The following specification describes the nature of the invention and manner in which it is performed

PREPARATION OF ESOMEPRAZOLE MAGNESIUM AND HYDRATES THEREOF

TECHNICAL FIELD
The present application relates to processes for the preparation of crystalline esomeprazole magnesium hydrates.

BACKGROUND
Esomeprazole magnesium is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl)magnesium trihydrate, and has the structure of Formula (I).
(I)
Esomeprazole magnesium and its hydrates are useful in inhibiting gastric acid secretion.
U.S. Patent No. 6,262,085 discloses a process for the preparation of the magnesium salt of S-omeprazole using magnesium metal, methanol, and a catalytic amount of methylene dichloride.
U.S. Patent No. 6,369,085 discloses a form of the magnesium salt of the S-enantiomer of omeprazole trihydrate. This patent also discloses processes for preparing that form of the S-omeprazole magnesium salt.
U.S. Patent No. 6,747,155 discloses a process for the preparation of the magnesium salt of esomeprazole trihydrate. The ‘155 patent also discloses a process for the preparation of esomeprazole magnesium dihydrate Form A and Form B.
U.S. 6,894,066 discloses a process for producing the magnesium salt of S-omeprazole with varying percents of crystallinity and varying amounts of residual solvents in the solid.
U.S. Patent Application Publication No. 2007/0259921 discloses processes for the preparation of different crystalline forms of esomeprazole sodium and a crystalline form of esomeprazole magnesium.
There still exists a need of a commercially viable processes for making crystalline esomeprazole magnesium hydrates, more particularly the dihydrate and trihydrate forms.

SUMMARY
The present invention includes processes for the preparation of crystalline esomeprazole magnesium trihydrate, which processes comprise at least one of the steps of:
(a) providing a solution comprising esomeprazole and a solvent comprising at least about 80% water;
(b) adding a magnesium salt to the solution to precipitate esomeprazole magnesium;
(c) isolating the precipitated esomeprazole magnesium; and
(d) drying the isolated, precipitated esomeprazole magnesium.

The present invention includes processes for the preparation of esomeprazole magnesium dehydrate and, in particular, Form B thereof, which processes comprise at least one of the steps of:
(a) providing a solution comprising esomeprazole magnesium trihydrate and an alcoholic solvent;
(b) adding an anti-solvent to the solution to precipitate esomeprazole magnesium dihydrate;
(c) isolating the precipitated esomeprazole magnesium dihydrate; and
(d) drying the isolated, precipitated esomeprazole magnesium dihydrate.

The present invention includes esomeprazole magnesium dihydrate Form B having a degree of crystallinity of about 70% or less, or in the range of from about 20% to about 70%, or in the range of from about 45% to about 70%.

The present invention includes micronized esomeprazole magnesium dihydrate Form B with a particle size distribution D90 equal to or less than about 10 µm, 7.5 µm, or 5.0 µm. The micronized esomeprazole magnesium dihydrate Form B may be produced in an air-jet miller.
The present invention includes a process for analysing the particle size of esomeprazole magnesium dihydrate Form B.

The present invention includes pharmaceutical compositions comprising esomeprazole magnesium dihydrate Form B and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline esomeprazole magnesium trihydrate.
Fig. 2 is an X-ray powder diffraction (XRPD) pattern of crystalline esomeprazole magnesium dihydrate Form B.

DETAILED DESCRIPTION OF THE INVENTION
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. The terms "about," "generally," "substantially," and the like, are to be construed as modifying another term or value such that it is not an absolute, but does not read on the prior art, as defined by the circumstances and context as understood by those of skill in the art. This includes, at least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. Whether so indicated or not, all values recited herein are approximate.
This document may refer to a material, such as in this instance, esomeprazole and its salts, crystalline forms, solvates, or optical isomers by reference to patterns, spectra, or other graphical data "substantially" as shown in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, and/or values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X ray diffraction arts, such shifts in peak positions or the relative intensities of one or more peaks can occur because of, without limitation: the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like. However, those of ordinary skill in the art should be able to compare the figures herein with a pattern generated of an unknown form of, in this case, esomeprazole, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques that may be reported herein.
Crystalline forms may be characterized by such analytical methods as X-ray powder diffraction (“XRPD”) pattern, differential scanning calorimetry (“DSC”) curves, and thermogravimetric analysis (“TGA”) curves. The XRPD data reported in this application were obtained a Bruker AXS D8 Advance Powder X-ray Diffractometer with Cu-Ka radiation having a wavelength of about 1.5418 Å.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure that uniquely define that crystalline form, salt, solvate, and/or optical isomer, within any associated and recited margin of error, for purposes of identification.

