INTRODUCTION

Aspects of the present application relate to processes for preparing amorphous esomeprazole magnesium.

Esomeprazole magnesium, in its anhydrous form, has a chemical name bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)me thyl]sulfinyl]-1 /-/- benzimidazole-1 -yl) magnesium, and has a structure represented by Formula I.

Formula I

Esomeprazole magnesium is a proton pump inhibitor, developed as an oral treatment for peptic ulcer, gastroesophangeal reflux disease (GERD), duodenal ulcer, and esophagitis.

Esomeprazole magnesium thhydrate is the active ingredient in products sold by AstraZeneca Pharmaceuticals as NEXIUM™, in the form of delayed- release capsules for oral administration. Each delayed release capsule contains 20 mg or 40 mg of esomeprazole (present as 22.3 mg or 44.5 mg of esomeprazole magnesium trihydrate) in enteric-coated pellets.

U.S. Patent No. 6,875,872 discloses esomeprazole magnesium and a process for its preparation. Example 5 therein involves drop-wise addition of 2 ml_ of an aqueous solution containing 46 mg of MgC^H ₂ O, to a solution of 0.165 g of esomeprazole sodium in 3 ml_ of water, and isolation of the compound by centrifugation.

International Application Publication No. WO 2004/020436 A1 discloses a process for preparation of amorphous esomeprazole magnesium involving use of a solvent anti-solvent system.

International Application Publication No. WO 2006/096709 A2 discloses a process for preparation of amorphous esomeprazole magnesium involving an agitated thin film drying (ATFD) technique. The specification for magnesium content in esomeprazole magnesium, in the monographs of United States Pharmacopeia 31, Supplement 1, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2008 ("USP"), and Pharmeuropa (Vol. 18, No. 4), is between 3.30% and 3.55% by weight, calculated on the anhydrous basis. Since the product was mentioned in these monographs as a trihydrate, it appears that these specifications are for the thhydrate form of esomeprazole magnesium, which is crystalline. Therefore, regulatory authorities require that the esomeprazole magnesium active ingredient to be used for making pharmaceutical formulations meet this magnesium content specification, and this requirement is independent of the nature of the final product, i.e., whether it is in a crystalline or in an amorphous form.

There is a need to provide simple, economical, ecologically friendly, and robust processes for the preparation of amorphous esomeprazole magnesium, which meets the specification for magnesium content between 3.30% and 3.55%.

SUMMARY

In embodiments, the present invention provides processes for preparing amorphous esomeprazole magnesium, comprising:

(a) reacting a salt of esomeprazole with a source of magnesium ions, in water, at temperatures less than about 20 ⁰ C;

(b) isolating amorphous esomeprazole magnesium; and

(c) optionally, drying the amorphous esomeprazole magnesium. In embodiments, the present invention provides pharmaceutical formulations comprising amorphous esomeprazole magnesium prepared according a process of the present invention, together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is an illustration of an X-ray powder diffraction ("XRPD") pattern of amorphous esomeprazole magnesium, obtained according to Example 5. DETAILED DESCRIPTION

In embodiments, the present invention provides processes for preparing amorphous esomeprazole magnesium, comprising:

(a) reacting a salt of esomeprazole with a source of magnesium ions, in water, at temperatures about 0 ⁰ C to about 20 ⁰ C;

(b) isolating amorphous esomeprazole magnesium; and

(c) optionally, drying the amorphous esomeprazole magnesium.

A salt of esomeprazole that is used step (a) as the starting material may be obtained by any process, including processes described in the art. The salt of esomeprazole, which is used as the starting material, is water-soluble and may be an alkali metal salt of esomeprazole, including a lithium, sodium, or potassium salt, or an organic amine salt of esomeprazole.

The mixture comprising a salt of esomeprazole and water may be obtained either by adding a salt of esomeprazole to water, or directly from a reaction mixture that is obtained during the course of synthesizing the compound. The amount of water used for the preparation of a mixture comprising a salt of esomeprazole and water may be about 50 ml_, or about 40 ml_, or about 30 ml_, or about 20 ml_, or about 10 ml_, per gram of the salt of esomeprazole. In embodiments, this operation is conducted at any suitable temperatures, such as ambient temperature.

