JP5017274B2 - S-omeprazole strontium salt or hydrate thereof, process for producing the same, and pharmaceutical composition containing the same - Google Patents

Description

  The present invention relates to an S-omeprazole strontium salt or hydrate thereof having improved optical purity, thermal stability, water solubility and non-hygroscopicity, a method for producing the same, and a pharmaceutical composition containing the same.

Omeprazole of the following formula II, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole is H + / K + -ATPase or proton pump inhibitor And represents the effect of inhibiting gastric acid secretion and protecting gastrointestinal cells (see European Patent No. 0,005,129), Losec® (Losec®) and Prilosec® It is marketed as a drug for preventing and treating gastric acid related diseases under the trade name (Prilose (registered trademark)). Omeprazole, which is a structurally neutral molecule, is thermally unstable and chemically unstable under conditions below the neutral pH value, so it needs to be formulated into an enteric-coated preparation.

  U.S. Pat. No. 4,738,974 discloses salts and hydrates of omeprazole, such as lithium, sodium, potassium, magnesium, calcium, titanium, ammonium, and guanidine salts. The salt of omeprazole as described above is more stable than the neutral form of omeprazole.

Omeprazole is a racemic mixture composed of equal amounts of R- and S-enantiomers. Since the R-isomer tends to be metabolized to inactive metabolites and the variation between individuals is greater, the S-omeprazole of formula (III) has gastrointestinal ulcers, duodenal ulcers, compared to the R-isomer, It is more suitable for treatment of gastroesophageal reflux disease and the like. Accordingly, various attempts have been made to develop methods for producing pure S-omeprazole substantially free of R-omeprazole.

  For example, a method of optical resolution of racemic omeprazole by high performance liquid chromatography is disclosed in a literature [Erlandsson et al., Journal of Chromatography, 535, 305-319 (1990)], and International Publication No. WO1992 / 08716 A method for producing each enantiomer of omeprazole is disclosed. However, the optically isolated S-omeprazole product is not recognized as a stable solid with pharmaceutically sought purity. US Pat. No. 6,162,816 discloses a crystalline form of S-omeprazole, which is also not sufficiently stable.

US Pat. Nos. 5,714,504 and 5,693,818 disclose salts such as lithium, sodium, potassium, magnesium, calcium and ammonium salts of S-omeprazole and their hydrates. Yes. US Pat. Nos. 6,369,085 and 6,511,996 include not only the crystalline potassium salt of S-omeprazole, but also magnesium salts dihydrates and trihydrates, The shape is disclosed. The salt of S-omeprazole as described above has excellent stability compared to S-omeprazole itself.
Currently, the sodium, potassium and magnesium salts of S-omeprazole, or hydrates thereof, are used for the prevention and treatment of ulcers under the trade name Nexium (registered trademark) (Nexium (registered trademark), manufactured by AstraZeneca Actevolag). It is marketed as a pharmaceutical agent. Sodium and potassium salts are suitable as injections because of their good water solubility, but they are not suitable for oral administration because they are hygroscopic. On the other hand, trihydrate of non-hygroscopic S-omeprazole magnesium salt is preferable in terms of oral administration of omeprazole solid, but it is difficult to achieve pharmacologically required optical purity. Therefore, in order to achieve satisfactory therapeutic efficacy, the salt of S-omeprazole magnesium trihydrate is salt-exchanged with a pre-made optically pure sodium or potassium salt (ref. [H. Cotton et al., Tetrahedron Asymmetry. 11, 3819-3825 (2000)]).
Internationally published patents WO 2004/099182, WO 2005/011692, WO 2003/074514, WO 2005/023796 and WO 2005/023797 include barium salts, zinc salts, t-butylamine salts of S-omeprazole, Adamantaneamine salts and α-methylcyclohexanemethaneamine salts are disclosed, and these salts have the above-mentioned water solubility, crystallinity, non-hygroscopicity, stability and optical purity. In terms of surface, it is not superior to the trihydrate of S-omeprazole magnesium salt.

  Therefore, in view of such conventional techniques, there has been a demand for development of an improved salt of S-omeprazole suitable for both oral administration and injection administration.

  Strontium is a Group IIA alkaline earth metal that is naturally divided into four types: 88Sr (82.58%), 87Sr (7.00%), 86Sr (9.86%) and 84Sr (0.56%). It exists in the form of an isotope. Strontium has also been reported to have no problems with stability when administered to rats at a dose of 633 mg / kg / day (PJ Marie et al., Mineral & Electric Metabolism, 11, 5 -13 (1985)]). It is known that humans ingest an average of about 3.3 mg of strontium per day based on an adult weighing 70 kg (Report of Toxicological Profile for Strontium, U.S. Department of Health and Human Services, 2004]). In addition, strontium functions in a complementary manner to calcium in the skeleton work to promote bone formation and suppress the resorption of the skeleton work (reference [SP Nielsen, Bone, 35, 583-588 ( 2004)]). As a typical example of a strontium salt that has been used pharmaceutically, strontium ranelate, which is a salt of strontium and ranelic acid, is known. However, there has never been a weakly acidic benzimidazole derivative or strontium salt containing omeprazole.

