time, preferably time periods from about 1 hour to about 10 hours frequently being sufficient.

[0056] In one embodiment the present invention provides amorphous esomeprazole having specific surface area from about 0.4 m²/g to about 1.5 m²/g as measured by BET (Brunauer-Emmett-Teller) method. Preferably the specific surface area of amorphous esomeprazole is in the range from about 0.5 m²/g to about 1.0 m²/g as measured by BET method.

[0057] Specific surface area is defined in units of square meters per gram (m²/g).

Specific surface area is defined in units of square meters per gram (m /g). It is usually measured by nitrogen absorption analysis. In this analysis, nitrogen is absorbed on the surface of the substance. The amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the BET formula. [0058] The dried product optionally can be milled to get the required particle size.

Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.

[0059] Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling can be performed prior to the drying operation. Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.

[0060] The esomeprazole or a salt thereof used as starting material in the process described herein above, may be of indefinite morphology, or may be crude esomeprazole or a salt thereof resulting from synthetic processing steps known in the art. Illustratively, the esomeprazole or a salt thereof used as starting material are as those described in U.S. Patent Nos. 5.714.504. 6, 124.464; and 6,369,085, which are included herein as references, in their entirety.

[0061] Advantageously, the process of the present invention provides a substantially pure amorphous form of esomeprazole having less than about 20%, more preferably less than about 10%, even more preferably less than about 5%, and most preferably less than about 1 %, of any one of crystalline forms A, B, C, E, G, I, and II of esomeprazole known in the art.

[0062] In one example, the present invention provides the XRPD pattern of the amorphous esomeprazole, which is substantially in accordance with Fig. 1.

[0063] The present invention provides amorphous esomeprazole obtained by process herein described, characterized by an X-ray diffractogram, which is substantially in accordance with Fig.1.

[0064] The present invention provides amorphous esomeprazole obtained by process herein described characterized by differential scanning calorimetry (DSC) glass transition temperature curve, which is substantially in accordance with Fig. 2.

[0065] The present invention provides amorphous esomeprazole obtained by process herein described characterized by thermogravimetric analysis curve, which is substantially in accordance with Fig. 3. [0066] The present invention provides amorphous esomeprazole having a purity of at least about 99.8%, as determined by chiral high performance liquid chromatography (HPLC).

[0067] The present invention provides amorphous esomeprazole having less than about 0.15% area of (R)-isomer impurity as determined by chiral HPLC.

[0068] The present invention provides amorphous esomeprazole having less than about 0.1% area of (R)-isomer impurity, as determined by chiral HPLC.

[0069] Advantageously, the present invention provides the esomeprazole amorphous compound prepared by the process herein described, exists in a well defined and stable state, which allows easier characterization and facile handling and storage. Additionally, the compound, prepared by the process herein described, is easier to synthesize in a reproducible manner and thereby easier to handle in a full scale production.

[0070] The amorphous esomeprazole obtained by the process of present invention is substantially free from other polymorphic forms of esomeprazole known in the art.

[0071] The amorphous esomeprazole obtained by the process of present invention is easily distinguishable from any other form esomeprazole disclosed in prior art.

[0072] With the expression "any other form" is meant anhydrates, hydrates, solvates, and polymorphs or amorphous forms thereof disclosed in the prior art. Examples of any other forms of esomeprazole or salt of esomeprazole includes, but are not limited to, anhydrates, monohydrates, dihydrates, sesquihydrates, trihydrates, alcoholates, such as methanolates and ethanolates, and polymorphs or amorphous forms thereof.

[0073] Advantageously the process of present invention consistently produces esomeprazole substantially in amorphous form and well suited on commercial scale.

[0074] The amorphous esomeprazole obtained by the process of present invention is substantially stable at about 2°C to about 8°C at relative humidity (RH) about 60%v/v for any give time period.

