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WO2007031845A2 - Formes polymorphiques de sels de magnesium de (s)-omeprazole et procedes de preparation desdites formes - Google Patents

Formes polymorphiques de sels de magnesium de (s)-omeprazole et procedes de preparation desdites formes Download PDF

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Publication number
WO2007031845A2
WO2007031845A2 PCT/IB2006/002520 IB2006002520W WO2007031845A2 WO 2007031845 A2 WO2007031845 A2 WO 2007031845A2 IB 2006002520 W IB2006002520 W IB 2006002520W WO 2007031845 A2 WO2007031845 A2 WO 2007031845A2
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Prior art keywords
omeprazole
magnesium salt
magnesium
polymorph form
salt
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PCT/IB2006/002520
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WO2007031845A3 (fr
Inventor
Bobba Venkata Siva Kumar
Pravin Bhalchandra Kulkarni
Changdev Namdev Raut
Anil Ganpat Suryawanshi
Nitin Sharad Chandra Pradhan
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Glenmark Pharmaceuticals Ltd
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Glenmark Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • 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.
  • 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.
  • the enantiomer (S)-omeprazole is commonly referred to as esomeprazole
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is provided.
  • 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
  • a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I is provided exhibiting characteristic peaks (expressed in degrees 2 ⁇ ⁇ 0.2° ⁇ ) at one or more of the positions: about 13.0671 and about 22.2772.
  • a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is provided.
  • 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.
  • a magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-2 is provided exhibiting characteristic peaks (expressed in degrees 2 ⁇ ⁇ 0.2° ⁇ ) at approximately one or more of the positions: about 5.6814, about 17.0203 and about
  • a pharmaceutical composition 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.
  • treating 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.
  • 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.
  • composition includes, but is not limited to, a powder, a solution, a suspension, a gel, an ointment, an emulsion and/or mixtures thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition 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.
  • terapéuticaally effective amount 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.
  • delivering 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.
  • 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.
  • 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.
  • binder 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 ethylcellulose
  • povidone ethylcellulose
  • pregelatinized starch ethylcellulose
  • binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONICTM F68, PLURONICTM 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.
  • filler 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.
  • 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.
  • 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.
  • 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. AvicelTM), carsium (e.g. AmberliteTM), 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.
  • starches such as corn starch, potato starch, pre- gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. AvicelTM), carsium (e.g. AmberliteTM), alginates, sodium starch glycolate, gums such
  • 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., TWEENTMs), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxye
  • Figure 1 is a characteristic powder XRD pattern of polymorph form G-I of a magnesium salt of (S)-omeprazole trihydrate.
  • Figure 2 is a characteristic powder XRD pattern of polymorph form G-2 of a magnesium salt of (S)-omeprazole trihydrate.
  • Figure 3 is a characteristic powder XRD pattern of a magnesium salt of (S)- omeprazole in an amorphous form.
  • 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 polymorph form G-I of a magnesium salt of (S)-omeprazole trihydrate has at least one and preferably all, of the following properties:
  • 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 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.
  • 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.
  • 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 20 0 C; to provide a magnesium salt of (S)-omeprazole; and (b) recovering the magnesium salt of (S)-omeprazole trihydrate substantially in polymorph form G-I.
  • 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 -10 0 C to about 20 0 C, preferably from about 0 0 C to about 10 0 C and most preferably from about 0 0 C to about 5 0 C.
  • 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.
  • 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.
  • Suitable sources of magnesium include, but are not limited to, magnesium sulfate, magnesium chloride, magnesium methoxide, magnesium acetate, and the like and mixtures thereof.
  • 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.
  • 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.
  • 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
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 C 1 -C 8 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 C 3 -Ci 2 alcohols such as, for example, benzyl alcohol, benzyloxyethanol, phenoxyethanol and the like and mixtures thereof.
  • 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.
  • 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.
  • 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 isobutyl ketone, propyl isobutyl ketone,
  • 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]
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a useful source of magnesium can be any of the magnesium sources discussed hereinabove.
  • a temperature sufficient to convert the potassium or sodium salt of esomeprazole to a magnesium salt of esomeprazole will ordinarily range from about -10 0 C and higher, e.g., up to about 50 0 C, preferably from about 0 0 C and higher, e.g., up to about 1O 0 C.
  • 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.
  • 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.
  • 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.
  • 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.
  • Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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 D 50 and D 90 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.
  • D x means that X% of the particles have a diameter less than a specified diameter D.
  • a D 50 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.
  • 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 D 9 0 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
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Abstract