  Therefore, as a result of intensive studies to develop a novel salt of S-omeprazole, the present inventors have found that the optical purity of S-omeprazole strontium salt or its hydrate is improved as compared with the existing S-omeprazole salt. It has been found that it has thermal stability, non-hygroscopicity and water solubility, and has achieved the present invention.

European Patent No. 0,005,129 U.S. Pat. No. 4,738,974 International Patent Publication WO 1992/08716 US Pat. No. 6,162,816 US Pat. No. 5,714,504 US Pat. No. 5,693,818 US Pat. No. 6,369,085 US Pat. No. 6,511,996 International Patent Publication WO 2004/099182 International Patent Publication WO 2005/011692 International Patent Publication WO 2003/077454 International Patent Publication No. WO 2005/023796 International Patent Publication WO 2005/023797 Errandsson et al., Journal of Chromatography, 535, 305-319 (1990). H. Cotton et al., Tetrahedron Asymmetry, 11, 3819-3825 (2000). P. J. et al. Marie et al., Mineral & Electric Metabolism, 11, 5-13 (1985). Report of Toxicological Profile for Strontium, U.S.A. S. Department of Health and Human Services, 2004 S. P. Nielsen, Bone, 35, 583-588 (2004)

  Therefore, the present invention has been made in view of the conventional problems as described above, and an object thereof is to provide an S-omeprazole strontium salt or a hydrate thereof and a method for producing the same.

In order to achieve the object of the present invention, according to one embodiment of the present invention, there is provided an S-omeprazole strontium salt of the following formula (I) or a hydrate thereof:

According to another embodiment of the present invention, a strontium hydroxide or other strontium salt is added to a neutral or basic solution containing S-omeprazole, and the resulting mixture is stirred. ) S-omeprazole strontium salt or a hydrate thereof.
According to yet another embodiment of the present invention, for the prevention or treatment of gastric acid related diseases, comprising as an active ingredient an S-omeprazole strontium salt of formula (I) or a hydrate thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition is provided.

  The S-omeprazole strontium salt of formula (I) or its hydrate according to the present invention is a novel salt of S-omeprazole, which is optically pure and thermally stable compared to existing magnesium salts. Also, the water solubility is increased while it is more non-hygroscopic.

  The S-omeprazole strontium salt of the present invention is obtained by binding two molecules of S-omeprazole to a divalent strontium ion, and one or more water molecules can be bound thereto. Such S-omeprazole strontium salts or hydrates thereof can exist in an amorphous form or a crystalline form, preferably in crystalline form, which are powder X-ray diffraction analysis or This can be confirmed using a differential scanning calorimeter.

According to a preferred embodiment of the present invention there is provided a crystalline tetrahydrate of S-omeprazole strontium salt of formula (IV):

  The crystalline tetrahydrate of the S-omeprazole strontium salt has a peak having an I / Io value of 3% or more (I: intensity of each peak, Io: intensity of the largest peak) in a powder X-ray diffraction spectrum. .6, 11.1, 13.5, 14.8, 16.2, 17.5, 18.0, 20.1, 20.4, 21.2, 22.2, 24.5, 25.2 26.3, 27.5, 29.8, 31.1, 32.8 and 36.5 (2θ ± 0.2) (see FIG. 1). In addition, the crystalline tetrahydrate has an endothermic peak (about 179 J / g) having a maximum point of about 118 ° C. starting from about 100 ° C. in a differential scanning calorimeter analysis (5 ° C./min), An exothermic peak (about 451 J / g) having a maximum of about 211 ° C. starting from about 203 ° C. is shown (see FIG. 2). In fact, the melting point of the crystalline tetrahydrate is observed to be about 202 ° C., and the water content measured by a loss-on-drying measuring device is 8.0 to 9.5%. This is 8.49% of the theoretical value and falls within the range of experimental error.

  The present invention also relates to a partial or heterogenous crystal form of S-omeprazole strontium salt or a hydrate thereof.

  Therefore, according to another embodiment of the present invention, an S-omeprazole strontium salt in which a peak having an I / Io value of 100% in a powder X-ray diffraction spectrum appears at a diffraction angle (2θ ± 0.2) of 5.8 Or a hybrid crystal form (see FIG. 3). The crystalline anhydride has no endothermic peak in the analysis with a differential scanning calorimeter (5 ° C./min), but exhibits an exothermic peak having a maximum of about 197 ° C. starting from about 186 ° C. (see FIG. 4). ). It was observed that the crystalline anhydride decomposes at temperatures above about 196 ° C.

