CA2570559C - Solid forms of the magnesium salt of (s)-omeprazole and processes for their preparation - Google Patents
Solid forms of the magnesium salt of (s)-omeprazole and processes for their preparation Download PDFInfo
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- CA2570559C CA2570559C CA2570559A CA2570559A CA2570559C CA 2570559 C CA2570559 C CA 2570559C CA 2570559 A CA2570559 A CA 2570559A CA 2570559 A CA2570559 A CA 2570559A CA 2570559 C CA2570559 C CA 2570559C
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- 159000000003 magnesium salts Chemical class 0.000 title claims abstract description 128
- 239000007787 solid Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims description 32
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 title description 2
- 229960004770 esomeprazole Drugs 0.000 title description 2
- 229960000381 omeprazole Drugs 0.000 claims abstract description 134
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 239000007858 starting material Substances 0.000 claims abstract description 26
- 239000003960 organic solvent Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 12
- 239000006184 cosolvent Substances 0.000 claims description 11
- 239000000725 suspension Substances 0.000 claims description 11
- 238000004807 desolvation Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 5
- 230000005855 radiation Effects 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 229940127557 pharmaceutical product Drugs 0.000 abstract 1
- 238000012776 robust process Methods 0.000 abstract 1
- 238000007614 solvation Methods 0.000 abstract 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000012535 impurity Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001174 sulfone group Chemical group 0.000 description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SUBDBMMJDZJVOS-XMMPIXPASA-N (R)-omeprazole Chemical compound C([S@@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-XMMPIXPASA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 238000005169 Debye-Scherrer Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- 206010057969 Reflux gastritis Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940124569 cytoprotecting agent Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000004684 trihydrates Chemical group 0.000 description 1
Classifications
-
- 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
-
- 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
Abstract
New solid forms of the active ingredient magnesium salt of S-omeprazole, obtainable by a preparation process that comprises: a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0,01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the prior step; c) separating the free organic solvent from the magnesium salt of S-omeprazole obtained or, alternatively, separating both the free solvent and the solvation solvent. The new solid forms are obtained by a reproducible and robust process, with high yield and elevated optical purity, which is useful for the preparation of pharmaceutical products that contain said active ingredient.
Description
= CA 02570559 2006-12-15 PCT'2005/053062 SOLID FORMS OF THE MAGNESIUM SALT OF (S)-OMEPRAZOLE AND PROCESSES FOR THEIR
PREPARATION
The present invention relates to new solid forms of the magnesium salt of S-omeprazole and to processes for their preparation, as well as intermediates for their preparation.
BACKGROUND ART
The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole, which has the generic name omeprazole, was described for the first time in the document EP 5.129-A.
Omeprazole is a sulphoxide that contains an asymmetric center in the sulphur atom, and therefore exists as a racemic mixture of two enantiomers, R-omeprazole and S-omeprazole. The R configuration corresponds to the (+)-enantiomer and the S configuration to the (-)-enantiomer.
Omeprazole is susceptible to degradation in acidic and neutral media. Its stability is also affected by other factors such as humidity, temperature and organic solvents. Certain salts of omeprazole are described in EP 124.495-A
where it indicates that they are more stable during storage than the neutral form of omeprazole.
Omeprazole and its alkaline salts are effective inhibitors of gastric acid secretion and,therefore, are useful for the prevention and treatment of gastric acid-related disorders and inflammatory gastrointestinal diseases (e.g., gastric ulcer, duodenal ulcer, reflux esophagitis and gastritis). In addition, they can also be used for the treatment of other gastrointestinal disorders where a cytoprotectant and/or anti-gastric secretion effect is desired (e.g., in patients with gastrinomas, in patients with acute upper gastrointestinal hemorrhage, and in patients with a history of chronic and excessive alcohol consumption).
EP 652.872-A describes the magnesium salt of S-omeprazole, the formula of which is included below, and indicates that it possesses pharmacokinetic and metabolic properties that give it an improved therapeutic profile. There are other documents that describe different solid forms of magnesium salt of S-omeprazole. EP 984.957-A describes a trihydrate form of magnesium salt of S-omeprazole. WO 04/20436 describes a hydrate of magnesium salt of S-omeprazole in amorphous solid form. Finally, EP 1.375.497-A describes a magnesium salt of S-omeprazole with a grade of crystallinity of less than 67%
and a magnesium salt of S-omeprazole with an amount of organic solvent of less than 7%.
N N
S N
Mg 2+
The different solid forms of a pharmaceutically active ingredient can have different characteristics, and offer certain advantages, for example with regard to solubility or bioavailability. Thus, the discovery of new solid forms allows for improving the characteristics of the pharmaceutical formulations of the active ingredients, since some forms are more adequate for one type of formulation, and other forms for other different formulations. Furthermore, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferred, hence omeprazole is commercialized, for example, in the form of capsules and vials, and S-omeprazole as gastroresistant tablets. It is hence of interest to have new solid forms of magnesium salt of S-omeprazole.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, it is provided a solid form of the magnesium salt of S-omeprazole having a crystalline structure and characterized by having an X-ray diffractogram that comprises characteristic peaks at approximately 5.9, 6.5, and 7.6 degrees 2 theta at a Cu-Kal radiation l~ =
1.5406 A
without any other significant peak.