[0075] The characterization of the amorphous form of esomeprazole by X-ray powder diffraction, previously described, were performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (Cu Ka l = 1.54060A). The X-ray source is operated at 45 kV and 40mA. Spectra are recorded at start angle from 2° to 50° 2Θ, a step size 0.0167° with a time per step of 1000 seconds. [0076] The amorphous esomeprazole obtained by the process of the present invention is characterised by differential scanning calorimetry (DSC), where the measurement uses a pproximately 1 -2mg sample accurately weighed into an aluminum DSC pan (40μΙ,) with a lid and then slightly pierced the lid. The sample was placed into the Mettler Toledo DSC822^6® equipped with a nitrogen cooling unit and allowed to equilibrate at 30°C until the stable heat flow reference was seen. A purge nitrogen as dry gas at a flow rate of 50ml/minute was used to produce inert atmosphere to prevent oxidation of sample during the heating. The sample was then scanned from 30- 350°C at rate of 10°C/minute.

[0077] Thermogravimetric analysis (TGA) of amorphous esomeprazole obtained by the process of present invention was recorded on TGA Q500 V6.5. Thermogram was recorded at 30°C -350°C at the rate of 10°C/min.

[0078] Also, of particular interest and importance in pharmaceutical formulations, is the particle size distribution of the API. The Dio, D₅₀ and D90 values are useful ways for indicating a particle size distribution. D_% refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the said value. Likewise D₅₀ and Dio refer, respectively, to the values for the particle size for which 50 volume percent, and 10 volume percent of the particles that have a size smaller than the said value. A D50 value can be considered as being the mean particle size of a powder. Methods for determining D₁₀, D₅₀ and D9₀ include laser diffraction using Malvern equipment.

[0079] Amorphous esomeprazole obtained by the process of present invention has a

D₁₀ less than about 20 μιτι, D₅₀ less than about 80 μιη, and D90 less than 250 μηι. There is no specific lower limit for any of the D values.

[0080] Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the amorphous esomeprazole into any desired particle size range as set forth above.

[0081] In a preferred embodiment, amorphous esomeprazole obtained by the process described herein has a residual organic solvent content of less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; i.e., less than about 2000ppm of isopropyl alcohol, less than about lOOOppm of methanol, less than about 500ppm of dichloromethane, less than about lOOOppm of acetone and acetic acid, toluene at below the detection limit. [0082] In another embodiment, the present invention provides a pharmaceutical composition comprising the amorphous esomeprazole obtained by the process of present invention, as an active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients.

[0083] Said pharmaceutical composition comprising the amorphous esomeprazole is useful in the manufacture of a medicament for use in the treatment of a gastric-acid related condition and a method of treating a gastric-acid related condition which method comprises administering to a subject suffering from said condition a therapeutically effective amount.

[0084] The compositions of the invention include compositions suitable for per oral or parental administration. The most preferred route is the oral route. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the art of pharmacy.

[0085] The dose, and dose frequency, may also vary according to the age, body weight, and response of the individual patient. Special requirements may be needed for patients having Zollinger-Ellison syndrome, such as a need for higher doses than the average patient. Children and patients with liver diseases generally will benefit from doses that are somewhat lower than the average. Thus, in some conditions it may be necessary to use doses outside the ranges stated below, for example long term treatments may request lower dosage. Such higher and lower doses are within the scope of the present invention. Such daily doses may vary between 5mg to 300mg. Dosage forms include capsules, tablets, dispersions, suspensions and the like.

[0086] The process for the preparation of amorphous esomeprazole of the present invention is simple, eco-friendly, robust, reproducible and easily scalable.