  According to still another aspect of the present invention, an S-omeprazole strontium salt in which a peak having an I / Io value of 100% in a powder X-ray diffraction spectrum appears at a diffraction angle (2θ ± 0.2) of 25.2. Or a hybrid crystal form (see FIG. 5). The crystalline hydrate was analyzed by a differential scanning calorimeter (5 ° C./min), with an endothermic peak starting at about 37 ° C. and a maximum point of about 68 ° C., and a maximum point starting from about 161 ° C. Shows an exothermic peak at about 189 ° C. (see FIG. 6). The crystalline hydrate was observed to decompose at temperatures above about 160 ° C.

  According to yet another aspect of the present invention there is provided an amorphous form of the S-omeprazole strontium salt of formula (I), which does not have a significantly characteristic peak in the powder X-ray diffraction spectrum (see FIG. 7). The amorphous form has an endothermic peak starting at about 29 ° C. and having a maximum point of about 56 ° C. in the analysis by a differential scanning calorimeter (5 ° C./min), and a maximum point starting from about 183 ° C. An exothermic peak at about 208 ° C. is shown (see FIG. 8). At this time, it can be seen that a phase transition occurs at about 196 ° C. It was also observed that the amorphous form of S-omeprazole strontium salt was decomposed at a temperature of about 180 ° C. or higher.

  The S-omeprazole strontium salt of formula I according to the present invention or a hydrate thereof has long-term storage conditions (temperature of 25 ° C. and 60% relative humidity), acceleration conditions (temperature of 40 ° C. and 75% relative humidity), and Under severe conditions (temperature of 60 ° C. and relative humidity of 75%), the initial water content, purity and crystallinity are maintained even after standing for 4 weeks or more in a closed state. In particular, the crystalline tetrahydrate of S-omeprazole strontium salt (Crystal Form A) is non-hygroscopic and after exposure to temperatures of 25 ° C. to 40 ° C. and relative humidity of 40% to 90% for more than 2 weeks. Maintain the initial water content.

In addition, the S-omeprazole strontium salt of the formula (I) or a hydrate thereof is pharmaceutically advantageous compared to other salts of S-omeprazole in terms of water solubility. For example, the water solubility of the S-omeprazole strontium salt of the present invention is about 17.6 mg / ml, which is more than about 10 times the water decomposition of the trihydrate of S-omeprazole magnesium salt.
According to the present invention, the S-omeprazole strontium salt of formula (I) or a hydrate thereof is added to a neutral or basic solution containing S-omeprazole by adding strontium hydroxide or other strontium salt, if necessary Manufactured by converting the crystal structure.
Specifically, the crystalline tetrahydrate of S-omeprazole strontium salt of formula (IV) is formed by adding strontium hydroxide to a neutral solution containing S-omeprazole of formula (III) below. After stirring the resulting mixture until it can be produced, the crystals produced can be filtered and dried in the usual way:

  At this time, the neutral solution is methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, tetrahydrofuran and acetone, preferably an organic solvent selected from methanol and acetone, or any one of the organic solvents and water. It means a solution prepared by dissolving or suspending S-omeprazole in a mixed solvent. At this time, the mixing ratio of the mixed solvent is preferably 99: 1 to 50:50 by volume. In the present invention, strontium hydroxide is preferably used in an amount of 0.5 to 0.75 molar equivalents relative to 1 molar equivalent of S-omeprazole of the formula (III). The stirring step is performed for 30 minutes to 24 hours within a temperature range of 0 ° C. to the boiling point of the solvent.

The crystalline tetrahydrate of S-omeprazole strontium salt was obtained until a crystal was formed by adding a reactive strontium salt to a basic solution containing S-omeprazole of formula (III) and a base. After stirring the mixture, the produced crystals can be filtered and dried by a conventional method to produce the crystals. Said reactive strontium salt is selected from strontium chloride, strontium bromide, strontium sulfate, strontium nitrate, strontium perchlorate, strontium acetate, strontium carbonate and strontium oxalate, preferably strontium chloride and strontium acetate. At this time, the basic solution is methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, tetrahydrofuran and acetone, preferably an organic solvent selected from methanol and acetone, or any one of the organic solvents and water. A solution prepared by dissolving or suspending S-omeprazole in a mixed solvent of 1), wherein the mixing ratio of the mixed solvent is preferably 99: 1 to 50:50 in volume ratio. The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine and triethylamine, preferably sodium hydroxide and potassium hydroxide. In this embodiment, the base is preferably used in an amount of 1 to 3 molar equivalents relative to 1 molar equivalent of S-omeprazole of the formula (III), and the reactive strontium salt is used in an amount of 0.1% relative to 1 molar equivalent of the base. It is preferable to use at 5-0.75 molar equivalent. The stirring step is performed for 30 minutes to 24 hours within a temperature range of 0 ° C. to the boiling point of the solvent.
The neutral or basic solution is preferably used in a volume ratio of 1 to 20 ml, preferably 3 to 10 ml, based on 1 g of S-omeprazole of the formula (III).