Said diffractogram differs from those of other forms of magnesium salt of S-omeprazole known in the state of the art. This new solid form of magnesium salt of S-omeprazole is characterized by exhibiting in the powder X-ray diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 28 ( ), which is shown in the following table:
28 ( ) d (A) Intensity (%) 5.9 15.1 100 6.5 13.6 81 7.6 11.7 90 8.2 r 10.8 40 This form is essentially free of organic solvent, whether it be free or of salvation. By the expression "essentially free of organic solvent" it is understood that it complies with the relevant pharmaceutical specifications for the presence of solvents. By free solvent it is understood that it does not form part of the product's crystalline structure, and by salvation solvent it is understood that it is incorporated into the crystalline structure of the same.
PREPARATION
The present invention relates to new solid forms of the magnesium salt of S-omeprazole and to processes for their preparation, as well as intermediates for their preparation.
BACKGROUND ART
The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole, which has the generic name omeprazole, was described for the first time in the document EP 5.129-A.
Omeprazole is a sulphoxide that contains an asymmetric center in the sulphur atom, and therefore exists as a racemic mixture of two enantiomers, R-omeprazole and S-omeprazole. The R configuration corresponds to the (+)-enantiomer and the S configuration to the (-)-enantiomer.
Omeprazole is susceptible to degradation in acidic and neutral media. Its stability is also affected by other factors such as humidity, temperature and organic solvents. Certain salts of omeprazole are described in EP 124.495-A
where it indicates that they are more stable during storage than the neutral form of omeprazole.
Omeprazole and its alkaline salts are effective inhibitors of gastric acid secretion and,therefore, are useful for the prevention and treatment of gastric acid-related disorders and inflammatory gastrointestinal diseases (e.g., gastric ulcer, duodenal ulcer, reflux esophagitis and gastritis). In addition, they can also be used for the treatment of other gastrointestinal disorders where a cytoprotectant and/or anti-gastric secretion effect is desired (e.g., in patients with gastrinomas, in patients with acute upper gastrointestinal hemorrhage, and in patients with a history of chronic and excessive alcohol consumption).
EP 652.872-A describes the magnesium salt of S-omeprazole, the formula of which is included below, and indicates that it possesses pharmacokinetic and metabolic properties that give it an improved therapeutic profile. There are other documents that describe different solid forms of magnesium salt of S-omeprazole. EP 984.957-A describes a trihydrate form of magnesium salt of S-omeprazole. WO 04/20436 describes a hydrate of magnesium salt of S-omeprazole in amorphous solid form. Finally, EP 1.375.497-A describes a magnesium salt of S-omeprazole with a grade of crystallinity of less than 67%
and a magnesium salt of S-omeprazole with an amount of organic solvent of less than 7%.
N N
S N
Mg 2+
The different solid forms of a pharmaceutically active ingredient can have different characteristics, and offer certain advantages, for example with regard to solubility or bioavailability. Thus, the discovery of new solid forms allows for improving the characteristics of the pharmaceutical formulations of the active ingredients, since some forms are more adequate for one type of formulation, and other forms for other different formulations. Furthermore, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferred, hence omeprazole is commercialized, for example, in the form of capsules and vials, and S-omeprazole as gastroresistant tablets. It is hence of interest to have new solid forms of magnesium salt of S-omeprazole.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, it is provided a solid form of the magnesium salt of S-omeprazole having a crystalline structure and characterized by having an X-ray diffractogram that comprises characteristic peaks at approximately 5.9, 6.5, and 7.6 degrees 2 theta at a Cu-Kal radiation l~ =
1.5406 A
without any other significant peak.
Said diffractogram differs from those of other forms of magnesium salt of S-omeprazole known in the state of the art. This new solid form of magnesium salt of S-omeprazole is characterized by exhibiting in the powder X-ray diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 28 ( ), which is shown in the following table:
28 ( ) d (A) Intensity (%) 5.9 15.1 100 6.5 13.6 81 7.6 11.7 90 8.2 r 10.8 40 This form is essentially free of organic solvent, whether it be free or of salvation. By the expression "essentially free of organic solvent" it is understood that it complies with the relevant pharmaceutical specifications for the presence of solvents. By free solvent it is understood that it does not form part of the product's crystalline structure, and by salvation solvent it is understood that it is incorporated into the crystalline structure of the same.
X-ray diffractogram is obtained using a Debye-Scherrer INEL CPS120 geometry diffractometer at a Cu-Kal radiation (a,=1.5406A) and at a power of 40 kV - 30 mA.
