WO2007031845A2

WO2007031845A2 - Polymorphic forms of (s)-omeprazole magnesium salts and processes for their preparation

Info

Publication number: WO2007031845A2
Application number: PCT/IB2006/002520
Authority: WO
Inventors: Bobba Venkata Siva Kumar; Pravin Bhalchandra Kulkarni; Changdev Namdev Raut; Anil Ganpat Suryawanshi; Nitin Sharad Chandra Pradhan
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2005-09-14
Filing date: 2006-09-13
Publication date: 2007-03-22
Anticipated expiration: 2008-03-14
Also published as: WO2007031845A3

Abstract

Novel polymorphs of a magnesium salt of (S)-omeprazole trihydrate and processes for their preparation are disclosed. Also disclosed is a process for the preparation of an amorphous form of a magnesium salt of (S)-omeprazole. Pharmaceutical compositions containing the magnesium salts are also disclosed.

Description

POLYMORPHIC FORMS OF (S)-OMEPRAZOLE MAGNESIUM SALTS AND PROCESSES FOR THEIR PREPARATION

PRIORITY

[0001] This application claims the benefit under 35 U.S.C. §119 to U.S.

Provisional Application No. 60/753,931, filed on December 23, 2005, and entitled "POLYMORPHIC FORMS (S)-OMEPRAZOLE MAGNESIUM SALTS AND PROCESSES FOR THEIR PREPARATION", and to Indian Provisional Application No. l l lO/MUM/2005, filed on September 14, 2005, and entitled "POLYMORPHIC FORMS OF (S)-OMEPRAZOLE MAGNESIUM SALTS AND PROCESS FOR THE PREPARATION THEREOF", the contents of each, of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

[0002] The present invention generally relates to novel polymorphs of a magnesium salt of hydrated (S) omeprazole and processes for their preparation. The present invention also generally relates to a process for the preparation of an amorphous form of a magnesium salt of (S) omeprazole.

2. Description of the Related Art

[0003] Omeprazole, also known as 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]-sulfinyl]-lH-benzimidazole, is a well known compound used for treating diseases related to increased secretion of gastric acid because of an H⁺ZK⁺ ATPase inhibitory action. See, for example, U.S. Patent Nos. 4,255,431 and 4,738,974 and European Patent Nos. 5129 and 124 495. The compound, being a sulfoxide, has an asymmetric center in the sulfur atom and may exist as a racemic mixture (a mixture of (R)-omeprazole and (S)-omeprazole). The optical isomers of omeprazole, particularly the (S) isomer, are believed to possess certain advantages over the racemic form. [0004] The enantiomer (S)-omeprazole is commonly referred to as esomeprazole

(also known as (5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl]- lH-benzimidazole-1-yl) and is represented by the structure of formula I.

Esomeprazole is marketed in the United States as the magnesium trihydrate salt under the name Nexium^® and is indicated for short-term treatment in the healing and symptomatic resolution of diagnostically confirmed erosive esophagitis. See, e.g., The Merck Index, Thirteenth Edition, 2001, pp. 1224-25, monograph 6913; and Physician's Desk Reference, "Nexium," 60th Edition, pp. 645-649 (2005).

[0005] WO 94/27988 discloses optically pure salts of single enantiomers of omeprazole. U.S. Patent No. 6,162,816 ("the '816 patent") discloses crystalline forms A and B of S-omeprazole in a neutral form. The '816 patent further discloses that the neutral form of S-omeprazole is not in the form of a salt.

[0006] Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, 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. [0007] A number of drugs have been found to exhibit desirable dissolution characteristics and, in some cases, desirable bioavailability patterns when used in a specific solid form, e.g., as an amorphous or crystalline solid. Therefore, there is a continuing need for new solid forms of esomeprazole and processes for their preparation.

SUMMARY OF THE INVENTION

[0008] In accordance with one embodiment of the present invention, a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is provided.

[0009] In accordance with a second embodiment of the present invention, a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is provided having an X-ray diffraction (XRD) pattern substantially in accordance with

Figure 1.

[0010] In accordance with a third embodiment of the present invention, a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is provided exhibiting characteristic peaks (expressed in degrees 2Θ ± 0.2°θ) at one or more of the positions: about 13.0671 and about 22.2772.

[0011] In accordance with a fourth embodiment of the present invention, a process for the preparation of a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is provided, the process comprising:

(a) treating a solution comprising a potassium or sodium salt of (S)-omeprazole in water with a source of magnesium at temperature ranging from about -10 to about 20⁰C; to provide a magnesium salt of (S)-omeprazole; and

(b) recovering the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I.

[0012] In accordance with a fifth embodiment of the present invention, a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is provided.

[0013] In accordance with a sixth embodiment of the present invention, a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is provided having an XRD pattern substantially in accordance with Figure 2.

