A method for preparing omeprazole sodium hemihydrate microcrystals

Abstract

The invention provides a method for preparing omeprazole sodium hemihydrate microcrystals, comprising the following steps: step 1: dissolving omeprazole sodium monohydrate in a solvent, removing insoluble impurities, and obtaining an omeprazole sodium solution; step 2: subjecting the omeprazole sodium solution obtained in step 1 to freeze-drying treatment, wherein the freeze-drying treatment comprises three stages: pre-freezing, sublimation, and heat preservation after sublimation, and after the heat preservation is completed, the material is cooled and discharged to obtain the omeprazole sodium hemihydrate microcrystals. The omeprazole sodium hemihydrate microcrystals of the invention have a simple preparation process, stable process, high reproducibility, small particle size, and uniform particle size distribution.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical crystal separation, and particularly relates to a method for preparing omeprazole sodium hemihydrate microcrystals. Background Art

[0002] Omeprazole Sodium is chemically named 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-benzimidazole sodium salt, molecular formula C 17 H 18 N3NaO3S is usually a white loose powder, odorless, bitter, with a relative molecular mass of 367.4. Its molecular structure is as follows:

[0003]

[0004] Omeprazole sodium is a proton pump inhibitor for gastric parietal cells, which can specifically inhibit the secretory microtubules composed of the apical membrane of parietal cells and the H + -K + -ATPase, thereby effectively inhibiting the secretion of gastric acid. It is mainly used clinically to treat duodenal ulcers and Zollinger-Ellison syndrome. AstraZeneca AB took the lead in developing the first generation of proton pump inhibitors, omeprazole, which was approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States in 1989 under the trade name "Losec". Benzimidazole, pyridine and sulfenyl are the three active parts in the proton pump inhibitor molecule.

[0005] Omeprazole sodium exists in a variety of crystal forms, a variety of solvates and amorphous forms. For example, patent EP124495 (US4738974) first reported the A crystal form of omeprazole sodium, which is a hydrate containing 1 to 2 water molecules, one of which has a strong bond with the crystal structure, and the other is easily removed by drying. The dried A crystal form is very hygroscopic and usually absorbs water quickly; patent EP0991641B1 reports omeprazole sodium monohydrate, which has better thermal stability and is non-hygroscopic than crystal form A. Patent CN104788426 discloses a hemihydrate of omeprazole sodium, which has the advantages of high purity, good stability, and low hygroscopicity. However, the hemihydrate of omeprazole sodium obtained by this technology has a larger particle size, and the microcrystals not only have good biological activity, but also can promote its rapid dissolution, thereby enhancing the efficacy of the drug. Although the freeze-drying method can effectively control the particle size of the drug, in most cases, the freeze-drying method generally only obtains an amorphous product, and it is difficult to obtain a crystalline product. Therefore, it is necessary to invent a method for preparing omeprazole sodium hemihydrate microcrystals with a simple preparation process, high yield and stability. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing omeprazole sodium hemihydrate microcrystals. After research, it is unexpectedly found that the freeze-drying technology proposed in the present invention can effectively control the particle size of omeprazole sodium hemihydrate while maintaining the crystalline state of omeprazole sodium hemihydrate, thereby unexpectedly obtaining omeprazole sodium hemihydrate microcrystals.

[0007] In order to achieve the above object, the present invention provides a method for preparing omeprazole sodium hemihydrate microcrystals, comprising the following steps:

[0008] Step 1: dissolving omeprazole sodium monohydrate in a solvent, removing insoluble impurities, and obtaining an omeprazole sodium solution;

[0009] Step 2: freeze-drying the omeprazole sodium solution obtained in step 1, wherein the freeze-drying process includes three stages: pre-freezing, sublimation, and heat preservation after sublimation. After the heat preservation is completed, the material is cooled and discharged to obtain the omeprazole sodium hemihydrate microcrystals.

[0010] Preferably, in step 1, the solvent is one or a mixed solvent of n-propanol, n-butanol, isopropanol, ethyl acetate, acetone, butanone, acetonitrile or n-heptane.

[0011] Any of the above is preferably that in step 1, the omeprazole sodium solution obtained in step 1 is 0.02-0.2 g / ml, more preferably 0.02, 0.05, 0.1, 0.12, 0.14, 0.16, 0.18, 0.2 g / ml and the range therebetween.

[0012] Any of the above is preferably that in step 1, the dissolution temperature is 30-50°C, and a further preferred dissolution temperature is 30, 35, 40, 45, 50°C and ranges therebetween.