According to another aspect, the present invention concerns a pharmaceutical composition characterized by comprising the solid form of the magnesium salt of S-omeprazole as defined above, together with pharmaceutically acceptable excipients or carriers.
Another aspect of the present invention relates to a process for the preparation of the solid form of magnesium salt of S-omeprazole as defined above that comprise the following steps:
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating the organic solvent from the magnesium salt of S-omeprazole obtained.
The process allows obtaining the solid form of magnesium salt of S-omeprazole essentially free of organic solvent.
Another aspect of the invention relates to a preparation process of the magnesium salt of S-omeprazole as defined above, from a methanol-solvated magnesium salt 4a of S-omeprazole characterized by comprising the desolvation of said methanol-solvated magnesium salt of S-omeprazole.
A further aspect of the invention relates to a magnesium salt of S-omeprazole obtained by a preparation process characterized by it comprises the following steps:
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating organic solvent from the magnesium salt of S-omeprazole obtained.
Preferably, the amount of water of the solvent system is between 0,01 and 4 ml/g of the magnesium salt of S-omeprazole starting material. It is more preferred that the amount of water is between 0,01 and 2 ml/g of the magnesium salt of S-omeprazole starting material. More preferred yet is that the amount of water of the solvent system is between 0,01 and 0,5 ml/g of the magnesium salt of S-omeprazole starting material. Even more preferred is that the amount of water of the solvent system is between 0,01 and 0,1 mllg of the magnesium salt of S-omeprazole starting material. The amount of water varies according to the dilution of the solution of the magnesium salt of S-omeprazole in the solvent system used and according to the solvents that 4b form part of said solvent system, and can be added at the beginning or once the crystallization of the product has begun. This last possibility is preferably used when the amounts of water are in the upper range, preferably from 2 ml/g and up of magnesium salt of S-omeprazole.
The isolation of the product can be done by a conventional method such as filtration. In a preferred embodiment the separation of the solvent Is done by suspension of the magnesium salt of S-omeprazole in water, followed by isolation of the magnesium salt of S-omeprazole obtained and subsequent drying. In general, the suspension of the magnesium salt in water is performed at a temperature between 2-30 C and during 30-60 minutes. At higher temperatures the suspension time is less. In another preferred embodiment the separation of the solvent is done by drying at a temperature between 60-120 C.
In one particular embodiment of this preparation process, a cosolvent 5 selected from (Ci-C4)-alkyl esters and acetonitrile is added to the solution of the magnesium salt of S-omeprazole in methanol/water. Preferably, the cosolvent is selected from ethyl acetate or acetonitrile.
The magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent, can also be obtained from a methanol-solvated magnesium salt of S-omeprazole, through a process of desolvation. A
preferred methanol-solvated_magnesium salt of S-omeprazole exhibitis a pattern of peaks in the X-ray diffractogram, expressed in 2 theta units in degrees, 20 ( ), which is shown in the following table:
( ) d (A) Intensity (%) 5.6 15.9 69 6.5 13.7 61 7.3 12.1 100 8.0 11.1 15 10.6 8.4 10 10.8 8.2 11 11.3 7.9 13 12.6 7.0 21 13.3 6.7 10 13.8 6.4 15 14.7 6.0 13 15.3 5.8 10 16.4 5.4 13 16.8 5.3 21 17.5 5.1 26 17.8 5.0 14 18.3 4.9 14 18.8 4.7 15 19.1 4.7 23 19.6 4.5 23 20.1 4.4 18 20.4 4.4 26 21.7 4.1 12 21.9 4.1 13 22.1 4.0 14 23.4 3.8 16 24.2 3.7 16 24.8 3.6 16 25.2 3.5 15 25.3 3.5 15 26.2 3.4 11 27.1 3.3 12 28.3 3.2 9 29.1 3.1 9 29.3 3.1 10 31.7 2.8 10 In a preferred embodiment, the desolvation process is carried out by suspension in water, generally at a temperature between 2-30 C for 30-60 minutes, followed by isolation of the obtained magnesium salt of S-omeprazole and by subsequent drying. In another preferred embodiment the desolvation process is performed by drying at a temperature between 60-120 C.
This methanol-solvated magnesium salt of S-omeprazole that acts as an intermediate for the preparation of the solid form, essentially free of organic solvent of the present invention, can be prepared by a process which comprises the following steps: a) crystallizing said magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water that is equal to or greater than 0,01 mI/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that is obtained in the first step; and c) drying the obtained magnesium salt of S-omeprazole at a temperature less than 60 C. The drying temperature is preferably room temperature.