[0014] In accordance with a seventh embodiment of the present invention, a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is provided exhibiting characteristic peaks (expressed in degrees 2Θ ± 0.2°θ) at approximately one or more of the positions: about 5.6814, about 17.0203 and about

18.0370.

[0015] In accordance with an eight embodiment of the present invention, a process for the preparation of a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is provided, the process comprising:

(a) treating a solution comprising a sodium salt of (S)-omeprazole in a first organic solvent with a source of magnesium to convert the sodium salt of (S)-omeprazole to a magnesium salt of (S)-omeprazole;

(b) treating the solution containing the magnesium salt of (S)-omeprazole with a second organic solvent; and

(c) recovering the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2.

[0016] In accordance with a ninth embodiment of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of one or more of the foregoing magnesium salts of (S)-omeprazole trihydrate substantially in polymorph forms G-I and/or G-2.

[0017] In accordance with a tenth embodiment of the present invention, a process for the preparation of a magnesium salt of (S)-omeprazole substantially in a solid amorphous form is provided, the process comprising:

(a) treating a solution comprising a potassium or sodium salt of (S)-omeprazole in one or more polar aprotic solvents with a magnesium source at a suitable temperature and for a suitable time to convert the potassium or sodium salt of (S)-omeprazole to a magnesium salt of (S)-omeprazole; and

(b) recovering the magnesium salt of (S)-omeprazole substantially in solid amorphous form.

DEFINITIONS

[0018] The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0019] The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes, but is not limited to, that which is customarily utilized for veterinary use and/or human pharmaceutical use.

[0020] The term "composition" includes, but is not limited to, a powder, a solution, a suspension, a gel, an ointment, an emulsion and/or mixtures thereof. The term "composition" is intended to encompass a product containing the specified ingredient(s) in the specified amount(s), as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. A "composition" may contain a single compound or a mixture of compounds. A "compound" is a chemical substance that includes molecules of the same chemical structure.

[0021] The term "pharmaceutical composition" is intended to encompass a product comprising the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the crystalline solids described herein, additional active ingredient(s), and pharmaceutically acceptable excipients. [0022] When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.

[0023] The term "substantially free of in reference to a composition, as used herein, means that the substance from which the composition is free of cannot be detected by methods known to those skilled in the art.

[0024] The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0025] The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

[0026] The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.

[0027] The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

[0028] The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g.,

NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.

[0029] When needed, other binders may also be included in the present invention.

Exemplary binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™ F127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, poly(propylene glycol), polyoxyethylene- polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.

[0030] The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

[0031] The term "glidant" as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

[0032] The term "lubricant" as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

[0033] The term "disintegrant" as used herein is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre- gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art. [0034] The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN™s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone (PVP), tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton), combinations thereof and other such materials known to those of ordinary skill in the art.

, [0035] Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is a characteristic powder XRD pattern of polymorph form G-I of a magnesium salt of (S)-omeprazole trihydrate.

[0037] Figure 2 is a characteristic powder XRD pattern of polymorph form G-2 of a magnesium salt of (S)-omeprazole trihydrate. [0038] Figure 3 is a characteristic powder XRD pattern of a magnesium salt of (S)- omeprazole in an amorphous form.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0039] One embodiment of the present invention is directed to a novel polymorph form of a magnesium salt of (S)-omeprazole trihydrate, designated polymorph form G-I. It shall be understood that the terms "(S)-omeprazole" and "esomeprazole" shall be used interchangeably herein. The X-Ray powder diffraction pattern for each of the polymorphs, i.e., forms G-I and G-2 as well as the amorphous form, were measured by an X-ray powder Diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 45kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-50° 20; step width=0.017°; and measuring time per step=5 sec.

[0040] The polymorph form G-I of a magnesium salt of (S)-omeprazole trihydrate has at least one and preferably all, of the following properties:

(a) a powder XRD pattern substantially in accordance with Figure 1; and/or

(b) an XRD pattern comprising characteristic peaks (expressed in degrees 2Θ ± 0.2°θ) summarized in Table I below.

TABLE I

[0041] In one embodiment, polymorph form G-I of a magnesium salt of (S)- omeprazole trihydrate can be substantially free from other forms. Accordingly, one embodiment provides a composition which includes polymorph form G-I of a magnesium salt of (S)-omeprazole trihydrate as a solid, in which at least about 50%, preferably about 90%, more preferably about 95%, and most preferably about 99% by weight of polymorph form G-I of a magnesium salt of (S)-omeprazole trihydrate can be present in the composition. The remainder of the magnesium salt of (S)-omeprazole in the composition, e.g., about 50%, preferably about 10%, more preferably about 5%, and most preferably about 1% or less of the total weight of the magnesium salt of (S)-omeprazole, may be amorphous or one or more other crystalline forms of the magnesium salt of (S)- omeprazole. All percentages are based upon the total amount of the solid magnesium salt of (S)-omeprazole in the composition. The preferred form of the composition of this embodiment of the present invention is a solid powder of bulk magnesium salt of (S)- omeprazole trihydrate in polymorph form G-I for use as an active pharmaceutical ingredient. This powder composition has a moisture content, which is from about 2% to about 10% and preferably from about 6% to about 8.5%. Moisture content may be measured by any accepted technology, for example by using Karl Fischer reagent (KF) and an appropriate instrument (goniometer) such as a Mettler DL-35, a Scintag PAD V, a Brukker D5000.