[0087] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages. EXAMPLES

EXAMPLE 1 : PREPARATION OF AMORPHOUS ESOMEPRAZOLE FROM

ESOMEPRAZOLE POTASSIUM BY SPRAY DRYING

Esomeprazole potassium (100 gm) was dissolved in demineralized (DM) water

(2000 ml) at about 25-30°C and methylene dichloride (1000 ml) was added to the solution. The pH of the mixture was adjusted to about 8 by adding acetic acid. The organic layer was taken and concentrated at about 30-35°C under reduced pressure. The residue was dissolved in acetone (500 ml) and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm² nitrogen pressure. Further the input temperature was maintained at about 40-45°C and the outlet temperature was maintained at about 30-35°C. The solid was collected from the spray drier and dried at about 30-35°C under vacuum to afford 50 gms of esomeprazole substantially in amorphous form.

Purity by Chiral HPLC: 99.8%, R-isomer: 0.1%.

EXAMPLE 2: PREPARATION OF AMORPHOUS ESOMEPRAZOLE FROM

ESOMEPRAZOLE SODIUM BY SPRAY DRYING

Sodium salt of esomeprazole (5g) was dissolved in water (250ml) at about room temperature. The pH of the mixture was adjusted to about 9-10 with acetic acid. The aqueous layer was further treated with methylene dichloride (100 ml). The organic layer was separated off and evaporated under vacuum at about 30°C to about 40°C to obtain a residue. The residue was dissolved in acetone (50ml) was added and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm² nitrogen pressure. Further the input temperature was maintained at about 40-45°C and the outlet temperature was maintained at about 30-35°C. The solid was collected from the spray drier and dried at about 30-35°C under vacuum to afford Esomeprazole base (3.5 g) in amorphous form.

Purity by Chiral HPLC: 99.8%, R-isomer: 0.05%.

EXAMPLE 3: PREPARATION OF AMORPHOUS ESOMEPRAZOLE FROM

ESOMEPRAZOLE MAGNESIUM BY SPRAY DRYING

Magnesium salt of esomeprazole (5g) was dissolved in water (250ml) at room temperature. The pH of the mixture was adjusted to about 9-10 with acetic acid. The aqueous layer was further treated with methylene dichloride (100 ml). The organic layer was separated off and evaporated under vacuum at about 30°C to about 40°C to obtain a residue. The residue was dissolved in acetone (50ml) and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm nitrogen pressure. Further the input temperature was maintained at about 40-45°C and the outlet temperature was maintained at about 30-35°C. The solid was collected from the spray drier and dried at about 30-35°C under vacuum to afford Esomeprazole base (3.5 g) in amorphous form.

EXAMPLE 4: ALTERNATE PROCESS FOR PREPARATION OF AMORPHOUS

ESOMEPRAZOLE FROM ESOMEPRAZOLE POTASSIUM BY SPRAY DRYING

Potassium salt of esomeprazole (5 gm) was dissolved in water (250ml) at about room temperature and treated with ammonium chloride solution (5 %). The aqueous layer was further treated with methylene dichloride. The organic layer was separated off and evaporated under vacuum at about 30°C to about 40°C. The residue was dissolved in acetone (50ml) and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm² nitrogen pressure. Further the input temperature was maintained at about 40-45°C and the outlet temperature was maintained at about 30-35°C. The solid was collected from the spray drier and dried at about 30-35°C under vacuum to afford Esomeprazole base (3.3 g) in amorphous form.

Purity by Chiral HPLC: 99.8%, R-isomer: 0.05%.

Stability data of amorphous esomeprazole obtained by spray drying process:

Stability condition: 5°C ± 3°C

concordant with

IR spectrum of

amorphous

esomeprazole

working std.

Identification XRPD must be Complies Complies Complies Complies by XRPD concordant with

the XRPD of

amorphous

esomeprazole

working std.