The source of magnesium that may be used in step (a) includes any compound that provides magnesium ions in aqueous media, such as, but not limited to, magnesium halides, including magnesium chloride, magnesium bromide, and magnesium iodide, magnesium sulfate, and the like, including any mixtures thereof. The source of magnesium may be added either in the form of a solid or in the form of a solution comprising a source of magnesium and water or in the form of a mixture comprising a source of magnesium and water in step (a). The amount of water and the temperatures used to prepare the solution of a source of magnesium in water may be readily determined by a person skilled in the art. For example, water that is used for preparing a solution of a source of magnesium may be about 20 ml_, or about 15 ml_, or about 10 ml_, or about 5 ml_, or any other suitable quantity of water, per gram of the source of magnesium. In embodiments, this operation is conducted at any suitable temperatures, such as ambient temperature.

The source of magnesium may be added to the mixture comprising a salt of esomeprazole and water using any suitable method known to a person ordinarily skilled in the art. The mixture comprising a salt of esomeprazole and water may be cooled to temperatures below room temperature, such as less than about 25°C, or less than about 20 ⁰ C, or less than about 15°C or less than about 10 ⁰ C, or less than about 5°C. The mixture will not be allowed to freeze. The source of magnesium may be added to a mixture comprising a salt of esomeprazole and water at temperatures below room temperature, such as less than about 25°C, or less than about 20 ⁰ C, or less than about 15°C or less than about 10 ⁰ C, or less than about 5°C. The source of magnesium may be added in a single lot or in multiple smaller portions, depending on the batch size of the reaction, and this may be readily determined by a person skilled in the art. After the addition of a source of magnesium, the mixture may be allowed to stand, or be stirred, for a sufficient time to complete the conversion of a salt of esomeprazole into amorphous esomeprazole magnesium, at temperatures less than about 25°C, or less than about 20 ⁰ C, or less than about 15°C or less than about 10 ⁰ C, or between about 0°C and about 5°C. The time period for said standing or stirring may range from about 30 minutes to several hours, such as about 24 hours, or longer, or any other suitable time period as long as the product does not degrade.

Optionally, a salt of esomeprazole may be added to a mixture comprising a source of magnesium and water, using any suitable method known in the art. The salt of esomeprazole may be added either in the form of a solid or as a solution comprising a salt of esomerpazole and water, or as a mixture comprising a salt of esomeprazole and water. A source of magnesium and water may be cooled to temperatures below room temperature, such as less than about 25°C, or less than about 20 ⁰ C, or less than about 15°C, or less than about 10 ⁰ C, or less than about 5°C. The mixture comprising a salt of esomeprazole and water may be added to a source of magnesium and water at temperatures below room temperature, such as less than about 25°C, or less than about 20 ⁰ C, or less than about 15°C, or less than about 10°C, or less than about 5°C. The mixture comprising a salt of esomeprazole and water may be added in a single lot or in multiple smaller portions, depending on the batch size of the reaction, and this may be readily determined by a person skilled in the art.

After the combination with a mixture comprising the salt of esomeprazole and water, the resultant reaction mixture may be allowed to stand, or be stirred, for a sufficient time to complete the conversion of a salt of esomeprazole into amorphous esomeprazole magnesium, at temperatures less than about 25°C, or less than about 20 ⁰ C, or less than about 15°C, or less than about 10 ⁰ C, or less than about 5°C. The time periods for standing or stirring may range from about 30 minutes to several hours, such as about 24 hours, or longer, or any other suitable time periods as long as the product does not degrade.

The amorphous product that is obtained in step (a) may be isolated in step (b), using conventional techniques known in the art. Such techniques include, but are not limited to, decantation, centrifugation, filtration, or any other suitable techniques.

The amorphous product may be optionally dried. Drying may be suitably carried out using any of a tray dryer, oven, rotary evaporator, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, rotary dryer, and the like. In embodiments, the drying may be carried out at temperatures about 60 ⁰ C or less, or less than about 50°C, or less than about 40 ⁰ C, or less than about 30°C, or less than about 20°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure. The drying may be carried out for any time periods to obtain a desired purity, such as from about 15 minutes to several hours, such as about 24 hours or more, or any other suitable time periods. In embodiments, drying is conducted in a reduced oxygen atmosphere, such as under nitrogen or another inert gas.

The amorphous esomeprazole magnesium obtained in the process of the present invention may have a moisture content less than about 12%, or less than about 10%, or less than about 9%, or less than about 8%, or less than about 7%, by weight, such as can be determined using the Karl Fischer ("KF") method.

The resulting amorphous esomeprazole magnesium may be characterized by an X-ray powder diffraction pattern having an absence of peaks, substantially as illustrated by Fig.1. XRPD patterns reported herein are obtained using copper Ka radiation, and have been generated using a Bruker AXS D8 Advance powder X-ray diffractometer. Magnesium content can be determined using the USP method.