[0042] To determine the relative amounts of amorphous and crystalline components in the composition of this embodiment of the invention, a suitable analytical methodology can be X-ray powder diffraction (XRD). XRD methodology is capable of providing both qualitative and quantitative information about compounds present in a solid sample. XRD is adaptable to quantitative applications because the intensities of the diffraction peaks of a given compound in a mixture are proportional to the fraction of the material in the mixture. By measuring the intensity of the diffraction lines and comparing them with standards, it can be possible to make a quantitative analysis of crystalline mixtures.

[0043] Generally, polymorph form G-I of a magnesium salt of (S)-omeprazole trihydrate can be obtained by at least (a) treating a solution containing at least a potassium or sodium salt of (S)-omeprazole in water with a source of magnesium at a temperature ranging from -10 to 20⁰C; to provide a magnesium salt of (S)-omeprazole; and (b) recovering the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I.

[0044] In step (a) of a process of the present invention, a solution can be formed by adding a potassium or sodium salt of (S)-omeprazole in a suitable solvent such as water with a source of magnesium at a temperature ranging from about -10⁰C to about 20⁰C, preferably from about 0⁰C to about 10⁰C and most preferably from about 0⁰C to about 5⁰C. Potassium and sodium salts of (S)-omeprazole are well known and may be prepared by any of the known methods, see, e.g., U.S. Patent. Nos. 4,738,974 and 5,693,818. In one embodiment, a first solution containing a potassium or sodium salt of (S)-omeprazole in a suitable solvent such as water can be added to a second solution containing a source of magnesium in a suitable solvent such as water.

[0045] Suitable sources of magnesium include, but are not limited to, magnesium sulfate, magnesium chloride, magnesium methoxide, magnesium acetate, and the like and mixtures thereof. Preferably, the magnesium source is magnesium sulfate, magnesium chloride, and/or magnesium methoxide. The molar ratio of the magnesium source to the potassium or sodium salt of (S)-omeprazole will ordinarily range from about 1:1 to about 1:5 and preferably from about 1:2 to about 1:3.

[0046] In step (b) of a process of the present invention, the magnesium salt of (S)- omeprazole trihydrate substantially in polymorph form G-I can be recovered by, for example, isolating the precipitate of the polymorph form G-I of a magnesium salt of (S)- omeprazole trihydrate crystals by known techniques, e.g., filtration, and drying the crystals. Drying may be accomplished by evaporation, spray drying, drying under vacuum freeze-drying and the like.

[0047] Another embodiment of the present invention is directed to a novel polymorph of a magnesium salt of (S)-omeprazole trihydrate, designated polymorph form G-2. The polymorph form G-2 of a magnesium salt of (S)-omeprazole trihydrate has at least one and preferably all, of the following properties

(a) a powder XRD pattern substantially in accordance with Figure 1; and/or

(b) an XRD pattern comprising characteristic peaks (expressed in degrees 20 ± 0.2°θ) summarized in Table II below. TABLE II

[0048] In one embodiment, polymorph form G-2 of a magnesium salt of (S)- omeprazole trihydrate can be substantially free from other forms. Accordingly, one embodiment provides a composition which includes polymorph form G-2 of a magnesium salt of (S)-omeprazole trihydrate as a solid, in which at least about 50%, preferably about 90%, more preferably about 95%, and most preferably about 99% by weight of polymorph form G-2 of a magnesium salt of (S)-omeprazole trihydrate can be present in the composition. The remainder of the magnesium salt of (S)-omeprazole in the composition, e.g., about 50%, preferably about 10%, more preferably about 5%, and most preferably about 1% or less of the total weight of the magnesium salt of (S)-omeprazole, may be amorphous or one or more other crystalline forms of the magnesium salt of (S)- omeprazole. All percentages are based upon the total amount of the solid magnesium salt of (S)-omeprazole in the composition. The preferred form of the composition of this embodiment of the present invention is a solid powder of bulk magnesium salt of (S)- omeprazole trihydrate in polymorph form G-2 for use as an active pharmaceutical ingredient. This powder composition has a moisture content, which is from about 2% to about 10% and preferably from about 6% to about 8%. Moisture content may be measured by any accepted technology, for example by using Karl Fischer reagent (KF) and an appropriate instrument (goniometer) such as a Mettler DL-35, a Scintag PAD V, a Brukker D5000.