[0013] Any of the above items is preferably that in step 2, the pre-freezing process conditions are: pre-freezing temperature -50°C to -35°C, and further preferred pre-freezing temperatures are -50, -45, -40, -35, -30, -35°C and ranges therebetween.

[0014] Any of the above is preferably that in step 2, the pre-freezing process conditions are: pre-freezing time 1 to 3 hours, and further preferably the pre-freezing time is 1, 2, 3 hours and the range therebetween.

[0015] Any of the above is preferably that in step 2, the sublimation process temperature is increased to 35-45°C, and a further preferred sublimation termination temperature is 35, 40, 45°C and a range therebetween.

[0016] Preferably, in any one of the above items, in step 2, the sublimation process includes a first sublimation and a second sublimation.

[0017] Any of the above is preferably that in step 2, the final temperature of the first sublimation is 0-5°C, more preferably 0, 1, 2, 3, 4, 5°C and the range therebetween.

[0018] Any of the above is preferably that in step 2, the process conditions for the first sublimation are: controlling the first sublimation temperature to rise to 0-5°C within 3-4.5h; further, the time is controlled at 3, 3.5, 4, 4.5°C and the range therebetween; further, the temperature is raised to 0, 1, 2, 3, 4, 5°C and the range therebetween.

[0019] Any of the above is preferably that in step 2, after the first sublimation to 0-5°C, the first insulation time is 3-4h, and the more preferred first insulation time is 3, 3.5, 4h and the range therebetween.

[0020] Any of the above is preferably that in step 2, the final temperature of the second sublimation is 35-45°C, more preferably 35, 40, 45°C and the range therebetween.

[0021] Any of the above is preferably that in step 2, the process conditions for the second sublimation are: raising the temperature to 35-45°C within 4-5h; further controlling the time to 4, 4.5, 5h and the range therebetween; further controlling the temperature to 35, 40, 45°C and the range therebetween.

[0022] Any of the above is preferably that in step 2, the process conditions for heat preservation after sublimation are: heat preservation at 35-45°C for 5-8h; further, the time is controlled to be 5, 6, 7, 8h and the range therebetween.

[0023] The present invention also provides omeprazole sodium hemihydrate microcrystals prepared according to any one of the above preparation methods.

[0024] Preferably, the omeprazole sodium hemihydrate microcrystals have a molecular formula of C 17 H 18 N3NaO3S·0.5H2O, the structural formula is as follows:

[0025]

[0026] Any one of the above is preferably that the average particle size of the omeprazole sodium hemihydrate microcrystals is in the range of 2 to 30 μm.

[0027] Any of the above is preferably that the omeprazole sodium hemihydrate microcrystals X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2θ=6.26±0.1, 11.10±0.1, 12.20±0.1, 15.58±0.1, 16.02±0.1, 17.12±0.1, 19.08±0.1, 21.00±0.1, 22.68±0.1, 23.48±0.1, 24.08±0.1, 26.52±0.1 and 28.08±0.1 degrees.

[0028] In a preferred embodiment of the present invention, a method for preparing the omeprazole sodium hemihydrate microcrystals is provided, and the steps are as follows:

[0029] Step 1: dissolving a certain amount of omeprazole sodium monohydrate in a solvent, and continuously stirring for 0.1 to 0.5 hours to obtain an omeprazole sodium solution; filtering the solution to remove impurities that may not be dissolved;

[0030] Step 2: After the solution is divided into freeze-drying trays, the trays are placed in a vacuum freeze dryer. The freeze-drying process includes three stages: pre-freezing, sublimation and heat preservation. After the heat preservation is completed, the temperature is lowered and the material is discharged to obtain the omeprazole sodium hemihydrate microcrystals;

[0031] In the step 1, the temperature is 30-50° C., the solvent is one or a mixed solvent of n-propanol, n-butanol, isopropanol, ethyl acetate, acetone, butanone, acetonitrile or n-heptane, and the concentration of the omeprazole sodium solution obtained in the step 1 is 0.02-0.2 g / ml;

[0032] In step 2, the pre-freezing process conditions are: temperature -50 to -35°C, time 1 to 3 hours;

[0033] In step 2, the sublimation process conditions are: controlling the temperature to rise to 0-5°C within 3-4.5 hours, keeping the temperature for 3-4 hours; and then raising the temperature to 35-45°C within 4-5 hours;

[0034] The method further comprises a drying step: the drying temperature is 20° C. and the drying time is 4 hours.