Preferably, the amount of water of the solvent system is between 0,01 and 4 ml/g of the magnesium salt of S-omeprazole starting material. It is more preferred that the amount of water is between 0,01 and 2 ml/g of the magnesium salt of S-omeprazole starting material. More preferred yet is that the amount of water of the solvent system is between 0,01 and 0,5 ml/g of the magnesium salt of S-omeprazole starting material. Even more preferred is that the amount of water of the solvent system is between 0,01 and 0,1 ml/g of the magnesium salt of S-omeprazole starting material. The amount of water varies according to the dilution of the solution of the magnesium salt of S-omeprazole in the solvent system used and 'according to the solvents that form part of said solvent system, and can be added at the beginning or once the crystallization of the product has begun. This last possibility is preferably used when the amounts of water are in the upper range, preferably from 2 ml/g and up of magnesium salt of S-omeprazole.
In one particular embodiment of this preparation process, a cosolvent selected from the group consisting of (C,-C4)-alkyl esters and acetonitrile is added to the solution of the magnesium salt of S-omeprazole in methanol/water. Preferably, the cosolvent is selected from ethyl acetate or acetonitrile.
The most adequate conditions for carrying out said processes vary depending on the parameters considered by the expert in the art, such as, for example, the concentration of the starting material, temperature, the cosolvent used, and the like. These can be easily determined by said skilled person in the art by routine tests and with the help of the teachings of the examples given in this description.
According to an additional aspect of the present invention, a preparation process is provided that allows for the obtaining of solid forms of the magnesium salt of S-omeprazole that comprises the following steps: a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water that is equal to or greater than 0,01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the prior step;
and c) separating the organic solvent from the obtained magnesium salt of S-omeprazole. Therefore, the present invention also includes any solid form of magnesium salt of S-omeprazole obtainable by this preparation process.
Another aspect of the present invention relates to a pharmaceutical composition that comprises as the active ingredient a therapeutically effective amount of the magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent, together with suitable pharmaceutically acceptable excipients or carriers.
An advantage of the solid forms of the present invention is that they have a high stability and physico-mechanical properties that allow for good manipulation for the preparation of solid pharmaceutical formulations. Another advantage of the solid forms of the present invention lies in the fact that they are obtained with high yields and elevated richness, that is, with a greater than 99% purity and with levels of sulphone and N-oxide sulphone -common impurities in the synthesis of prazoles that are difficult to eliminate-significantly inferior to the beginning levels, staying below 0.10%. Likewise they are obtained with an elevated optical purity, that is, with an enantiomeric excess (e.e.) equal to or greater than 99%, even when the starting material is an optically contaminated magnesium salt of S-omeprazole. Furthermore, the solid forms of the present invention have another additional advantage, given that their preparation process is reproducible and robust, and, therefore, easily industrializable.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I shows the X-ray diffraction spectrum of the magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent.
EXAMPLES
Example 1. Preparation of a new solid form of the methanol-solvated magnesium salt of S-omeprazole 20 g of magnesium salt of S-omeprazole (90.6% ee; Karl-Fischer: 2.3%) were dissolved in 60 ml of methanol at room temperature. 300 ml of acetonitrile were added. The solid in suspension was filtered and dried at room temperature and at reduced pressure. 17 g of the title compound were 5 obtained (85% of yield; 99.3% ee; 4.3% p/p of methanol by gas chromatography).
Example 2. Preparation of a new solid form of magnesium salt of S-omeprazole, essentially free of organic solvent 5.0 g of the magnesium salt of S-omeprazole obtained in Example 1 were dried at 70 C and at reduced pressure and 4.9 g of the title compound were obtained. The X-ray diffraction analysis gave the diffractogram shown in FIG.
1.
Example 3. Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 10.0 g of the magnesium salt of S-omeprazole, obtained according to Example 1 from a magnesium salt of S-omeprazole of a richness of 97.7% a/a (N-oxide sulphone impurity: 0.6% a/a and sulphone impurity: 0.4% a/a), were suspended in 50 ml of water. It was left stirring for about 45 minutes at room temperature and then the solid in suspension was filtered. It was dried at 50 C and at reduced pressure. 9.5 g of the title compound were obtained (95%
of yield; richness: 99.7% a/a, N-oxide sulphone impurity: 0.02% a/a; sulphone impurity: 0.05% a/a). The X-ray diffraction analysis gave a diffractogram equal to the one shown in FIG. 1.
Example 4: Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 15.0 g of a magnesium salt of S-omeprazole (90.6% ee; Karl-Fischer: 9.2%) were dissolved in 45 ml of methanol at room temperature. 270 ml of ethyl acetate were added. It was left stirring until the appearance of a solid in suspension. The solid was filtered and dried at 90 C and at reduced pressure. 12.8 g of magnesium salt of S-omeprazole (85% of yield, 99.2% ee) were obtained, which gives an X-ray diffractogram equal to that shown in FIG.
1.
Example 5: Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 2.0 g of the magnesium salt of S-omeprazole (Karl-Fischer: 2.3%) were dissolved in 6 ml of methanol. It was left stirring until the appearance of a solid in suspension. It was filtered, and dried at 70 C and at reduced pressure. 1.2 g of magnesium salt of S-omeprazole (60% of yield) were obtained, which gives an X-ray diffractogram equal to that shown in FIG. 1.