[0049]^' Generally, polymorph form G-2 of a magnesium salt of (S)-omeprazole trihydrate can be obtained by at least (a) treating a solution comprising a sodium salt of (S)-omeprazole in a first organic solvent with a source of magnesium to convert the sodium salt of (S)-omeprazole to a magnesium salt of (S)-omeprazole; (b) treating the solution containing the magnesium salt of (S)-omeprazole with a second organic solvent; and (c) recovering the magnesium salt of (S)-omeprazole trihydrate substantially in the polymorph form G-2.

[0050] As discussed above sodium salts of (S)-omeprazole are well known and may be prepared by any of the known methods, see, e.g., U.S. Patent. Nos. 4,738,974 and 5,693,818. Suitable sources of magnesium can be any of the magnesium sources discussed hereinabove. Preferably, the magnesium source is magnesium sulfate, magnesium chloride, and/or magnesium methoxide. The molar ratio of magnesium source to sodium salt of (S)-omeprazole will ordinarily range from about 1:1 to about 1 :5 and preferably from about 1:2 to about 1:3. In one embodiment, a first solution containing a sodium salt of (S)-omeprazole in a first solvent such as an alcohol, e.g., methanol, can be added to a second solution containing a source of magnesium in a suitable solvent such as water.

[0051] Useful solvents in step (a) of a process of the present invention include, but are not limited to, aliphatic alcohols, aromatic alcohols and the like and mixtures thereof. Suitable aliphatic alcohols include C₁-C₈ alcohols such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like and mixtures thereof. Suitable aromatic alcohols include C₃-Ci₂ alcohols such as, for example, benzyl alcohol, benzyloxyethanol, phenoxyethanol and the like and mixtures thereof. The solvent in step (a) will ordinarily be added in a concentration ranging from about 5 to about 30% weight per volume (w/v) and preferably from about 10 to about 15% w/v in the solution. [0052] Useful solvents in step (b) of the process of the present invention include ketones such as, for example, ketones having from 3 to about 12 carbon atoms. Representative examples of such ketones include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl propyl ketone, ethyl isopropyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl isobutyl ketone, methyl sec butyl ketone, methyl tert-butyl ketone, ethyl butyl ketone, ethyl isobutyl ketone, ethyl sec-butyl ketone, ethyl tert-butyl ketone, propyl butyl ketone, isopropyl butyl ketone, propyl isobutyl ketone, propyl sec-butyl ketone, propyl tert butyl ketone, isopropyl isobutyl ketone, isopropyl sec-butyl ketone, isopropyl tert-butyl ketone, dibutyl ketone, diisobutyl ketone, di-sec-butyl ketone, di-tert-butyl ketone, butyl isobutyl ketone, butyl sec-butyl ketone, butyl tert-butyl ketone, isobutyl sec-butyl ketone, isobutyl tert-butyl ketone, sec-butyl tert-butyl ketone, 5-heptanone, 5-methyl-2-hexanone (methyl isoamyl ketone), 4-methyl-2-hexanone, 3-methyl-2-hexanone, 3,4-dimethyl-2- pentanone, 3,3-dimethyl-2-pentanone, 4,4-dimethyl-2-pentanone, 3-octanone, 4-methyl-3- heptanone, 5-methyl-3-heptanone, 6-methyl-3-heptanone, 4,4-dimethyl-3-hexanone, 4,5- dimethyl-3-hexanone, 5,5-dimethyl-3-hexanone, 4-nonanone, 5-methyl-4-octanone, 6- methyl-4-octanone, 7-methyl-4-octanone, 5,5-dimethyl-4-neptanone, 5,6-dimethyl-4- heptanone, 6,6-dimethyl-4-heptanone, 2-undecanone, cyclopropanone, cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone, cyclononanone, cyclodecanone, cycloundecanone, cyclododecanone and the like and mixtures thereof. The solvent in step (b) will ordinarily be added in a concentration ranging from about 5 to about 30% w/v and preferably from about 10 to about 20% w/v in the solution [0053] In step (c) of the process of the present invention, the magnesium salt of

(S)-omeprazole substantially in polymorph form G-2 can be recovered by, for example, isolating the precipitate of the magnesium salt of (S)-omeprazole crystals by filtration, and drying the crystals.

[0054] Still another embodiment of the present invention is directed to a process for the preparation of a magnesium salt of esomeprazole substantially in the form of an amorphous solid. In general, the process includes at least (a) treating a solution comprising a potassium or sodium salt of (S)-omeprazole in one or more polar aprotic solvents with a source of magnesium at a temperature and for a time period sufficient to convert the potassium or sodium salt of (S)-omeprazole to a magnesium salt of (S)- omeprazole; and (b) recovering the magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid.