[0035] The omeprazole sodium hemihydrate microcrystals prepared according to the preferred embodiment have characteristic peaks in the X-ray powder diffraction pattern at diffraction angles 2θ=6.26±0.1, 11.10±0.1, 12.20±0.1, 15.58±0.1, 16.02±0.1, 17.12±0.1, 19.08±0.1, 21.00±0.1, 22.68±0.1, 23.48±0.1, 24.08±0.1, 26.52±0.1 and 28.08±0.1 degrees, such as Figure 1 shown.

[0036] The differential scanning calorimetry diagram of the omeprazole sodium hemihydrate microcrystals is as follows: Figure 2 As shown;

[0037] The omeprazole sodium hemihydrate microcrystals have an average particle size range of 2 to 30 μm and a particle size distribution as shown in Figure 3 shown.

[0038] The omeprazole sodium hemihydrate microcrystals of the invention have simple preparation process, stable process, high reproducibility, small particle size and uniform particle size distribution. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The characteristic peaks of omeprazole sodium hemihydrate microcrystals provided in the preferred embodiment of the present invention.

[0040] Figure 2 A differential scanning calorimetry diagram of omeprazole sodium hemihydrate microcrystals provided in a preferred embodiment of the present invention.

[0041] Figure 3 A microcrystalline particle size distribution diagram of omeprazole sodium hemihydrate provided in a preferred embodiment of the present invention.

[0042] Figure 4 This is a microcrystalline particle size distribution diagram of omeprazole sodium hemihydrate in preferred embodiment 1 of the present invention.

[0043] Figure 5 This is a microcrystalline particle size distribution diagram of omeprazole sodium hemihydrate in preferred embodiment 2 of the present invention.

[0044] Figure 6 This is a microcrystalline particle size distribution diagram of omeprazole sodium hemihydrate in preferred embodiment 3 of the present invention. DETAILED DESCRIPTION

[0045] The present invention is further described in detail below through the accompanying drawings and specific embodiments.

[0046] The X-ray powder diffraction pattern of the omeprazole sodium hemihydrate microcrystals of the present invention has characteristic peaks at diffraction angles 2θ=6.26±0.1, 11.10±0.1, 12.20±0.1, 15.58±0.1, 16.02±0.1, 17.12±0.1, 19.08±0.1, 21.00±0.1, 22.68±0.1, 23.48±0.1, 24.08±0.1, 26.52±0.1 and 28.08±0.1 degrees, as shown in FIG. Figure 1 shown.

[0047] The differential scanning calorimetry diagram of the omeprazole sodium hemihydrate microcrystals is as follows: Figure 2 As shown;

[0048] According to the method provided by the present invention, preferably, in the step 1, the temperature is 30-50°C, the solvent is one or a mixed solvent of n-propanol, n-butanol, isopropanol, ethyl acetate, acetone, butanone, acetonitrile or n-heptane, and the omeprazole sodium solution obtained in step 1 is 0.02-0.2 g / ml; preferably, in the step 2, the pre-freezing process conditions are: temperature -50--35°C, time 1-3h; preferably, in the step 2, the sublimation process conditions are: control the temperature to rise to 0-5°C within 3-4.5h, keep warm for 3-4h; then raise the temperature to 35-45°C within 4-5h; preferably, the method further includes a drying step: the drying temperature is 20°C, and the drying time is 4h; the omeprazole sodium hemihydrate microcrystals are prepared, and the average particle size range is 2-30μm, and the particle size distribution is as follows Figure 3 shown.

[0049] Example 1

[0050] 45 g of omeprazole sodium monohydrate was dissolved in 1500 ml of acetonitrile + 500 ml of acetone mixed solvent, and then stirred at a constant temperature of 45°C for 0.2 h to obtain a clear omeprazole sodium solution; the solution was filtered and divided into freeze-drying plates, and then placed in a vacuum freeze dryer, and the pre-freezing mode was turned on to make the solution temperature in the freeze-drying plate reach -45°C, and the temperature was kept for 3 h; then, the vacuum freeze dryer was turned on the sublimation mode, the vacuum degree was turned on to below 25 Pa, the temperature was raised to 0°C within 4 h, and the temperature was kept for 3 h; then the temperature was continued to be raised to 40°C within 5 h, and the temperature was kept for 4 h; after the insulation was completed, the temperature was lowered to 25°C, and the material was discharged to obtain white powdery omeprazole sodium hemihydrate microcrystals with an average particle size of 9.45 μm and a particle size distribution as shown in Figure 4 shown.