According to the method of the present invention, a salt of S-omeprazole having high optical purity can be produced even when optically impure S-omeprazole is used as a starting material.
On the other hand, a portion of S-omeprazole strontium salt or a mixed crystalline anhydride can be prepared by drying crystalline tetrahydrate of S-omeprazole strontium salt at 80 to 130 ° C. for 30 minutes to 24 hours, If necessary, this drying process can be carried out under reduced pressure.

  The S-omeprazole strontium salt portion or mixed crystalline hydrate is prepared by suspending the crystalline anhydride of the S-omeprazole strontium salt in water and stirring at room temperature for 1 to 24 hours. It can manufacture by filtering on the conditions of and drying.

  The amorphous form of S-omeprazole strontium salt can be obtained by dissolving the crystalline tetrahydrate of S-omeprazole strontium salt in an organic solvent such as acetone and then evaporating the resulting solution under reduced pressure or spray drying. It can be produced by removing the organic solvent.

  The S-omeprazole strontium salt of formula (I) of the present invention produced as described above or a hydrate thereof has a high optical purity of 99% ee or more, non-hygroscopicity, excellent stability against moisture and heat. Therefore, it can be used pharmacologically for the prevention and treatment of gastric acid related diseases such as gastroesophageal reflux disease caused by excessive gastric acid, gastrointestinal inflammation or gastrointestinal ulcer.

  Therefore, the present invention provides a pharmaceutical composition comprising an S-omeprazole strontium salt of formula (I) or a hydrate thereof as an active ingredient.

  The pharmaceutical composition according to the present invention can be administered in various forms such as oral, rectal and injection, and the most preferred form is oral administration.

  The pharmaceutical composition of the present invention can be formulated in the form of tablets, capsules, pills and the like for oral administration, and can be mixed with a pharmaceutically acceptable carrier, diluent or excipient. it can. Suitable carriers, diluents and excipients include, for example, excipients such as starch, sugar and mannitol; fillers or extenders such as calcium phosphate and silica derivatives; celluloses such as carboxymethylcellulose or hydroxypropylcellulose Binders such as derivatives, gelatin, alginate, and polyvinylpyrrolidone; lubricants such as talc, magnesium or calcium stearate, hydrogenated castor oil, and solid phase polyethylene glycol; povidone, croscarmellose sodium, and crospovidone Disintegrants; and surfactants such as polysorbate, cetyl alcohol, glycerol monostearate, and the like. In addition, various pharmaceutical compositions containing a specific amount of an active ingredient without an additive such as the carrier, diluent or excipient or together with the additive can be produced by a known ordinary method ( Literature [See Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 19th Edition, 1995].

  The sterile injectable composition of the present invention can be produced by directly filling a vial with the aseptic S-omeprazole strontium salt of the present invention or a hydrate thereof and a pharmaceutically acceptable carrier, Alternatively, the S-omeprazole strontium salt of the present invention or a hydrate thereof and a pharmaceutically acceptable carrier are dissolved in sterilized water, and then lyophilized to fill the obtained amorphous powder into a vial. Which can be prepared by adding sterile water just before administration.

  In a preferred embodiment of the invention, the pharmaceutical composition for oral administration contains S-omeprazole strontium salt of formula I in an amount of 0.1 to 95%, preferably 1 to 70% by weight relative to the total weight of the composition. can do.

  The S-omeprazole strontium salt of formula (I) or a hydrate thereof is once in an amount of about 0.5 to 500 mg / kg body weight, preferably 5 to 100 mg / kg body weight per day for mammals including humans. Or it can be administered in several divided doses.

  Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention and do not limit the scope of the present invention.

The analysis conditions of the high performance liquid chromatography (HPLC) used in the following examples are as follows, and the unit “% ee” described below means an enantiomeric excess (ee). .
Condition A: For measuring the content of omeprazole- Column: Zorbax C8 XDB, 5 μm (150 mm × 4.6 mm)
-Detection wavelength: 281 nm
-Flow rate: 1.0 ml / min-Elution conditions: Na2HPO4-NaH2PO4 buffer solution / CH3CN = 75/25 (v / v)
Condition B: For optical purity measurement of S-omeprazole strontium salt -Column: Chiral-AGP, 5 μm (150 mm × 4 mm)
-Detection wavelength: 280nm
-Flow rate: 0.8 ml / min-Elution condition: NaH2PO4 buffer solution (pH 6.5) / CH3CN = 10/90 (v / v)