[0055] Suitable polar aprotic solvents include, but are not limited to, amides, e.g., dimethyl formamide, N,N-dimethylacetamide and the like; sulfoxides, e.g., dimethyl sulfoxide and the like; nitriles, e.g., acetonitrile, and the like and mixtures thereof. In general, the molar ratio of potassium or sodium salt of (S)-omeprazole to polar aprotic solvent can be about 1:5 and preferably about 1:2.

[0056] A useful source of magnesium can be any of the magnesium sources discussed hereinabove. Generally, a temperature sufficient to convert the potassium or sodium salt of esomeprazole to a magnesium salt of esomeprazole will ordinarily range from about -10⁰C and higher, e.g., up to about 50⁰C, preferably from about 0⁰C and higher, e.g., up to about 1O⁰C. The time period sufficient to convert the potassium or sodium salt of esomeprazole to a magnesium salt of esomeprazole will be a time that results in high conversion of the potassium or sodium salt of esomeprazole to a magnesium salt of esomeprazole without causing any decomposition of either compounds thereby resulting in a relatively good yield.

[0057] The magnesium salt of esomeprazole substantially in the form of an amorphous solid can then be recovered by conventional techniques, e.g., filtration, and optionally washed and dried.

[0058] Yet another embodiment of the present invention is directed to pharmaceutical compositions containing a therapeutically effective amount of one or more of the magnesium salts of (S)-omeprazole disclosed herein, i.e., the magnesium salts of (S)-omeprazole trihydrate substantially in polymorph forms G-I and/or G-2 and the magnesium salts of (S)-omeprazole in an amorphous form. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The magnesium salts of (S)-omeprazole of the present invention may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The dosage forms may contain the magnesium salts of (S)-omeprazole of the present invention as is or, alternatively, may contain the magnesium salts of (S)-omeprazole of the present invention as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.

[0059] Capsule dosages will contain the magnesium salts of (S)-omeprazole of the present invention within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings containing at least phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating. [0060] Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g., lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

[0061] Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

[0062] In one embodiment, the magnesium salts of (S)-omeprazole trihydrate substantially in polymorph forms G-I and/or G-2 disclosed herein for use in the pharmaceutical compositions of the present invention can have a D₅₀ and D₉₀ particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. It is noted the notation D_x means that X% of the particles have a diameter less than a specified diameter D. Thus, a D₅₀ of about 400 microns means that 50% of the micronized particles in a composition have a diameter less than about 400 microns. The particle sizes of the magnesium salts of (S)-omeprazole trihydrate substantially in polymorph forms G-I and/or G-2 prepared according to the present invention can be obtained by any milling, grinding micronizing or other particle size reduction method known in the art to bring the solid state magnesium salts of (S)- omeprazole trihydrate substantially in polymorph forms G-I and/or G-2 into any of the foregoing desired particle size range.

[0063] In another embodiment, the magnesium salts of (S)-omeprazole in an amorphous form for use in the pharmaceutical compositions of the present invention can have a D50 and D₉0 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. [0064] Another embodiment of the present invention is directed to methods of treatment using one or more of the magnesium salts of this invention and the pharmaceutical compositions of this invention. In particular, the magnesium salts such as polymorph forms G-I and/or G-2 of a magnesium salt of (S)-omeprazole trihydrate may be administered to a subject in an amount effective to reduce secretion of gastric acid by that subject. Although it is possible to use the polymorphs and compositions of this invention to prevent secretion of gastric acid by establishing a dosage level effective to do so, such treatment would only be applicable in special cases, since to alleviate or eliminate most of the conditions which are treated with the compounds of this invention, gastric acid secretion should not be eliminated altogether, but only reduced in amount or duration. In general, the treatment may be determined to alleviate, to eliminate, or to prevent a given condition based on factors determinable by a skilled physician as discussed below in the context of determining an effective amount for dosage. Further, the polymorphs of this invention may be administered to a subject for treating a disorder caused by gastric acid secretion by administering to a subject an amount effective to reduce gastric acid secretion by the subject.

[0065] The magnesium salts and compositions of this invention may be used for treatment of any specific disorder or condition related to other conditions known to be suitable for treatment by omeprazole compounds. These polymorphs and compositions are useful for ameliorating or preventing conditions related to secretion of gastric acid, such as ulcers (including those caused by H. pylori), heartburn, gastroesophageal reflux, esophagitis, hypersecretory conditions (e.g., Zollinger-Ellison, endocrine adenoma, systemic mastocytosis), gastritis, duodenitis, dyspepsia, acute gastrointestinal bleeding (especially upper), for patients on NSAID therapy or in intensive care, to reduce or prevent gastric acid aspiration and stress ulceration. The polymorphs are also useful for treating inflammatory conditions such as psoriasis and lysosomal enzyme problems, and infections such as those caused by H. pylori.