The present invention includes processes for the preparation of crystalline esomeprazole magnesium trihydrate, which processes comprise at least one of the steps of:
(a) providing a solution comprising esomeprazole and a solvent comprising at least about 80% water;
(b) adding a magnesium salt to the solution to precipitate esomeprazole magnesium;
(c) isolating the precipitated esomeprazole magnesium; and
(d) drying the isolated, precipitated esomeprazole magnesium.
Each step is contemplated separately, as well as in the context of multi-step sequences.

Step (a) involves providing a solution comprising esomeprazole and a solvent comprising at least about 80% water. For example, the solvent system may comprise 100% water.
The solution may be prepared at a temperature ranging from about 15°C to about 45°C.

Step (b) involves adding a magnesium salt to the solution to precipitate esomeprazole magnesium.
The addition of the magnesium salt leads to precipitation of esomeprazole magnesium that is less soluble in water than esomeprazole sodium.
Suitable magnesium salts include and are not limited to magnesium sulphate.
The magnesium salt may be added as solid crystals or a solution in a solvent such as, for example, water, methanol, and the like. The mode of addition may be by dumping, slow addition, lot wise addition, or fast addition. The temperature for addition and reaction may range from between 15°C to 45°C.
After addition of the magnesium salt is completed, the mass may be maintained at a temperature from about 15°C to about 45°C for a time period from about 30 minutes to about 5 hours, preferably with concurrent stirring, to facilitate complete precipitation of esomeprazole magnesium.

Step (c) involves isolating the precipitated esomeprazole magnesium.
Once the precipitation is completed, the precipitated solid may be collected by various methods, such as, for example, gravity filtration suction, centrifugation, and the like. The crystals so isolated may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals may be washed on the filter with a solvent to wash out the mother liquor.

Step (d) involves drying the isolated, precipitated esomeprazole magnesium.
The wet cake obtained in Step (c) may be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, and the like. Drying may be carried out at a temperature from about 25°C to about 60°C under atmospheric pressure or reduced pressure, e.g., about 200 mmHg to about 300 mmHg. Drying may be carried out for any desired time ranging from about 30 minutes to about 30 hours until the required product quality is achieved.

The present invention includes processes for the preparation of Form B of esomeprazole magnesium dihydrate, which processes comprise at least one of the steps of:
(a) providing a solution comprising esomeprazole magnesium trihydrate and an alcoholic solvent;
(b) adding an anti-solvent to the solution to precipitate esomeprazole magnesium dihydrate;
(c) isolating the precipitated esomeprazole magnesium dihydrate; and
(d) drying the isolated, precipitated esomeprazole magnesium dihydrate.
Each step is contemplated separately, as well as in the context of multi-step sequences.

Step (a) involves providing a solution comprising esomeprazole magnesium trihydrate and an alcoholic solvent.
The esomeprazole magnesium trihydrate may be prepared according to the processes of the present invention described hereinabove.
A solution of esomeprazole magnesium trihydrate may be prepared by dissolution thereof in any alcoholic solvent, such as, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol, and tertiary-butyl alcohol; or mixtures thereof. For example, the solution may comprise esomeprazole magnesium trihydrate and methanol.
A suitable temperature for dissolution of esomeprazole magnesium trihydrate may range from about 15°C to about 45°C. Stirring may be carried out for a desired time periods ranging from 30 minutes to about 5 hours to achieve complete dissolution.