In embodiments, the present application provides pharmaceutical formulations comprising amorphous esomeprazole magnesium obtained by a process of the present invention, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical formulations comprising amorphous esomeprazole magnesium together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release formulations may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release formulations may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combinations of matrix and reservoir systems. The formulations may be prepared using techniques such as direct blending, dry granulation, wet granulation, and by extrusion and spheronization. Formulations may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, thcalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

Certain specific aspects and embodiments of the present application are explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLE 1 Esomeprazole sodium (15 g) and water (300 ml_) were charged into a round bottom flask at 26°C and stirred for 20 minutes. The resulting solution was cooled to 3°C over 30 minutes. A solution of MgSO ₄ ^» 7H ₂ O (4.43 g) in water (75 ml_) was slowly added over 10 minutes to the above solution at 3°C. The mixture was stirred for 20/4 hours at 3°C. The formed solid was filtered, washed with water (30 ml_), and dried under reduced pressure at 50 ⁰ C for 4 ¹ /4 hours, to obtain amorphous esomeprazole magnesium. Yield: 8.4 g.

Magnesium content: 3.514% by weight (anhydrous basis). Water content by KF: 7.16% by weight. No peaks indicating crystallinity were observed in the PXRD pattern.

EXAMPLE 2

Esomeprazole sodium (-10 g) and water (230 mL) were charged into a round bottom flask at 25°C and stirred for 10 minutes. The resulting solution was stirred and cooled to 5°C over 10 minutes. A solution of MgSO ₄ ^» 7H ₂ O (2.95 g) in water (20 mL) was added to the above solution over 5 minutes at 5°C. The mixture was stirred for 2Vz hours at 7°C. The formed solid was filtered, washed with water (20 ml_), and dried at 50°C for AVi hours, to obtain amorphous esomeprazole magnesium.

Yield: 5.94 g.

Magnesium content: 3.498% by weight (anhydrous basis). Water content by KF: 9.94% by weight.

No peaks indicating crystallinity were observed in the PXRD pattern.

EXAMPLE 3

Esomeprazole sodium (-10 g) and water (230 ml_) were charged into a round bottom flask at 25°C and stirred for 10 minutes. The resulting solution was stirred and cooled to 10 ⁰ C over 10 minutes. A solution of MgSO ₄ ^» 7H ₂ O (2.95 g) in water (20 ml_) was added to the above solution over 5 minutes at 10 ⁰ C. The mixture was stirred for 2 ^Λ A hours at 12°C. The formed solid was filtered, washed with water (20 ml_), and dried at 50°C for 3 hours, to obtain amorphous esomeprazole magnesium. Yield: 6.3 g.

Magnesium content: 3.475% by weight (anhydrous basis). Water content by KF: 9.36% by weight. No peaks indicating crystallinity were observed in the PXRD pattern.

EXAMPLE 4

Esomeprazole sodium (1 Kg) and water (17 L) were charged into a round bottom flask at 25-35°C and stirred for 30 minutes. The resulting solution was stirred and cooled to 5±2°C over 10 minutes. A solution of MgSO ₄ ^» 7H ₂ O (0.295 Kg) in water (3 L) was added slowly to the above solution over 35 minutes at 5±2°C. The mixture was stirred for 2 hours at 5±2°C. The formed solid was filtered, washed with water (5 L), and dried at 37.5±2.5°C for 15 hours, to obtain amorphous esomeprazole magnesium.

Yield: 0.56 Kg. Magnesium content: 3.34% by weight (anhydrous basis).

Water content by KF: 8.05% by weight. No peaks indicating crystallinity were observed in the PXRD pattern. EXAMPLE 5

Esomeprazole sodium (1.93 Kg) and water (33 L) were charged into a round bottom flask at room temperature and stirred for 30 minutes. The resulting solution was stirred and cooled to 5±2°C in 10 minutes. A solution of MgSO ₄ TH ₂ O (0.574 Kg) in water (6 L) was added to the above solution at 5±2°C. The mixture was stirred for 90 minutes at 5±2°C. The formed solid was filtered, washed with water (10 L), and spin dried under a nitrogen atmosphere for 3 hours. The solid was dried at 32.5±2.5°C for 23 hours, to obtain amorphous esomeprazole magnesium. Yield: 1.07 Kg.

Magnesium content: 3.43% by weight (anhydrous basis). Water content by KF: 8.77% by weight.

No peaks indicating crystallinity were observed in the PXRD pattern, shown as Fig. 1.