[0066] By subject is meant a human or an animal, preferably human. Animals contemplated by this invention include any animal safely treatable by the polymorphs of this invention, preferably mammals such as bovines, ovines, caprines, equines, felines, canines, rodents, leporids, and other mammalian farm and zoo animals or domestic pets. The effective amount (i.e. dosage) of active compound for treatment will vary depending on the route of administration, the condition being treated, its severity, and duration, and the state and age of the subject. A skilled physician will monitor the progress of the subject and will adjust the dosage accordingly, depending on whether the goal is to eliminate, alleviate, or prevent a given condition. Generally, the starting dosage may be low, but must at least start from the low end of the effective range, and in cases of severe ulcers it may be increased, and the active substance may be administered as maintenance therapy. The dosage of the active compound may be towards the high end of the effective range, or if needed even higher, but should be considered in proportion to the subject's weight. Depending on the solubility of the particular formulation of active compound administered, the daily dose may be divided among one or several unit dose administrations. Administration of the active compounds may be carried out therapeutically, i.e., as a rescue treatment, or prophylactically, and may be maintained for prolonged periods of time. One skilled in the art will take such factors into account when determining dosage. In general, oral and parenteral dosages will be in the range of about 5 to about 350 to 400 mg per day of active ingredient, preferably about 8 mg to about 60 mg, most preferably about 20 mg to about 40 mg.

[0067] The examples which follow will further illustrate the preparation of the compound of invention. The examples are not intended to limit the scope of the invention as defined herein above or as claimed below.

EXAMPLE l

[0068] Preparation of Polymorph Form G-I of Magnesium of (S)-Omeprazole

Trihydrate

[0069] A solution of sodium salt of (S)-omeprazole (25 g) in 500 ml 5% sodium chloride brine in water was treated with a solution of magnesium sulfate (15 g) in water (250 ml) at -5°C to O⁰C. The reaction mixture was stirred for 2 hours. The precipitated product was filtered and dried to obtain a magnesium salt of (S)-omeprazole trihydrate in polymorph form G-I (15 g) as identified by the XRD pattern in Figure 1 and the XRD pattern comprising characteristic peaks summarized in Table I. Karl Fischer titration of the sample after X-ray diffraction reveals a water content of 8.54%. EXAMPLE 2

[0070] Preparation of Polymorph Form G-2 of Magnesium of (S)-Omeprazole

Trihydrate

[0071] A solution of sodium salt of (S)-omeprazole (25 g) in methanol (500 ml) was treated with a solution of magnesium sulfate (15 g) in water (250 ml) at room temperature. The reaction mixture was stirred for 24 hours. The reaction mixture was filtered to remove any inorganic material and the filtrate was concentrated. The residue was treated with 400 ml acetone, stirred for 2 to 3 hours and filtered to obtain a magnesium salt of (S)-omeprazole trihydrate in polymorph form G-2 (10 g) as identified by the XRD pattern in Figure 2 and the XRD pattern comprising characteristic peaks summarized in Table II. Karl Fischer titration of the sample after X-ray diffraction reveals a water content of 7.69%.

EXAMPLE 3

[0072] Preparation of Amorphous Form of Magnesium Salt of (S)-Omeprazole

[0073] To a four-neck 250 ml flask equipped with a mechanical stirring condenser and thermometer charged with dimethylsulfoxide (DMSO) (20 ml) was added a potassium salt of esomeprazole (10 g). Next, activated carbon (0.2 g) was added to the solution and stirred for 20 minutes. The solution was filtered through a hyflo bed and washed with DMSO (2 ml). The clear filtrate was cooled to 0-5⁰C.

[0074] In a separate flask, a solution was prepared containing magnesium sulphate

(5 g) in water (60 ml). The solution was filtered and cooled to 0-5⁰C and then slowly added to the potassium salt solution at 0-10⁰C within 1 hour. The reaction mixture was stirred for 2 hours at 0-10⁰C. The product was filtered on a buchner funnel, washed with chilled water (200 ml) and dried. The product obtained was the amorphous form of the magnesium salt of esomeprazole (8.2 g) as identified by the XRD pattern in Figure 3.

EXAMPLE 4

[0075] Preparation of Amorphous Form of Magnesium Salt of S-Omeprazole

[0076] To a four-neck 250 ml flask equipped with a mechanical stirring condenser and thermometer and charged with dimethyl formamide (DMF) (25 ml) was added a potassium salt of esomeprazole (10 g). Activated carbon (0.2 g) was added to the solution and stirred for 20 minutes. The solution was filtered through a hyflo bed and wash with DMF (2 ml). The clear filtrate was cooled to 0-5⁰C.

[0077] In a separate flask, a solution was prepared containing magnesium sulphate

(5 g) in water (60 ml). The solution was filtered and cooled to 0-5⁰C and then slowly added to the potassium salt solution at 0-10⁰C within 1 hour. The reaction mixture was stirred for 2 hours at 0-10⁰C. The product was filtered on a buchner funnel, washed with chilled water (300 ml) and dried. The product obtained was the amorphous form of magnesium salt of esomeprazole (7.8 g).