Step (b) involves adding an anti-solvent to the solution to precipitate esomeprazole magnesium dihydrate.
The anti-solvent may be any suitable organic solvent. Suitable anti-solvents include and are not limited to: ketones, such as, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, and tert-butyl ketone; esters, such as, for example, ethyl acetate and propylacetate; or mixtures thereof. For example, the anti-solvent may be acetone or ethylacetate.
The present inventors have discovered that only fast addition, i.e., charging of anti-solvent to the reaction mass, resulted in Form B of esomeprazole magnesium dihydrate with a degree of crystallinity of less than about 70%, or in the range of from about 20% to about 70%, or in the range of from about 45% to about 70%. Fast addition means charging the anti-solvent to the reaction mass over a period of time that is less than about 30 minutes, or less than about 20 minutes, or less than about 15 minutes.
Form B of esomeprazole magnesium dihydrate may be obtained by removing the solvent of Step (a) and adding an anti-solvent. The removal of the solvent may be accomplished by techniques, such as distillation either under vacuum or without vacuum.
A suitable temperature for evaporation of the solvent may be from about 20°C to about 65°C. A suitable time for evaporation of the solvent may be any desired time periods for about 30 minutes to about 10 hours or longer to achieve the desired product yield and purity.

Step (c) involves isolating the precipitated esomeprazole magnesium dihydrate.
The method by which the solid material is isolated from the final mixture, with or without cooling below the operating temperature, may be any of techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals may be washed on the filter with a solvent to wash out the mother liquor.

Step (d) involves drying the isolated, precipitated esomeprazole magnesium dihydrate.
The wet cake obtained in step (d) may be dried. Drying may be suitably carried out in an air tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash dryer and the like. Drying may be carried out at temperatures of from about 25°C to about 60°C under the reduced pressure of 200 mmHg to 300 mmHg. Drying may be carried out for any desired time until the required product purity is achieved, time periods from about 1 to about 30 hours. Preferably in an air tray drier at about 50°C for about 10 hours.

In a further embodiment, there is provided a process for the conversion of amorphous esomeprazole magnesium to crystalline esomeprazole magnesium dihydrate which process includes the steps of; (a) stirring amorphous esomeprazole magnesium in acetone for an optimum time; (b) collecting the solid; (c) drying the solid; (d) stirring the dried solid in mixture of methanol and ethyl acetate; (e) collecting the solid and; (f) drying the solid.

An embodiment of the present application provides esomeprazole magnesium dihydrate Form B with particle size distribution D90 equal to or less than about 10 µm, 7.5 µm, or 5.0 µm.

An embodiment of the present application provides a method for particle size analysis of esomeprazole magnesium dihydrate Form B for which method conditions are tabulated below:
Conditions:
instrument Malvern MASTERSIZER® 2000
accessory Hydro 2000S (A)
analysis mode general purpose
sensitivity enhanced
size range 0.02 to 2000 µm
dispersant 1% sorbitan trioleate in light liquid paraffin
particle ri 1.5
dispersant ri 1.168
absorption 0.8
stir speed 2500 RPM
obscuration 10 to 20%
manual shaking 30 sec
cyclo mixture one minute
sonication 30 sec
sample concentration 100 mg/20 mL of dispersant
measurement and background time 12 seconds

Along with the active compound, a pharmaceutical composition may include one or more excipients that may, for example, enhance the stability, bioavailability, and the ease of use of the pharmaceutical composition. The excipients may be solid, semisolid, or liquid and may be formulated with the compound in bulk form.
Esomeprazole magnesium of the present invention may be used in pharmaceutical compositions that may be contemplated in various formulations suitable for various modes of administration, including and not limited to inhalation, oral, rectal, parental, and intravenous.

The process of the present invention is cost effective, eco-friendly, and commercially suitable, to get a stable crystalline form of esomeprazole magnesium which is free flowing and directly compressible into stable pharmaceutical formulations.

The following examples further describe certain features and embodiments of the invention in greater detail, and are not intended to limit any aspect of the invention.