Example 6: Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 20.0 g of the magnesium salt of S-omeprazole (Karl-Fischer: 9.7%) were dissolved in 100 ml of methanol. 300 ml of acetonitrile and 40 ml of water were added. The solid in suspension was filtered and dried at 70 C and reduced pressure. 12.7 g of magnesium salt of S-omeprazole (64% of yield) were obtained, which gives an X-ray diffractogram equal to that shown in FIG.
1.
According to another aspect, the present invention concerns a pharmaceutical composition characterized by comprising the solid form of the magnesium salt of S-omeprazole as defined above, together with pharmaceutically acceptable excipients or carriers.
Another aspect of the present invention relates to a process for the preparation of the solid form of magnesium salt of S-omeprazole as defined above that comprise the following steps:
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating the organic solvent from the magnesium salt of S-omeprazole obtained.
The process allows obtaining the solid form of magnesium salt of S-omeprazole essentially free of organic solvent.
Another aspect of the invention relates to a preparation process of the magnesium salt of S-omeprazole as defined above, from a methanol-solvated magnesium salt 4a of S-omeprazole characterized by comprising the desolvation of said methanol-solvated magnesium salt of S-omeprazole.
A further aspect of the invention relates to a magnesium salt of S-omeprazole obtained by a preparation process characterized by it comprises the following steps:
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating organic solvent from the magnesium salt of S-omeprazole obtained.
Preferably, the amount of water of the solvent system is between 0,01 and 4 ml/g of the magnesium salt of S-omeprazole starting material. It is more preferred that the amount of water is between 0,01 and 2 ml/g of the magnesium salt of S-omeprazole starting material. More preferred yet is that the amount of water of the solvent system is between 0,01 and 0,5 ml/g of the magnesium salt of S-omeprazole starting material. Even more preferred is that the amount of water of the solvent system is between 0,01 and 0,1 mllg of the magnesium salt of S-omeprazole starting material. The amount of water varies according to the dilution of the solution of the magnesium salt of S-omeprazole in the solvent system used and according to the solvents that 4b form part of said solvent system, and can be added at the beginning or once the crystallization of the product has begun. This last possibility is preferably used when the amounts of water are in the upper range, preferably from 2 ml/g and up of magnesium salt of S-omeprazole.
The isolation of the product can be done by a conventional method such as filtration. In a preferred embodiment the separation of the solvent Is done by suspension of the magnesium salt of S-omeprazole in water, followed by isolation of the magnesium salt of S-omeprazole obtained and subsequent drying. In general, the suspension of the magnesium salt in water is performed at a temperature between 2-30 C and during 30-60 minutes. At higher temperatures the suspension time is less. In another preferred embodiment the separation of the solvent is done by drying at a temperature between 60-120 C.
In one particular embodiment of this preparation process, a cosolvent 5 selected from (Ci-C4)-alkyl esters and acetonitrile is added to the solution of the magnesium salt of S-omeprazole in methanol/water. Preferably, the cosolvent is selected from ethyl acetate or acetonitrile.
The magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent, can also be obtained from a methanol-solvated magnesium salt of S-omeprazole, through a process of desolvation. A
preferred methanol-solvated_magnesium salt of S-omeprazole exhibitis a pattern of peaks in the X-ray diffractogram, expressed in 2 theta units in degrees, 20 ( ), which is shown in the following table:
( ) d (A) Intensity (%) 5.6 15.9 69 6.5 13.7 61 7.3 12.1 100 8.0 11.1 15 10.6 8.4 10 10.8 8.2 11 11.3 7.9 13 12.6 7.0 21 13.3 6.7 10 13.8 6.4 15 14.7 6.0 13 15.3 5.8 10 16.4 5.4 13 16.8 5.3 21 17.5 5.1 26 17.8 5.0 14 18.3 4.9 14 18.8 4.7 15 19.1 4.7 23 19.6 4.5 23 20.1 4.4 18 20.4 4.4 26 21.7 4.1 12 21.9 4.1 13 22.1 4.0 14 23.4 3.8 16 24.2 3.7 16 24.8 3.6 16 25.2 3.5 15 25.3 3.5 15 26.2 3.4 11 27.1 3.3 12 28.3 3.2 9 29.1 3.1 9 29.3 3.1 10 31.7 2.8 10 In a preferred embodiment, the desolvation process is carried out by suspension in water, generally at a temperature between 2-30 C for 30-60 minutes, followed by isolation of the obtained magnesium salt of S-omeprazole and by subsequent drying. In another preferred embodiment the desolvation process is performed by drying at a temperature between 60-120 C.
This methanol-solvated magnesium salt of S-omeprazole that acts as an intermediate for the preparation of the solid form, essentially free of organic solvent of the present invention, can be prepared by a process which comprises the following steps: a) crystallizing said magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water that is equal to or greater than 0,01 mI/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that is obtained in the first step; and c) drying the obtained magnesium salt of S-omeprazole at a temperature less than 60 C. The drying temperature is preferably room temperature.