EXAMPLE 5

[0078] Preparation of Amorphous Form of Magnesium Salt of (S)-Omeprazole

[0079] To a four-neck 250 ml flask equipped with a mechanical stirring condenser and thermometer and charged with DMSO (22 ml) was added a sodium salt of esomeprazole (10 g). Activated carbon (0.2 g) was added to the solution and stirred for 20 minutes. The solution was filtered through a hyflo bed and wash with DMSO (3 ml). The clear filtrate was cooled to 0-5⁰C.

[0080] In a separate flask, a solution was prepared containing magnesium sulphate

(5 g) in water (60 ml). The solution was filtered and cooled to 0-5⁰C and then slowly added to the sodium salt solution at 0-10⁰C within 1 hour. The reaction mixture was stirred for 2 hours at 0-10⁰C. The product was filtered on a buchner funnel, washed with chilled water (200 ml) and dried. The product obtained was the amorphous form of magnesium salt of esomeprazole (7.9 g).

[0081] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I.

2. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I characterized by an X-ray diffraction pattern (XRD) substantially in accordance with Figure 1.

3. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I exhibiting characteristic peaks (expressed in degrees 2Θ ± 0.2°θ) at one or more of the positions: about 13.0671 and about 22.2772.

4. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I exhibiting characteristic peaks (expressed in degrees 2Θ ± 0.2°θ) at one or more of the positions: about 5.1652, about 13.0671, about 22.2772, about 25.1439, about 26.9166 and about 44.5797.

5. A composition comprising a magnesium salt of (S)-omeprazole, wherein at least 50% of the magnesium salt of (S)-omeprazole is the magnesium salt of (S)- omeprazole trihydrate substantially in polymorph form G-I of Claims 1-4.

6. A composition comprising the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I of Claims 1-4, which has a moisture content of from about 2% to about 10% as measured by the Karl Fischer method.

7. A composition comprising the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I of Claims 1-4, which has a moisture content of from about 6% to about 8.5% as measured by the Karl Fischer method.

8. A pharmaceutical composition comprising a therapeutically effective amount of the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I of Claims 1-4.

9. The pharmaceutical composition of Claim 8, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I having a D₅₀ and D₉₀ particle size of less than about 400 microns.

10. The pharmaceutical composition of Claim 8, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I having a D₅₀ and D₉₀ particle size of less than about 200 microns.

11. The pharmaceutical composition of Claim 8, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I having a D50 and D90 particle size of less than about 150 microns.

12. The pharmaceutical composition of Claim 8, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I having a D₅₀ and D₉₀ particle size of less than about 50 microns.

13. The pharmaceutical composition of Claim 8, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I having a D₅₀ and D₉₀ particle size of less than about 15 microns.

14. The pharmaceutical composition of Claims 8-13, further comprising one or more pharmaceutically acceptable excipients.

15. The pharmaceutical composition of Claims 8-14, in the form of a tablet, capsule, troche, sachet, suspension, powder, lozenge or elixir.

16. A method of treating a gastric acid related condition, the method comprises administering to a subject suffering from the condition a therapeutically effective amount of the magnesium salt of S-omeprazole trihydrate substantially in polymorph form G-I according to Claims 1-4.

17. A method of treating a gastric acid related condition, the method comprises administering to a subject suffering from the condition the compositions according to Claims 5-15.

18. A process for the preparation of a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I, the process comprising:

(a) treating a solution comprising a potassium or sodium salt of (S)-omeprazole in water with a source of magnesium at a temperature of about -10⁰C to about 20⁰C to provide a magnesium salt of (S)-omeprazole; and

19. The process of Claim 18, wherein the source of magnesium is selected from the group consisting of magnesium sulfate, magnesium chloride, magnesium methoxide, magnesium acetate and mixtures thereof.

20. The process of Claim 18, wherein the source of magnesium is selected from the group consisting of magnesium sulfate, magnesium chloride and mixtures thereof..

21. The process of Claims 18-20, wherein the molar ratio of the source of magnesium to the potassium or sodium salt of (S)-omeprazole is about 1:1 to about 1:5.

22. The process of Claims 18-21, wherein the step of recovering the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I comprises precipitating the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I from the solution and filtering the precipitate to obtain the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I.

23. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2.

24. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 characterized by an XRD pattern substantially in accordance with Figure 2.

25. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 and exhibiting characteristic peaks (expressed in degrees 2Θ ± 0.2°θ) at approximately one or more of the positions: about 5.6814, about 17.0203 and about 18.0370.

26. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 and exhibiting characteristic peaks (expressed in degrees 20 ± 0.2°θ) at approximately one or more of the positions: about 5.6814, about 17.0203, about 17.2063, about 18.0370 and about 18.1513.