Solubility Soluble in Complies Complies Complies Complies methanol and

acetone

Water by KF NMT 2.5% w/w 1.90 2.10 2.5 2.99

Related Imp. A: NMT 0.02 0.03 0.02 0.02 substances by 0.15% BDL BDL BDL BDL

HPLC Imp. B: NMT BDL BDL BDL BDL

0.15% 0.02 0.02 BDL BDL

Imp. C: NMT BDL BDL BDL BDL

0.15% BDL BDL BDL BDL

Imp. D: NMT BDL BDL BDL BDL

0.15% 0.03 0.04 0.04 0.05

Imp. E: NMT

0.15% 0.1 1 0.20 0.16 0.20

Imp. F: NMT

0.15%

Imp. G: NMT

0.15%

Any other unknown max.

imp : NMT

0.1%

Total imp:

NMT 1.0%

Assay by NLT 98.0% and 98.6 98.4 99.0 98.6

HPLC NMT 102.0%

(on

anhydrous

basis)

StereoNLT 99.0% 100.0 100.0 100.0 100.0 chemical

purity

BDL: Below detection limit ; NMT: Not more than ; NLT: Not less than.

Impurity A: 5-Methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl) methyl] sulfo nyl}-lH- benzimidazole

Impurity B: 5-Methoxy-2-{[(4-nitro-3,5-dimethylpyridin-2-yl) methyl]sulfonyl}-l H- benzimidazole

Impurity C: 5-Methoxy-2-{(S)-[(4-nitro- 3,5-dimethylpyridin-2-yl) methyl]sulfinyl}-l H- benzimidazole

Impurity D: 5-Methoxy-2{(S)-[(4-chloro-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-lH- benzimidazole

Impurity E: 5-Methoxy-2-{[(4-methoxy-3,5-dimethylpyridih-2-yl) methyl]thio}-lH- benzimidazole

Impurity F: 5-Methoxy-2-{[(3,5-dimethyl-4-nitropyridin-2-yl)methyl] thio}-lH- benzimidazole

Impurity G: 5-Methoxy-2-{[(4-chloro-3,5-dimethylpyridin-2-yl) methyl]thio}-lH- benzimidazole

Claims

CLAIMS 1. A process for the preparation of amorphous esomeprazole comprising:

c) removing the solvent from the solution to provide the residue;

d) adding a suitable solvent to the residue to form a solution; and

e) recovering the esomeprazole substantially in amorphous form by spray drying.

2. The process as claimed in claim 1, wherein the solvent is selected from the

group consisting of chloroform, carbon tetrachloride, perchloroethylene,

methylene dichloride and mixtures thereof.

3. The process as claimed in claim 1, wherein the acid is selected from the group

consisting of acetic acid, formic acid, succinic acid, hydrochloric acid,

sulfuric acid and aqueous mixtures thereof.

4. The process as claimed in claim 1 , wherein the suitable solvent is selected from the

group consisting of C₃-Cs aliphatic ketones; Ci-C₆ chlorinated hydrocarbons; Ci-C₆ aliphatic alcohols; C₃-C₆ aliphatic esters; C₂-C₅ aliphatic nitriles; ethers and mixtures thereof.

5. The process as claimed in claim 4, wherein the solvent used is acetone.

6. The amorphous esomeprazole obtained by the process as claimed in claims 1-5

characterized by an X-ray diffractogram, which is substantially in accordance with Fig. 1.

7. The amorphous esomeprazole obtained by the process as claimed in claims 1 -5

characterized by glass transition temperature as determined by differential scanning" calorimetry, which is substantially in accordance with Fig. 2.

8. The amorphous esomeprazole obtained by the process as claimed in claims 1 -5 characterized by thermogravimetric analysis curve, which is substantially in accordance

5 with Fig. 3.

9. Amorphous esomeprazole obtained by the process as claimed in claims 1-5 having a purity at least about 99.9% purity as measured by high performance liquid

chromatography (HPLC).

0

10. Amorphous esomeprazole obtained by the process as claimed in claims 1-5 having less than about 0.1% area of R-isomer as measured by chiral HPLC.

1 1. Amorphous esomeprazole having a specific surface area from about 0.4 m²/g to about

2

5 1.5 m /g as measured by Brunauer-Emmett-Teller (BET) method.

v 0