Preferably, the amount of water of the solvent system is between 0,01 and 4 ml/g of the magnesium salt of S-omeprazole starting material. It is more preferred that the amount of water is between 0,01 and 2 ml/g of the magnesium salt of S-omeprazole starting material. More preferred yet is that the amount of water of the solvent system is between 0,01 and 0,5 ml/g of the magnesium salt of S-omeprazole starting material. Even more preferred is that the amount of water of the solvent system is between 0,01 and 0,1 ml/g of the magnesium salt of S-omeprazole starting material. The amount of water varies according to the dilution of the solution of the magnesium salt of S-omeprazole in the solvent system used and 'according to the solvents that form part of said solvent system, and can be added at the beginning or once the crystallization of the product has begun. This last possibility is preferably used when the amounts of water are in the upper range, preferably from 2 ml/g and up of magnesium salt of S-omeprazole.
In one particular embodiment of this preparation process, a cosolvent selected from the group consisting of (C,-C4)-alkyl esters and acetonitrile is added to the solution of the magnesium salt of S-omeprazole in methanol/water. Preferably, the cosolvent is selected from ethyl acetate or acetonitrile.
The most adequate conditions for carrying out said processes vary depending on the parameters considered by the expert in the art, such as, for example, the concentration of the starting material, temperature, the cosolvent used, and the like. These can be easily determined by said skilled person in the art by routine tests and with the help of the teachings of the examples given in this description.
According to an additional aspect of the present invention, a preparation process is provided that allows for the obtaining of solid forms of the magnesium salt of S-omeprazole that comprises the following steps: a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water that is equal to or greater than 0,01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the prior step;
and c) separating the organic solvent from the obtained magnesium salt of S-omeprazole. Therefore, the present invention also includes any solid form of magnesium salt of S-omeprazole obtainable by this preparation process.
Another aspect of the present invention relates to a pharmaceutical composition that comprises as the active ingredient a therapeutically effective amount of the magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent, together with suitable pharmaceutically acceptable excipients or carriers.
An advantage of the solid forms of the present invention is that they have a high stability and physico-mechanical properties that allow for good manipulation for the preparation of solid pharmaceutical formulations. Another advantage of the solid forms of the present invention lies in the fact that they are obtained with high yields and elevated richness, that is, with a greater than 99% purity and with levels of sulphone and N-oxide sulphone -common impurities in the synthesis of prazoles that are difficult to eliminate-significantly inferior to the beginning levels, staying below 0.10%. Likewise they are obtained with an elevated optical purity, that is, with an enantiomeric excess (e.e.) equal to or greater than 99%, even when the starting material is an optically contaminated magnesium salt of S-omeprazole. Furthermore, the solid forms of the present invention have another additional advantage, given that their preparation process is reproducible and robust, and, therefore, easily industrializable.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I shows the X-ray diffraction spectrum of the magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent.
EXAMPLES
Example 1. Preparation of a new solid form of the methanol-solvated magnesium salt of S-omeprazole 20 g of magnesium salt of S-omeprazole (90.6% ee; Karl-Fischer: 2.3%) were dissolved in 60 ml of methanol at room temperature. 300 ml of acetonitrile were added. The solid in suspension was filtered and dried at room temperature and at reduced pressure. 17 g of the title compound were 5 obtained (85% of yield; 99.3% ee; 4.3% p/p of methanol by gas chromatography).
Example 2. Preparation of a new solid form of magnesium salt of S-omeprazole, essentially free of organic solvent 5.0 g of the magnesium salt of S-omeprazole obtained in Example 1 were dried at 70 C and at reduced pressure and 4.9 g of the title compound were obtained. The X-ray diffraction analysis gave the diffractogram shown in FIG.
1.
Example 3. Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 10.0 g of the magnesium salt of S-omeprazole, obtained according to Example 1 from a magnesium salt of S-omeprazole of a richness of 97.7% a/a (N-oxide sulphone impurity: 0.6% a/a and sulphone impurity: 0.4% a/a), were suspended in 50 ml of water. It was left stirring for about 45 minutes at room temperature and then the solid in suspension was filtered. It was dried at 50 C and at reduced pressure. 9.5 g of the title compound were obtained (95%
of yield; richness: 99.7% a/a, N-oxide sulphone impurity: 0.02% a/a; sulphone impurity: 0.05% a/a). The X-ray diffraction analysis gave a diffractogram equal to the one shown in FIG. 1.
Example 4: Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 15.0 g of a magnesium salt of S-omeprazole (90.6% ee; Karl-Fischer: 9.2%) were dissolved in 45 ml of methanol at room temperature. 270 ml of ethyl acetate were added. It was left stirring until the appearance of a solid in suspension. The solid was filtered and dried at 90 C and at reduced pressure. 12.8 g of magnesium salt of S-omeprazole (85% of yield, 99.2% ee) were obtained, which gives an X-ray diffractogram equal to that shown in FIG.