27. A composition comprising the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 of Claims 23-26, which has a moisture content of from about 2% to about 10% as measured by the Karl Fischer method.

28. A composition comprising the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 of Claims 23-26, which has a moisture content of from about 5% to about 8% as measured by the Karl Fischer method.

29. A pharmaceutical composition comprising a therapeutically effective amount of the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 of Claims 23-26.

30. The pharmaceutical composition of Claim 29, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 having a D50 and D₉0 particle size of less than about 400 microns.

31. The pharmaceutical composition of Claim 29, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 having a D50 and D₉₀ particle size of less than about 200 microns.

32. The pharmaceutical composition of Claim 29, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 having a D50 and D₉0 particle size of less than about 150 microns.

33. The pharmaceutical composition of Claim 29, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 having a D50 and Dg₀ particle size of less than about 50 microns.

34. The pharmaceutical composition of Claim 29, wherein the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is a micronized magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 having a D₅₀ and D₉₀ particle size of less than about 15 microns.

35. The pharmaceutical composition of Claims 29-34, further comprising one or more pharmaceutically acceptable excipients.

36. The pharmaceutical composition of Claims 29-35, in the form of a tablet, capsule, troche, sachet, suspension, powder, lozenge or elixir.

37. A method of treating a gastric acid related condition, the method comprises administering to a subject suffering from the condition a therapeutically effective amount of the magnesium salt of S-omeprazole trihydrate substantially in polymorph form G-2 according to Claims 23-26.

38. A method of treating a gastric acid related condition, the method comprises administering to a subject suffering from the condition the compositions according to Claims 27-36.

39. A process for the preparation of a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2, the process comprising:

40. The process of Claim 39, wherein the source of magnesium is selected from the group consisting of magnesium sulfate, magnesium chloride, magnesium methoxide, magnesium acetate and mixtures thereof.

41. The process of Claim 39, wherein the source of magnesium is selected from the group consisting of magnesium sulfate, magnesium chloride and mixtures thereof.

42. The process of Claims 39-41, wherein the first solvent is an alcohol.

43. The process of Claims 39-42, wherein the first solvent is methanol.

44. The process of Claims 39-43, wherein the second solvent is a ketone.

45. The process of Claims 39-44, wherein the second solvent is acetone.

46. The process of Claims 39-45, wherein the first solvent is methanol and the second solvent is acetone.

47. The process of Claims 39-46, wherein the concentration of the first solvent in the solution is about 5 to about 30% weight per volume (w/v).

48. The process of Claims 39-47, wherein the concentration of the second solvent in the solution is about 5 to about 30% w/v.

49. The process of Claims 39-48, further comprising concentrating the reaction mixture of step (a) to obtain a residue; combining the residue with a C₃-C₆ ketone; and isolating the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2.

50. The process of Claim 49, further comprising stirring the residue combined with the C₃-C₆ ketone and filtering the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2.

51. A process for the preparation of a magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid, the process comprising:

(a) treating a solution comprising a potassium or sodium salt of (S)-omeprazole in one or more polar aprotic solvents with a source of magnesium at a temperature and for a time period sufficient to convert the potassium or sodium salt of (S)-omeprazole to a magnesium salt of (S)-omeprazole; and (b) recovering the magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid.

52. The process of Claim 51, wherein the polar aprotic solvent is selected from the group consisting of dimethyl formamide, dimethyl sulfoxide, acetonitrile and mixtures thereof.

53. The process of Claims 51 and 52, wherein the source of magnesium is selected from the group consisting of magnesium sulfate, magnesium chloride, magnesium methoxide, magnesium acetate and mixtures thereof.

54. A pharmaceutical composition comprising a therapeutically effective amount of a magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid prepared in accordance with the process of Claims 51-53.

55. A pharmaceutical composition comprising a therapeutically effective amount of a magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid wherein the magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid is a micronized magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid having a D₅₀ and D₉₀ particle size of less than about 400 microns.

56. A pharmaceutical composition comprising a therapeutically effective amount of a magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid wherein the magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid is a micronized magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid having a D50 and D₉₀ particle size of less than about 200 microns.

57. A pharmaceutical composition comprising a therapeutically effective amount of a magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid wherein the magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid is a micronized magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid having a D₅₀ and D₉₀ particle size of less than about 150 microns.

58. A pharmaceutical composition comprising a therapeutically effective amount of a magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid wherein the magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid is a micronized magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid having a Ds₀ and D₉₀ particle size of less than about 50 microns.

59. A pharmaceutical composition comprising a therapeutically effective amount of a magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid wherein the magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid is a micronized magnesium salt of (S)-omeprazole substantially in the form of an amorphous solid having a D5₀ and D₉₀ particle size of less than about 15 microns.

60. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I prepared in accordance with the process of Claims 18-22.

61. A magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 prepared in accordance with the process of Claims 39-50.