<Production of S-omeprazole strontium salt or hydrate thereof>
Examples 1 to 8: Preparation of crystalline tetrahydrate (crystal form A) of S-omeprazole strontium salt
Example 1
An S-omeprazole (30.0 g, 86.9 mmol) having an optical purity of 95% ee was dissolved in 200 ml of methanol, and a solution of strontium hydroxide octahydrate (13.8 g, 51.9 mmol) dissolved in 100 ml of methanol. After gradually adding, the mixture was stirred at room temperature for 3 hours. The produced solid was filtered, washed with 100 ml of methanol, and dried at 45 ° C. for 12 hours to obtain 33.8 g (yield: 92%) of the title compound as a white crystalline powder.
Melting point: 201-203 ° C
Water content (loss on drying test): 9.0% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.1% (theoretical value of anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.5% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.9% ee
Specific rotation: [α] D20 = −31.1 ° (c = 1.0, acetone)
1H-NMR (DMSO-d6): δ 8.26 (s, 1H), 7.38 (d, 1H), 7.02 (bs, 1H), 6.54 (dd, 1H), 4.58 (d , 2H, J = 13.3), 4.46 (d, 2H, J = 13.4), 3.68 (s, 3H), 3.66 (s, 3H), 2.22 (s, 3H) ), 2.10 (s, 3H)
IR (KBr, cm-1): 3422, 2991, 2831, 2364, 1638, 1611, 1569, 1561, 1476, 1444.4, 1390, 1365, 1271, 1204, 1156, 1077, 1027, 1000, 855, 844 798, 637, 487

As a result of analyzing the crystal state of the tetrahydrate of the obtained S-omeprazole strontium salt using a powder X-ray diffractometer (XRD), the crystalline tetrahydrate of S-omeprazole strontium salt is markedly characteristic. It was found to be a crystal having a diffraction pattern (see FIG. 1). The main peak having an I / Io value of 3% or more is shown in Table 1 below.
[Table 1]

  In addition, as shown in FIG. 2, the crystalline tetrahydrate of S-omeprazole strontium salt according to the present invention has the highest starting point at 100.04 ° C. by DSC analysis (5 ° C./min) using a differential scanning calorimeter. An endothermic peak having a point of 118.33 ° C. (178.9 J / g) and an exothermic peak having a maximum point of 210.68 ° C. starting from 203.06 ° C. (451.3 J / g) were exhibited. .

Example 2
A solution prepared by dissolving S-omeprazole (10.4 g, 30.1 mmol) having an optical purity of 90% ee in 100 ml of methanol and strontium hydroxide octahydrate (4.6 g, 17.3 mmol) in 50 ml of methanol was obtained. After gradually adding, the mixture was stirred at room temperature for 3 hours. The produced solid was filtered, washed with 50 ml of methanol and dried at 45 ° C. for 12 hours to obtain 10.7 g (yield: 84%) of the title compound as a white crystalline powder.
Melting point: 201-203 ° C
Water content (loss on drying test): 8.9% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.2% (theoretical anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.4% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.9% ee

Example 3
A solution prepared by dissolving S-omeprazole (10.4 g, 30.1 mmol) having an optical purity of 80% ee in 100 ml of methanol and strontium hydroxide octahydrate (4.6 g, 17.3 mmol) in 50 ml of methanol was obtained. After gradually adding, the mixture was stirred at room temperature for 3 hours. The resulting solid was filtered, washed with 50 ml of methanol, and dried at 45 ° C. for 12 hours to obtain 9.3 g (yield: 73%) of the title compound as a white crystalline powder.
Melting point: 201-203 ° C
Water content (loss on drying test): 8.7% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.2% (theoretical anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.5% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.7% ee

Example 4
Sodium hydroxide (3.8 g, 95.0 mmol) was dissolved in 150 ml of water, and S-omeprazole (27.5 g, 79.6 mmol) with an optical purity of 90% ee was added and dissolved. A solution of strontium chloride hexahydrate (12.7 g, 47.8 mmol) dissolved in 150 ml of methanol was gradually added, followed by stirring at room temperature for 3 hours. The produced solid was filtered, washed with a mixed solvent of 20 ml of water and 80 ml of methanol, and then dried at 45 ° C. for 12 hours to obtain 29.7 g (yield: 88%) of the title compound as a white crystalline powder. .
Melting point: 201-203 ° C
Water content (loss on drying test): 8.9% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.35% (theoretical value of anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.6% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.8% ee

Example 5
After potassium hydroxide (5.3 g, 94.5 mmol) was dissolved in 150 ml of water, S-omeprazole (27.5 g, 79.6 mmol) with an optical purity of 95% ee was added and dissolved. A solution of strontium chloride hexahydrate (12.7 g, 47.8 mmol) dissolved in 150 ml of methanol was gradually added, followed by stirring at room temperature for 3 hours. The produced solid was filtered, washed with a mixed solvent of 20 ml of water and 80 ml of methanol, and then dried at 45 ° C. for 12 hours to obtain 28.7 g (yield: 85%) of the title compound as a white crystalline powder. .
Melting point: 201-203 ° C
Water content (loss on drying test): 9.0% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.3% (theoretical value of anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.5% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.8% ee

Example 6
After potassium hydroxide (5.3 g, 94.5 mmol) was dissolved in 150 ml of water, S-omeprazole (27.5 g, 79.6 mmol) with an optical purity of 95% ee was dissolved. After adding 150 ml of methanol, a solution of strontium acetate (12.7 g, 47.8 mmol) dissolved in 50 ml of water was gradually added and stirred at room temperature for 3 hours. The produced solid was filtered, washed with a mixed solvent of 20 ml of water and 80 ml of methanol, and then dried at 45 ° C. for 12 hours to obtain 28.0 g (yield: 83%) of the title compound as a white crystalline powder. .
Melting point: 201-203 ° C
Water content (loss on drying test): 8.9% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.2% (theoretical anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.5% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.9% ee