1.
Example 5: Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 2.0 g of the magnesium salt of S-omeprazole (Karl-Fischer: 2.3%) were dissolved in 6 ml of methanol. It was left stirring until the appearance of a solid in suspension. It was filtered, and dried at 70 C and at reduced pressure. 1.2 g of magnesium salt of S-omeprazole (60% of yield) were obtained, which gives an X-ray diffractogram equal to that shown in FIG. 1.
Example 6: Preparation of a new solid form of the magnesium salt of S-omeprazole, essentially free of organic solvent 20.0 g of the magnesium salt of S-omeprazole (Karl-Fischer: 9.7%) were dissolved in 100 ml of methanol. 300 ml of acetonitrile and 40 ml of water were added. The solid in suspension was filtered and dried at 70 C and reduced pressure. 12.7 g of magnesium salt of S-omeprazole (64% of yield) were obtained, which gives an X-ray diffractogram equal to that shown in FIG.
1.
Claims (27)
1. Solid form of the magnesium salt of S-omeprazole having a crystalline structure and characterized by having an X-ray diffractogram that comprises characteristic peaks at approximately 5.9, 6.5, and 7.6 degrees 2 theta at a Cu-Ka1 radiation .lambda. = 1.5406 .ANG. without any other significant peak.
2. Solid form of the magnesium salt of S-omeprazole according to claim 1, characterized by an X-ray diffractogram that further comprises a peak at 8.2 degrees 2 theta at a Cu-Ka1 radiation .lambda. = 1.5406 .ANG..
3. Preparation process of the solid form of magnesium salt of S-omeprazole defined in any one of claims 1 and 2, characterized by comprising the following steps:
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating the organic solvent from the magnesium salt of S-omeprazole obtained.
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating the organic solvent from the magnesium salt of S-omeprazole obtained.
4. Process according to claim 3, characterized by the amount of water being comprised between 0.01 and 4 ml/g of the magnesium salt of S-omeprazole starting material.
5. Process according to claim 4, characterized by the amount of water being comprised between 0.01 and 2 ml/g of the magnesium salt of S-omeprazole starting material.
6. Process according to claim 5, characterized by the amount of water being comprised between 0.01 and 0.5 ml/g of the magnesium salt of S-omeprazole starting material.
7. Process according to claim 6, characterized by the amount of water being between 0.01 and 0.1 ml/g of the magnesium salt of S-omeprazole starting material.
8. Process according to any one of claims 3 to 7, characterized by the separation of the organic solvent comprises the steps of suspension of the magnesium salt of S-omeprazole in water, isolation of the obtained magnesium salt of S-omeprazole and subsequent drying.
9. Process according to any one of claims 3 to 7, characterized by the separation of the solvent is carried out by drying at a temperature comprised between 60-120 °C.
10. Process according to any one of claims 3 to 9, characterized by it comprises adding a cosolvent selected from the group consisting of (C1-C4)-alkyl esters and acetonitrile to the solution of the magnesium salt of S-omeprazole in methanol/water.
11. Process according to claim 10, characterized by the cosolvent being ethyl acetate.
12. Process according to claim 10, characterized by the cosolvent being acetonitrile.
13. Preparation process of the magnesium salt of S-omeprazole defined in any one of claims 1 and 2, from a methanol-solvated magnesium salt of S-omeprazole characterized by comprising the desolvation of said methanol-solvated magnesium salt of S-omeprazole.
14. Process according to claim 13, wherein the methanol-solvated magnesium salt of S-omeprazole have an X-ray diffractogram that comprises characteristic peaks at approximately 5.6, 6.5, 7.3, 8.0; 10.8; 12.6; 13.8;
14.7; 16.8; 17.5; 17.8; 19.1; 19.6; 20.1; 20.4; 22.1; 23.4; 24.2 ; 25.2 degrees 2 theta.
14.7; 16.8; 17.5; 17.8; 19.1; 19.6; 20.1; 20.4; 22.1; 23.4; 24.2 ; 25.2 degrees 2 theta.
15. Process according to any one of claims 13 and 14, characterized by the desolvation comprises the steps of suspension of the magnesium salt of S-omeprazole in water, isolation of the magnesium salt of S-omeprazole obtained and subsequent drying.
16. Process according to any one of claims 13 and 14, characterized by the desolvation being carried out by drying at a temperature comprised between 60-120 °C.
17. Process according to any one of claims 13 to 16, wherein the solid form of methanol-solvated magnesium salt of S-omeprazole is previously prepared by a process comprising the following steps:
a) crystallizing said magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) drying the magnesium salt of S-omeprazole obtained at a temperature less than 60°C.
a) crystallizing said magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) drying the magnesium salt of S-omeprazole obtained at a temperature less than 60°C.
18. Process according to claim 17, characterized by the amount of water being comprised between 0.01 and 4 ml/g of the magnesium salt of S-omeprazole starting material.