L'invention concerne de nouveaux polymorphes d'un sel de magnésium de (S)-oméprazole trihydrate et des procédés pour préparer ces polymorphes. Cette invention concerne également un procédé de préparation d'une forme amorphe d'un sel de magnésium de (S)-oméprazole. Ladite invention se rapporte en outre à des compositions pharmaceutiques contenant ces sels de magnésium.
PCT/IB2006/002520 2005-09-14 2006-09-13 Formes polymorphiques de sels de magnesium de (s)-omeprazole et procedes de preparation desdites formes Ceased WO2007031845A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074997A3 (fr) * 2007-12-10 2009-12-30 Lee Pharma Ltd. Nouveau procédé de préparation de sel de magnésium cristallin de (s)-oméprazole dihydraté
EP2147918A1 (fr) 2008-07-21 2010-01-27 LEK Pharmaceuticals D.D. Procédé de préparation de magnésium d'oméprazole S dans une forme stable
EP2240496A4 (fr) * 2008-02-01 2011-05-11 Reddys Lab Ltd Dr Préparation de magnésium d ésoméprazole et de ses hydrates
EP2385046A1 (fr) 2010-05-03 2011-11-09 Produits Chimiques Auxiliaires Et De Synthese Phase précurseur et son utilisation pour préparer le sel de magnésium tétrahydraté d'un énantiomère d'oméprazole
CN102911158A (zh) * 2011-07-31 2013-02-06 连云港润众制药有限公司 埃索美拉唑镁的晶型
CN103509001A (zh) * 2012-06-15 2014-01-15 石药集团中奇制药技术（石家庄）有限公司 一种埃索美拉唑镁三水合物及其制备方法
CN105936632A (zh) * 2016-05-23 2016-09-14 江苏中邦制药有限公司 三水合埃索美拉唑镁粗品的精制方法
WO2024156195A1 (fr) * 2023-01-29 2024-08-02 山东省分析测试中心 Procédé de préparation d'ésoméprazole magnésium trihydrate par transformation cristalline

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SE9301830D0 (sv) * 1993-05-28 1993-05-28 Ab Astra New compounds
SE510650C2 (sv) * 1997-05-30 1999-06-14 Astra Ab Ny förening
CA2501424A1 (fr) * 2002-08-30 2004-03-11 Dr. Reddy's Laboratories Limited Hydrates amorphes d'esomeprazole magnesium et leur procede de preparation
AU2003278406A1 (en) * 2002-10-22 2004-05-13 Ranbaxy Laboratories Limited Amorphous form of esomeprazole salts
US20040242642A1 (en) * 2002-11-18 2004-12-02 Dr. Reddy's Laboratories Limited Crystalline esomeprazole compounds and process for the preparation thereof
WO2004089935A1 (fr) * 2003-04-10 2004-10-21 Hetero Drugs Limitd Nouvelles formes cristallines de s-omeprazole magnesium
US20050267159A1 (en) * 2004-05-28 2005-12-01 Aaipharma, Inc. Magnesium complexes of S-omeprazole

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074997A3 (fr) * 2007-12-10 2009-12-30 Lee Pharma Ltd. Nouveau procédé de préparation de sel de magnésium cristallin de (s)-oméprazole dihydraté
EP2240496A4 (fr) * 2008-02-01 2011-05-11 Reddys Lab Ltd Dr Préparation de magnésium d ésoméprazole et de ses hydrates
EP2147918A1 (fr) 2008-07-21 2010-01-27 LEK Pharmaceuticals D.D. Procédé de préparation de magnésium d'oméprazole S dans une forme stable
US8362259B2 (en) 2008-07-21 2013-01-29 Lek Pharmaceuticals, D.D. Process for the preparation of esomeprazole magnesium in a stable form
EP2385046A1 (fr) 2010-05-03 2011-11-09 Produits Chimiques Auxiliaires Et De Synthese Phase précurseur et son utilisation pour préparer le sel de magnésium tétrahydraté d'un énantiomère d'oméprazole
US8592601B2 (en) 2010-05-03 2013-11-26 Produits Chimiques Auxiliaires Et De Synthese Precursor phase and use thereof for preparing the magnesium tetrahydrate salt of an omeprazole enantiomer
CN102911158A (zh) * 2011-07-31 2013-02-06 连云港润众制药有限公司 埃索美拉唑镁的晶型
CN102911158B (zh) * 2011-07-31 2015-07-22 连云港润众制药有限公司 埃索美拉唑镁的晶型
CN103509001A (zh) * 2012-06-15 2014-01-15 石药集团中奇制药技术（石家庄）有限公司 一种埃索美拉唑镁三水合物及其制备方法
CN103509001B (zh) * 2012-06-15 2016-12-21 石药集团中奇制药技术（石家庄）有限公司 一种埃索美拉唑镁三水合物及其制备方法
CN105936632A (zh) * 2016-05-23 2016-09-14 江苏中邦制药有限公司 三水合埃索美拉唑镁粗品的精制方法
WO2024156195A1 (fr) * 2023-01-29 2024-08-02 山东省分析测试中心 Procédé de préparation d'ésoméprazole magnésium trihydrate par transformation cristalline

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