Example 7
(S)-(−)-Binol (25.0 g, 87.3 mmol) was added to a mixed solution of 400 ml of ethanol and 100 ml of water, heated to 60 ° C. or higher to dissolve all, and then 50 ° C. to 55 ° C. While maintaining the temperature, 5.0 ml (35.9 mmol) of triethylamine and omeprazole (50.0 g, 144.8 mmol) were sequentially added to the solution, and the mixture was gradually cooled to room temperature and stirred at room temperature for 12 hours. . The produced solid was filtered, washed successively with a mixed solvent of 85 ml of ethanol and 15 ml of water and 100 ml of n-hexane, dried at 40 ° C. and inclusion of (S)-(−)-binol and S-omeprazole. A complex was obtained (optical purity: 97.0% ee).

80 g of the inclusion complex of (S)-(−)-binol and S-omeprazole obtained above (optical purity of S-omeprazole: 97.0% ee) was dissolved in 400 ml of methanol, and strontium hydroxide 8 After adding hydrate (20 g, 75.3 mmol), the mixture was stirred at room temperature for 3 hours. The resulting white solid was filtered, washed with 150 ml of methanol, and dried at 45 ° C. for 12 hours to obtain 49.0 g (yield: 91%) of the title compound as a white crystalline powder.
Melting point: 201-203 ° C
Water content (loss on drying test): 9.0% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.2% (theoretical anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.5% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.9% ee

Example 8
50 g of the inclusion complex of (S)-(−)-binol and S-omeprazole obtained in Example 7 (optical purity of S-omeprazole: 97.0% ee) was dissolved in 500 ml of isopropyl acetate, and hydroxylated. A solution of 3.8 g (95.0 mmol) of sodium in 150 ml of water was added. Thereafter, the mixture was stirred at room temperature for 3 hours to separate and remove isopropyl acetate, and the aqueous layer was washed with 200 ml of isopropyl acetate. A solution obtained by dissolving strontium chloride hexahydrate (12.6 g, 47.5 mmol) in 150 ml of methanol was gradually added dropwise to a basic aqueous layer solution containing S-omeprazole. After stirring this suspension for 3 hours, the product was filtered. Subsequently, the mixture was washed with a mixed solution of 20 ml of water and 80 ml of methanol and dried at 45 ° C. for 12 hours to obtain 28.5 g (yield: 85%) of the title compound as a white crystalline powder.
Melting point: 201-203 ° C
Water content (loss on drying test): 8.8% (theoretical value of tetrahydrate: 8.49%)
Strontium content (EDTA titration): 11.3% (theoretical value of anhydride: 11.3%)
Omeprazole content (HPLC, condition A): 88.6% (theoretical value of anhydride: 88.7%)
Optical purity (HPLC, condition B): 99.7% ee

Example 9:
Production of S-omeprazole strontium salt part or mixed crystalline anhydride (crystalline form B ) 30.0 g of crystalline tetrahydrate of S-omeprazole strontium salt (crystalline form A) obtained in Example 1 at 100 ° C Drying for 5 hours gave 27.0 g of the title compound.
Melting point: decomposition water content at 196 ° C or higher (loss on drying test): 0.9%
Optical purity (HPLC, condition B): 99.9% ee
Condition B: For optical purity measurement of S-omeprazole strontium salt

  In the obtained S-omeprazole strontium salt, a peak having an I / Io value of 100% in analysis by a powder X-ray diffractometer appears at a diffraction angle (2θ ± 0.2) of 5.8 (see FIG. 3). DSC analysis (5 ° C / min) with a differential scanning calorimeter showed no substantial endothermic peak but an exothermic peak with a maximum of 197.23 ° C starting from 186.09 ° C (see Fig. 4). ), Which is in the form of a partial or hybrid crystalline anhydride.

Example 10:
Preparation of S-omeprazole strontium salt part or mixed crystalline hydrate (crystalline form C ) 20.0 g of crystalline anhydrous S-omeprazole strontium salt (crystalline form B) obtained in Example 9 in 150 ml of water Suspended and stirred at room temperature for 12 hours. The solid was filtered and dried at 45 ° C. for 12 hours to give 16.5 g of the title compound.
Melting point: Phase transition in the range of 105-107 ° C, decomposition water content at 160 ° C or higher (loss on drying test): 8.5%
Optical purity (HPLC, condition B): 99.9% ee

In the obtained S-omeprazole strontium salt, a peak having an I / Io value of 100% in analysis by a powder X-ray diffractometer appears at a diffraction angle (2θ ± 0.2) of 25.2 (see FIG. 5). The differential scanning calorimeter DSC analysis (5 ° C./min) has an endothermic peak starting at 37.11 ° C. and the highest point being 68.09 ° C., and the highest point starting from 161.3 ° C. An exothermic peak at 188.81 ° C. appears (see FIG. 6), which is in the form of a partial or mixed crystalline hydrate.