19. Process according to claim 18, characterized by the amount of water being comprised between 0.01 and 2 ml/g of the magnesium salt of S-omeprazole starting material.
20. Process according to claim 19, characterized by the amount of water being comprised between 0.01 and 0.5 ml/g of the magnesium salt of S-omeprazole starting material.
21. Process according to claim 20, characterized by the amount of water being comprised between 0.01 and 0.1 ml/g of the magnesium salt of S-omeprazole starting material.
22. Process according to any one of claims 17 to 20, characterized by the drying temperature being room temperature.
23. Process according to any one of claims 17 to 22, characterized by it comprises adding a cosolvent selected from the group consisting of (C1-C4)-alkyl esters and acetonitrile to the solution of the magnesium salt of S-omeprazole in methanol/water.
24. Process according to claim 23, characterized by the cosolvent being ethyl acetate.
25. Process according to claim 23, characterized by the cosolvent being acetonitrile.
26. Magnesium salt of S-omeprazole obtained by a preparation process characterized by it comprises the following steps:
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating organic solvent from the magnesium salt of S-omeprazole obtained.
a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material;
b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating organic solvent from the magnesium salt of S-omeprazole obtained.
27. A pharmaceutical composition characterized by comprising the solid form of the magnesium salt of S-omeprazole as defined in any one of claims 1 and 2, together with pharmaceutically acceptable excipients or carriers.
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| ES200401729A ES2246149B1 (en) | 2004-07-02 | 2004-07-02 | SOLID FORMS OF S-OMEPRAZOL MAGNETIC SALT AND PROCEDURES FOR PREPARATION. |
| PCT/EP2005/053062 WO2006003163A1 (en) | 2004-07-02 | 2005-06-29 | Solid forms of the magnesium salt of (s)-omeprazole and processes for their preparation |
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| FR2920428B1 (en) * | 2007-08-29 | 2012-06-15 | Univ Rouen | PROCESS FOR DEDOLDING SALTS OF OMEPRAZOLE |
| EP2147918A1 (en) * | 2008-07-21 | 2010-01-27 | LEK Pharmaceuticals D.D. | Process for the preparation of S-omeprazole magnesium in a stable form |
| CN103044400A (en) * | 2012-12-21 | 2013-04-17 | 北京华禧联合科技发展有限公司 | Esomeprazole magnesium salt and preparation method thereof |
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| US20030212274A1 (en) * | 2000-05-15 | 2003-11-13 | Bakthavathsalan Vijayaraghavan | Novel amorphous form of omeprazole salts |
| CA2386716C (en) * | 2002-05-17 | 2012-07-24 | Bernard Charles Sherman | Magnesium salt of s-omeprazole |
| US7271182B2 (en) * | 2000-08-04 | 2007-09-18 | Takeda Pharmaceutical Company Limited | Salts of benzimidazole compound and use thereof |
| SI20875A (en) * | 2001-04-25 | 2002-10-31 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Crystal form of omeprazole |
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| US6894066B2 (en) * | 2002-05-09 | 2005-05-17 | Bernard Charles Sherman | Magnesium salt of S-omeprazole |
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| EP1556043A1 (en) | 2002-10-22 | 2005-07-27 | Ranbaxy Laboratories, Ltd. | Amorphous form of esomeprazole salts |
| WO2004046134A2 (en) * | 2002-11-18 | 2004-06-03 | Dr. Reddy's Laboratories Limited | Crystalline form ii of esomeprazole magnesium trihydrate and process for its preparation |
| WO2004089935A1 (en) * | 2003-04-10 | 2004-10-21 | Hetero Drugs Limitd | Novel crystalline forms of s-omeprazole magnesium |
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| CN1976923B (en) | 2011-08-24 |
| DK1765807T3 (en) | 2009-06-08 |
| DE602005013382D1 (en) | 2009-04-30 |
| NZ552458A (en) | 2010-07-30 |
| CN1976923A (en) | 2007-06-06 |
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| AU2005259205A1 (en) | 2006-01-12 |
| MXPA06014736A (en) | 2007-06-25 |
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| JP2008505160A (en) | 2008-02-21 |
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| US7902370B2 (en) | 2011-03-08 |
| EP1765807B1 (en) | 2009-03-18 |
| CA2570559A1 (en) | 2006-01-12 |
| ATE425975T1 (en) | 2009-04-15 |
| JP2014169302A (en) | 2014-09-18 |
| WO2006003163A1 (en) | 2006-01-12 |
| AU2005259205B2 (en) | 2011-01-27 |
| EP1765807A1 (en) | 2007-03-28 |
| KR101290035B1 (en) | 2013-07-30 |
| PT1765807E (en) | 2009-04-13 |
| ZA200700865B (en) | 2009-09-30 |
| ES2246149A1 (en) | 2006-02-01 |
| NO20070635L (en) | 2007-03-20 |
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