EXAMPLES

EXAMPLE 1
To a solution of methanol (175 ml) and sodium hydroxide (8.7 g) in a four-neck round-bottom flask, esomeprazole (50 g) (dissolved in methanol (175 ml)) is added and the contents are stirred for about 2 hours at about 25°C to 35°C. The reaction mass is then subjected to distillation at about 70°C. The residue is cooled to 25°C to 35°C. Ethyl acetate (250 ml) is added and the solution is subjected to distillation at about 25°C to 35°C under vaccum. The process of charging ethyl acetate and distilling is repeated twice using 250 ml of ethyl acetate to meet the specification that methanol content in the reaction mass must be less than 5%. To the resulting residue, which is substantially free of methanol, ethyl acetate (250 ml) is charged and stirred for about one hour at about 25°C to 30°C. The separated solid is filtered and washed with ethyl acetate (100 ml). The above wet compound is charged in a round bottom flask containing ethyl acetate (250 ml) and stirred for about one hour at 25°C to 35°C. The compound is filtered, washed with ethyl acetate (100 ml), and suction dried to afford esomeprazole sodium.

EXAMPLE 2
To a solution of methanol (98.5 L) and sodium hydroxide (4.87 kg) in a four-neck round-bottom flask, esomeprazole (28 kg) (dissolved in methanol (98.5 L)) is added and the contents are stirred for about 2 hours at about 25°C to 35°C. The reaction mass is then subjected to distillation at about 50°C. The residue is cooled to 25°C to 35°C. Ethyl acetate (140 L) is added and the solution is subjected to distillation at about 25oC to 35oC under vacuum. The process of charging ethyl acetate and distilling is repeated twice using 2×140 L of ethyl acetate to meet the specification that methanol content in the reaction mass must be less than 5%. To the resulting residue, which is substantially free of methanol, ethyl acetate (140 L) is charged and stirred for about one hour at about 25°C to 30°C. The separated solid is filtered and washed with ethyl acetate (56 L). The above wet compound is charged in a round bottom flask containing ethyl acetate (168 L) and stirred for about one hour at 25°C to 35°C. The compound is filtered, washed with ethyl acetate (112 L), and dried under vacuum to afford esomeprazole sodium.

EXAMPLE 3
Demineralized water (300 ml) and esomeprazole sodium (50 g) are charged into a round-bottom flask and the contents are stirred for a clear solution. To this solution, magnesium sulphate (26.9 g) (dissolved in demineralised water (200 ml)) is added at about 25°C to 35°C. Solid separation may be observed during addition. The reaction mass is stirred for about 2 hours at 25°C to 30°C. The solid is filtered and washed with demineralized water (300 ml). The wet cake obtained is dried at about 50°C under vacuum for about 20 hours to afford 45 g of esomeprazole magnesium trihydrate.
EXAMPLE 4
Methanol (10 ml) and esomeprazole magnesium trihydrate (10 g) are charged into a round-bottom flask and stirred for complete dissolution. Acetone (50 ml) is added to the reaction mass and stirred for about 2 hours. The separated solid is filtered and washed with acetone (20 ml). The wet cake is dried in a rotary evaporator at about 55°C under vacuum for about 8 hours to afford 8 g of esomeprazole magnesium dihydrate form B.

EXAMPLE 5
Methanol (10 ml), acetone (90 ml), and esomeprazole magnesium trihydrate (10 g) are charged into a round bottom flask and stirred for about 2 hours. The separated solid is filtered and washed with acetone (20ml). The wet cake is dried in a rotary evaporator at about 50°C under vaccum for about 8 hours to afford 8 g of esomeprazole magnesium dihydrate Form B.

EXAMPLE 6
Methanol (100 ml) and esomeprazole magnesium trihydrate (10 g) are charged into a round bottom flask and stirred for complete dissolution. About 90% of the solvent is distilled under vaccum at about 60°C. Ethyl acetate (90 ml) is added to the residue and stirred for about 2 hours. The separated solid is filtered and washed with acetone (20 ml). The wet cake is dried in a rotary evaporator at about 55°C under vacuum for about 8 hours to afford 8 g of esomeprazole magnesium dihydrate form B.

EXAMPLE 7
Methanol (10 ml), ethyl acetate (90 ml), and esomeprazole magnesium trihydrate (10gm) are charged in a round-bottom flask and stirred for about 2 hours. The separated solid is filtered and washed with acetone (20ml). The wet cake is dried in a rotary evaporator at about 50°C under vacuum for about 8 hours to afford 8 g of esomeprazole magnesium dihydrate form B.