Example 11:
Preparation of amorphous form of S-omeprazole strontium salt After dissolving 25.0 g of the crystalline tetrahydrate of S-omeprazole strontium salt (crystal form A) obtained in Example 1 in 250 ml of acetone, a vacuum rotary evaporator The solvent was distilled off under reduced pressure to give 21.0 g of the title compound.
Melting point: decomposition water content at 180 ° C. or higher (drying loss test): 6.0%
Optical purity (HPLC, condition B): 99.8% ee
Condition B: For optical purity measurement of S-omeprazole strontium salt

As shown in FIG. 7, it can be seen that the obtained amorphous form of S-omeprazole strontium salt does not have a characteristic peak by analysis with a powder X-ray diffractometer.
Further, as shown in FIG. 8, in DSC analysis (5 ° C./min) by a differential scanning calorimeter, it has an endothermic peak starting at about 29.16 ° C. and having a maximum of 55.88 ° C. While a phase mutation occurred at 13 ° C., an exothermic peak having a maximum point of 207.78 ° C. starting from 182.85 ° C. was exhibited.

<Production of trihydrate of S-omeprazole magnesium salt>
Comparative Example 1
S-omeprazole magnesium salt trihydrate was prepared according to Example 7 of US Pat. No. 6,369,085.
Specifically, potassium hydroxide (1.26 g, 22.5 mmol) was dissolved in 30 ml of water, and S-omeprazole (5.18 g, 15.0 mmol) having an optical purity of 95% ee was added and dissolved. After gradually adding a solution of magnesium sulfate (1.81 g, 15.0 mmol) in 10 ml of water, the mixture was stirred at room temperature for 3 hours. The produced solid was filtered, washed with 15 ml of water, and then dried with warm air at 45 ° C. for 12 hours to obtain the title compound as a white crystalline powder in a yield of 95%.

Comparative Examples 2-3
The procedure was the same as that of Comparative Example 1 except that S-omeprazole having optical purity of 90% ee and 80% ee was used.

Test Example 1: Optical purity test The tetrahydrate of S-omeprazole strontium salt prepared in Examples 1 to 3 and the trihydrate of S-omeprazole magnesium salt prepared in Comparative Examples 1 to 3 were respectively described above. Under condition B, optical purity was measured by high performance liquid chromatography (HPLC). The results are shown in Table 2 below.
[Table 2]

  As shown in Table 2, the optical purity of the tetrahydrate of the S-omeprazole strontium salt of the present invention was significantly improved as compared with the starting material and the trihydrate of S-omeprazole magnesium salt.

前記表３に示したように、Ｓ−オメプラゾールストロンチウム塩またはその水和物は、公知のＳ−オメプラゾールマグネシウム塩の三水和物に比べて１０倍以上に水分解度が向上しており、これによって、本発明によるＳ−オメプラゾールストロンチウム塩及びその水和物が注射剤に好適であることが分かる。 Test Example 2: Water Solubility Test Each of the S-omeprazole strontium salt according to the present invention or this hydrate and the trihydrate of S-omeprazole magnesium salt was dissolved in deionized water so as to reach saturation. Each saturated solution was analyzed by high performance liquid chromatography (HPLC) according to the condition A to determine the amount dissolved. The results are shown in Table 3 below.
[Table 3]

As shown in Table 3, S-omeprazole strontium salt or a hydrate thereof has a water decomposition degree improved by 10 times or more as compared with the trihydrate of the known S-omeprazole magnesium salt. This shows that the S-omeprazole strontium salt according to the present invention and its hydrate are suitable for injection.

Test Example 3: Non-Hygroscopic Test Crystalline S-omeprazole strontium salt tetrahydrate prepared according to the present invention was exposed for 15 days under conditions of 25 ° C to 40 ° C and 40% to 90% relative humidity. I let you. The water content of the salt according to the invention was measured by performing a loss on drying test. The water content corresponding to the storage periods 0, 3, 7, and 15 days is as shown in Table 4 below.
[Table 4]

  As can be seen from Table 4, the tetrahydrate of the S-omeprazole strontium salt of the present invention hardly absorbs moisture even under high humidity conditions, and the initial water content was maintained under low humidity conditions.

Test Example 4: Thermal Stability Test The tetrahydrate of S-omeprazole strontium salt produced according to the present invention was stored in a closed state under severe conditions of a temperature of 60 ° C. and a relative humidity of 75%, respectively. The remaining amount of active omeprazole was analyzed by High Performance Liquid Chromatography (HPLC) according to Condition A on the samples after 21 and 28 days. The results are shown in Table 5.
[Table 5]

As apparent from Table 5, the tetrahydrate of S-omeprazole strontium salt of the present invention was very stable under severe conditions.