[0051] Example 2

[0052] 80g of omeprazole sodium monohydrate was dissolved in 3000ml of ethyl acetate, and then stirred at a constant temperature of 40°C for 0.1h to obtain a clear omeprazole sodium solution; the solution was filtered and divided into freeze-drying plates, and then placed in a vacuum freeze dryer, and the pre-freezing mode was turned on to make the solution temperature in the freeze-drying plate reach -45°C, and the temperature was kept for 2h; then, the vacuum freeze dryer was turned on the sublimation mode, the vacuum degree was turned on to below 25Pa, the temperature rose to 2°C within 3.5h, and the temperature was kept for 3h; then the temperature was continued to rise to 40°C within 4h, and the temperature was kept for 5h; after the insulation was completed, the temperature was lowered to 25°C, and the material was discharged to obtain white powdery omeprazole sodium hemihydrate microcrystals with an average particle size of 16.5μm and a particle size distribution as shown in Figure 5 shown.

[0053] Example 3

[0054] 150g of omeprazole sodium monohydrate was dissolved in 2500ml of n-butanol, and then stirred at a constant temperature of 50°C for 0.5h to obtain a clear omeprazole sodium solution; the solution was filtered and divided into freeze-drying plates, and then placed in a vacuum freeze dryer, and the pre-freezing mode was turned on to make the solution temperature in the freeze-drying plate reach -50°C, and the temperature was kept for 3h; then, the vacuum freeze dryer was turned on the sublimation mode, the vacuum degree was turned on to below 25Pa, the temperature rose to 3.5°C within 4.5h, and the temperature was kept for 3h; then the temperature was continued to rise to 45°C within 5h, and the temperature was kept for 5h; after the insulation was completed, the temperature was lowered to 25°C, and the material was discharged to obtain white powdery omeprazole sodium hemihydrate microcrystals with an average particle size of 13.7μm and a particle size distribution as shown in Figure 6 shown.

[0055] The above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method for preparing omeprazole sodium hemihydrate microcrystals, comprising the following steps: Step 1: dissolving omeprazole sodium monohydrate in a solvent, removing insoluble impurities, and obtaining an omeprazole sodium solution; Step 2: freeze-drying the omeprazole sodium solution obtained in step 1, wherein the freeze-drying process includes three stages: pre-freezing, sublimation, and heat preservation after sublimation. After the heat preservation is completed, the material is cooled and discharged to obtain the omeprazole sodium hemihydrate microcrystals.

2. The freeze-drying method according to claim 1, characterized in that In step 1, the solvent is one or a mixed solvent of n-propanol, n-butanol, isopropanol, ethyl acetate, acetone, butanone, acetonitrile or n-heptane.

3. The preparation method according to claim 2, characterized in that: In step 1, the concentration of the omeprazole sodium solution obtained in step 1 is 0.02 to 0.2 g / ml.

4. The preparation method according to claim 2, characterized in that: In step 1, the dissolving temperature is 30-50°C.

5. The preparation method according to claim 1, characterized in that: In step 2, the pre-freezing process conditions are: pre-freezing temperature -50°C to -35°C, and pre-freezing time 1 to 3 hours.

6. The preparation method according to claim 1, characterized in that: In step 2, the temperature of the sublimation process is raised to 35-45° C., and the sublimation process includes a first sublimation and a second sublimation.

7. The preparation method according to claim 6, characterized in that: In step 2, the process conditions of the first sublimation are: controlling the first sublimation temperature to rise to 0-5°C within 3-4.5 hours, and the first insulation time is 3-4 hours; the process conditions of the second sublimation are: further raising the temperature to 35-45°C within 4-5 hours.

8. The preparation method according to claim 1, characterized in that: In step 2, the process conditions for heat preservation after sublimation are: heat preservation at 35-45° C. for 5-8 hours.

9. Omeprazole sodium hemihydrate microcrystals prepared according to the preparation method according to any one of claims 1 to 8.

10. The omeprazole sodium hemihydrate microcrystals according to claim 1, characterized in that: The average particle size of the omeprazole sodium hemihydrate microcrystals is in the range of 2 to 30 μm; The X-ray powder diffraction pattern of the omeprazole sodium hemihydrate microcrystals has characteristic peaks at diffraction angles 2θ=6.26±0.1, 11.10±0.1, 12.20±0.1, 15.58±0.1, 16.02±0.1, 17.12±0.1, 19.08±0.1, 21.00±0.1, 22.68±0.1, 23.48±0.1, 24.08±0.1, 26.52±0.1 and 28.08±0.1 degrees.

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