EXAMPLE 8
Amorphous esomeprazole magnesium (10 g) and acetone (100 ml) are charged into a round-bottom flask and stirred for about 2 hours at about 25°C to about 35°C. The solid is filtered, washed with acetone (200 ml), and dried for about 5 hours at about 50°C. The dried solid is charged in a round-bottom flask containing methanol (10 ml) and ethyl acetate (90 ml) and stirred for about 2 hours. The separated solid is filtered and washed with ethyl acetate (20 ml). The wet cake is dried in a rotary evaporator at about 50°C under vacuum for about 8 hours to afford 7 g of esomeprazole magnesium dihydrate form B.

EXAMPLE 9
An injecting pressure of 3.3 kg/cm2 and N2 milling pressure of 3.5 kg/cm2 are set in an air jet miller and esomeprazole magnesium dihydrate Form B (5.0 g) is charged and micronised for about 20 minutes. The compound is unloaded and packed to afford esomeprazole magnesium dihydrate Form B with a particle size distribution D90 of about 8.1 µm. Approx. yield: 3.4 g

EXAMPLE 10
An injecting pressure of 2.9 kg/cm2 and N2 milling pressure of 3.0 kg/cm2 are set in an air jet miller and esomeprazole magnesium dihydrate Form B (10.0 g) with D90: 7.7 µm is charged and micronised for about 20 minutes. The compound is unloaded and packed to afford esomeprazole magnesium dihydrate Form B with mean particle size D90 of about 3.7 µm. Approx. yield: 8.5 g.

WHAT IS CLAIMED IS:

1. A process for preparing esomeprazole magnesium dihydrate, comprising the steps of:
(a) providing a solution comprising esomeprazole magnesium trihydrate and an alcoholic solvent; and
(b) adding an anti-solvent to the solution to precipitate esomeprazole magnesium dihydrate.

2. The process of claim 1, further comprising the steps of
(c) isolating the precipitated esomeprazole magnesium dihydrate; and
(d) optionally drying the isolated, precipitated esomeprazole magnesium dihydrate.

3. The process according to claim 1 or 2, wherein the alcoholic solvent comprises methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, or mixtures thereof.

4. The process according to any of claims 1–3, wherein the solvent comprises methanol.

5. The process according to any of claims 1–4, wherein the anti-solvent comprises acetone, ethyl methyl ketone, methyl isobutyl ketone, tert-butyl ketone, ethyl acetate, propyl acetate, or mixtures thereof.

6. The process according to any of claims 1–4, wherein the anti-solvent comprises acetone or ethyl acetate.

7. The process according to any of claims 1–4, wherein the esomeprazole magnesium trihydrate is produced by a process comprising the steps of:
(a) providing a solution comprising esomeprazole and a solvent comprising at least about 80% water;
(b) adding a magnesium salt to the solution to precipitate esomeprazole magnesium trihydrate.

8. The process of claim 7, further comprising the steps of:
(c) isolating the precipitated esomeprazole magnesium trihydrate; and
(d) optionally drying the isolated, precipitated esomeprazole magnesium trihydrate.

9. The process of claims 7 or 8, wherein the magnesium salt comprises magnesium sulphate.

10. The process according to any of claims 7–9, wherein the solvent is about 100% water.

11. Esomeprazole magnesium dihydrate Form B having a degree of crystallinity of about 70% or less.

12. Esomeprazole magnesium dihydrate Form B according to claim 11 having a degree of crystallinity of about 25% to about 70%.

13. Esomeprazole magnesium dihydrate Form B according to claim 11 having a degree of crystallinity of about 40% to about 70%.

14. Solid esomeprazole magnesium dihydrate Form B having a particle size D90 equal to or less than about 10 µm.

15. Solid esomeprazole magnesium dihydrate Form B according to claim 14 having a particle size distribution D90 equal to or less than about 7.5 µm.

16. Solid esomeprazole magnesium dihydrate Form B according to claim 14 having a particle size D90 equal to or less than about 5 µm.