EXAMPLE 6

Esomeprazole sodium (-12 g) and water (375 mL) were charged into a round bottom flask at 28°C and stirred for 10 minutes. The resulting solution was stirred and cooled to 20 ⁰ C. A solution of MgSO ₄ ^» 7H ₂ O (4.83 g) in water (75 mL) was added to the above solution over 15 minutes at 18°C. The mixture was stirred for 2 hours 45 minutes at 17-19°C. The formed solid was filtered, washed with water (125 mL), and dried at 45°C for 43 hours, to obtain amorphous esomeprazole magnesium.

Yield: 10.7 g. Magnesium content: 3.46% by weight (anhydrous basis).

Water content by KF: 9.41 % by weight. No peaks indicating crystallinity were observed in the PXRD pattern.

EXAMPLE 7 Esomeprazole sodium (-12 g) and water (375 mL) were charged into a round bottom flask at 28°C and stirred for 5 minutes. The resulting solution was stirred and cooled to 21 ⁰ C. A solution of MgSO ₄ ^» 7H ₂ O (4.83 g) in water (75 mL) was added to the above solution over 15 minutes at 21 ⁰ C. The mixture was stirred for 2 ¹ /4 hours at 21 -23°C. The formed solid was filtered, washed with water (125 ml_), and dried at 45°C for 44 hours, to obtain amorphous esomeprazole magnesium.

Yield: 10.7 g. Magnesium content: 3.47% by weight (anhydrous basis).

Water content by KF: 9.31 % by weight.

No peaks indicating crystallinity were observed in the PXRD pattern.

EXAMPLE 8 MgSO ₄ ^» 7H ₂ O (4.83 g) and water (75 ml_) were charged into a round bottom flask at 28°C and stirred for 10 minutes. The resulting solution was stirred and cooled to 3°C. A solution of esomeprazole sodium (-12 g) in water (375 ml_) was added to the above solution over 10 minutes at 3°C. The mixture was stirred for 2 ¹ /2 hours at 2°C. The formed solid was filtered, washed with water (125 ml_), and dried at 45°C for 12 hours, to obtain amorphous esomeprazole magnesium. Yield: 11.1 g.

Magnesium content: 3.49% by weight (anhydrous basis). Water content by KF: 9.50% by weight. No peaks indicating crystallinity were observed in the PXRD pattern.

EXAMPLE 9

MgSO ₄ ^» 7H ₂ O (4.83 g) and water (450 mL) were charged into a round bottom flask at 28°C and stirred for 10 minutes. The resulting solution was stirred and cooled to 3°C. Esomeprazole sodium (-12 g) was added to the above solution at 2°C. The mixture was stirred for 2 hours 15 minutes at 2°C. The formed solid was filtered, washed with water (125 mL), and dried at 45°C for 3 hours, to obtain amorphous esomeprazole magnesium. Yield: 11.2 g.

Magnesium content: 3.45% by weight (anhydrous basis). Water content by KF: 9.68% by weight.

No peaks indicating crystallinity are observed in the PXRD pattern. EXAMPLE 10

Esomeprazole sodium (-12 g) and water (450 ml_) were charged into a round bottom flask at 28°C and stirred for 25 minutes. The resulting solution was stirred and cooled to 3°C. MgSO ₄ ^» 7H ₂ O (4.83 g) was added to the above solution at 3°C. The mixture was stirred for 3 hours, 15 minutes at 2°C. The formed solid was filtered, washed with water (125 ml_), and dried at 45°C for 18 hours, to obtain amorphous esomeprazole magnesium. Yield: 1 1 .1 g.

Magnesium content: 3.46% by weight (anhydrous basis). Water content by KF: 9.63% by weight.

No peaks indicating crystallinity were observed in the PXRD pattern.

COMPARATIVE EXAMPLE

Esomeprazole sodium (~8 g) and water (200 mL) were charged into a round bottom flask at 28°C and stirred for 20 minutes. A solution of MgSO ₄ ^» 7H ₂ O (4.3 g) in water (20 mL) was added to the above solution over 5 minutes at 28°C. The mixture was stirred for 2 hours 10 minutes at 28°C. The formed solid was filtered, washed with water (40 mL), and dried at 50 ⁰ C for 3 hours.

Yield: 5.6 g. Magnesium content: 3.39% by weight (anhydrous basis).

Water content by KF: 7.70% by weight.

Crystalline peaks are observed at 5.1 , 12.6, 13.1 , 22.3, and 25.1 , ± 0.2° 2Θ in the PXRD pattern.