  While the invention has been described in terms of the specific embodiments described above, various modifications and changes can be made by those skilled in the art within the scope of the invention as defined in the appended claims.

FIG. 2 is a powder X-ray diffraction spectrum of a crystalline tetrahydrate of S-omeprazole strontium salt (Crystal Form A) according to Preferred Example 1 of the present invention; FIG. 2 is a DSC curve obtained by differential scanning calorimetry of a crystalline tetrahydrate of S-omeprazole strontium salt (Crystal Form A) according to Preferred Example 1 of the present invention; FIG. 7 is a powder X-ray diffraction spectrum of a crystalline anhydride (crystal form B) of S-omeprazole strontium salt according to Preferred Example 9 of the present invention; It is a DSC curve by the differential scanning calorimeter of the crystalline anhydride (crystal form B) of S-omeprazole strontium salt which concerns on preferable Example 9 of this invention; FIG. 6 is a powder X-ray diffraction spectrum of a crystalline hydrate of S-omeprazole strontium salt (Crystal Form C) according to Preferred Example 10 of the present invention; FIG. 6 is a DSC curve of a crystalline hydrate of S-omeprazole strontium salt (Crystal Form C) according to Preferred Example 10 of the present invention by differential scanning calorimetry; FIG. 4 is an amorphous powder X-ray diffraction spectrum of S-omeprazole strontium salt according to preferred example 11 of the present invention; It is a DSC curve by the differential scanning calorimeter of the amorphous form of S-omeprazole strontium salt which concerns on preferable Example 11 of this invention.

Claims (18)

Crystalline tetrahydrate of S-omeprazole strontium salt of the following formula ( IV ):

Peaks having an I / Io value of 3% or more in the powder X-ray diffraction spectrum are 5.6, 11.1, 13.5, 14.8, 16.2, 17.5, 18.0, 20.1. 2θ ± 0.2 of 20.4, 21.2, 22.2, 24.5, 25.2, 26.3, 27.5, 29.8, 31.1, 32.8 and 36.5 The crystalline tetrahydrate of S-omeprazole strontium salt according to claim 1 , wherein the crystalline tetrahydrate is represented by a diffraction angle of 2. The S-omeprazole strontium according to claim 1 , wherein a peak having an I / Io value of 100% in a powder X-ray diffraction spectrum is a crystal form represented by a 2θ diffraction angle of 25.2 ± 0.2. Salt crystalline tetrahydrate. Crystalline tetrahydrate of S-omeprazole strontium salt of the following formula (IV) comprising adding strontium hydroxide to a neutral solution containing S-omeprazole of the following formula (III) and stirring the resulting mixture Japanese manufacturing method:

Manufacturing method according to claim 4, wherein the strontium hydroxide is used in 0.5 to 0.75 molar equivalents relative to S- omeprazole 1 molar equivalent. The neutral solution is S-omeprazole in an organic solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, tetrahydrofuran, acetone and mixtures thereof, or a mixed solvent of the organic solvent and water. manufacturing method according to claim 4, characterized in that one prepared by dissolving or suspending the. Manufacturing method according to claim 4, wherein the organic solvent is selected among methanol, acetone and mixtures thereof. Crystals of S-omeprazole strontium salt of the following formula (IV) comprising adding a reactive strontium salt to a basic solution containing S-omeprazole of the following formula (III) and a base and stirring the resulting mixture method of manufacturing a sexual tetrahydrate:

Manufacturing method according to claim 8, wherein the base is used in 1 to 3 molar equivalents relative to S- omeprazole 1 molar equivalent. Manufacturing method according to claim 8, wherein the reactive strontium salt is used in 0.5 to 0.75 molar equivalents relative to the base 1 molar equivalent. The basic solution is S-omeprazole in an organic solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, tetrahydrofuran, acetone and mixtures thereof, or a mixed solvent of the organic solvent and water. and manufacturing method according to claim 8, wherein the base in which the manufactured dissolved or suspended. The base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine and mixtures thereof. manufacturing method according to claim 8,. The reactive strontium salt is selected from the group consisting of strontium chloride, strontium bromide, strontium sulfate, strontium nitrate, strontium perchlorate, strontium acetate, strontium carbonate, strontium oxalate and mixtures thereof. manufacturing method according to claim 8. A gastroesophageal reflux disease, gastrointestinal enteritis or gastrointestinal tract comprising the crystalline tetrahydrate of S-omeprazole strontium salt according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier. A pharmaceutical composition for the prevention or treatment of ulcers . Set composition as claimed in claim 14, which is a preparation for oral administration. Set composition as claimed in claim 15, wherein the crystalline tetrahydrate of the S- omeprazole strontium salt is present in an amount of 0.1 to 95 wt% total weight to of the composition. Set composition as claimed in claim 16, wherein the crystalline tetrahydrate of the S- omeprazole strontium salt is present in an amount of 1 to 70% by weight relative to the total weight of the composition. Set composition as claimed in claim 14 which is a sterile injectable preparation.

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