Preparation process of Melsartan potassium tablet
By optimizing the preparation process of measartan potassium tablets, including mannitol screening and the formulation of binders, combined with the use of crosslinked materials, the problem of insufficient stability of measartan potassium tablets is solved, achieving higher stability and storage safety.
Patent Information
- Application Number
- CN202411831823.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-12
- Publication Date
- 2025-02-25
AI Technical Summary
Measartan potassium tablets are prone to hydrolysis under moisture or high humidity conditions, resulting in insufficient stability and affecting long-term preservation.
By optimizing the preparation process, including the sieve treatment of mannitol, the formulation of binder and the granulation process, combining the mixture of croscarmellose sodium, microcrystalline cellulose and magnesium stearate, tableting and drying treatment, measartan potassium tablets with higher stability were prepared.
It improves the stability of Measartan potassium tablets, reduces impurity content, enhances storage safety, and improves production efficiency and safety.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceuticals, and in particular to a preparation process of Asartan potassium tablets. Background Art
[0002] Asartan Potassium Tablets are an oral drug preparation developed by Takeda Pharmaceuticals of Japan for the treatment of essential hypertension. It is an angiotensin II receptor blocker. Angiotensin II is converted from angiotensin I under the catalysis of angiotensinase. Angiotensin II is the main pressor of the renin-angiotensin system, which has multiple physiological effects such as promoting vasoconstriction, stimulating the synthesis and release of aldosterone, exciting the heart and promoting sodium reabsorption by the kidney.
[0003] Miasartan potassium is an oral prodrug that can be rapidly metabolized by esterase in the body to the active ingredient azilsartan during absorption. Miasartan potassium is an ester salt that is easily hydrolyzed to azilsartan in the presence of moisture or high humidity. Therefore, it is crucial to develop a relatively stable formulation of Miasartan potassium tablets in pharmaceutical terms for the long-term storage of Miasartan potassium tablets. Summary of the invention
[0004] In view of this, the technical problem to be solved by the present invention is to provide a preparation process of mersartan potassium tablets, and the prepared mersartan potassium tablets have higher stability.
[0005] The present invention provides a preparation process of Asartan Potassium Tablets, comprising the following steps:
[0006] S1) firstly sieving mannitol for a first time to remove agglomerated particles; then mixing the sieved mannitol and mesartan potassium and sieving for a second time to obtain a sieved material;
[0007] S2) dissolving DL-tartaric acid, sodium hydroxide and hydroxypropyl cellulose in pure water to obtain an adhesive;
[0008] S3) mixing the sieved material and the binder to form granules, and then drying and granulating to obtain intermediate material granules;
[0009] S4) mixing the intermediate material granules with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate, tableting and drying to obtain mesartan potassium tablets.
[0010] Preferably, the mass ratio of mesartan potassium, mannitol, DL-tartaric acid, sodium hydroxide, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate and cross-linked sodium carboxymethyl cellulose is (20-25): (50-55): (0.9-1.3): (0.2-0.6): (2.8-3.2): (8-12): (1.0-2.0): (7-8).
[0011] In some specific embodiments of the present invention, the mass ratio of mesartan potassium, mannitol, DL-tartaric acid, sodium hydroxide, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, and cross-linked sodium carboxymethyl cellulose is 23.7:52.6:1.1:0.4:3.0:10.0:1.5:7.7.
[0012] The present invention firstly pretreats the raw materials.
[0013] Preferably, the mannitol is first sieved to remove the agglomerated particles. The first sieve is a 40-mesh sieve. The first sieve can well remove the agglomerated particles in the mannitol and ensure good dispersion performance of the material.
[0014] Then the sieved mannitol and mesartan potassium are mixed and sieved for a second time to obtain a sieved material.
[0015] The second screening is preferably a 30 mesh sieve.
[0016] The sieved materials can be mixed with other materials more evenly.
[0017] Before preparing the Asartan potassium tablets, the present invention also requires the preparation of an adhesive.
[0018] DL-tartaric acid, sodium hydroxide and hydroxypropyl cellulose are dissolved in pure water to obtain an adhesive.
[0019] Preferably, DL-tartaric acid and sodium hydroxide are dissolved in pure water, and then hydroxypropyl cellulose is added to dissolve to obtain the adhesive. Adding the raw materials step by step for dissolution can ensure better dissolution of the materials and a more uniform adhesive is obtained.
[0020] It should be noted that there is no particular order in which steps S1) and S2) of the present invention are performed.
[0021] Then the screened material and the binder are mixed and granulated.
[0022] Preferably, the granulation is specifically:
[0023] Add the sieved mesartan potassium and mannitol into the fluidized bed for preheating, set the air inlet temperature to above 60°C for preheating for 10 to 20 minutes, and use a binder for granulation;
[0024] The atomization pressure of the granulation is 0.1-0.3 MPa, and the material temperature is above 25°C.
[0025] The limitation of the above parameters can make the prepared Asartan Potassium tablets have higher stability.
[0026] After granulation, the product is dried and sized to obtain intermediate material particles.
[0027] The drying temperature is preferably 50-60°C, more preferably 60°C.
[0028] The drying is preferably carried out until the material temperature is 40-50° C. and the moisture content is less than 1.0%.
[0029] The granulation is preferably performed through a 40-mesh sieve.
[0030] Finally, a total mixing is performed to mix the above intermediate material particles with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate.
[0031] Preferably, the intermediate material particles obtained in step S3) are premixed with cross-linked sodium carboxymethyl cellulose and microcrystalline cellulose for 3 to 8 minutes, more preferably for 5 minutes, and then magnesium stearate is added and mixed for 8 to 12 minutes, more preferably for 10 minutes. Adding the raw materials step by step can make the mixing of the materials more uniform and the tablets more stable.
[0032] After the total mixing, tableting and drying are performed to obtain Asartan Potassium Tablets.
[0033] Preferably, the tabletting pressure is 9-21 KN, and the tabletting speed is 8-21 r / min.
[0034] The tableting results show that the tablet weight difference of the present invention is ±5% of the target tablet weight, and the hardness of the obtained plain tablet is 40N to 100N.
[0035] The drying temperature is preferably 30-50°C, more preferably 40°C.
[0036] Preferably, the drying is vacuum drying, and the vacuum degree of the drying is preferably 0.1 mbar.
[0037] Preferably, the drying is performed until the moisture content of the tablet is less than 0.5%.
[0038] After obtaining the Asartan Potassium tablets, the present invention also includes conventional operations before drug sales, such as aluminum packaging, air tightness detection, outer packaging, and warehousing.
[0039] The test results show that the total impurity content of the lasartan potassium tablets prepared by the present invention does not exceed 0.28%, and the solubility of lasartan potassium is 91% to 98%.
[0040] Compared with the prior art, the present invention provides a preparation process of measartan potassium tablets, comprising the following steps: S1) firstly sieving mannitol for the first time to remove agglomerated particles; then mixing the sieved mannitol and measartan potassium for the second sieving to obtain a sieved material; S2) dissolving DL-tartaric acid, sodium hydroxide, and hydroxypropyl cellulose in pure water to obtain a binder; S3) mixing the sieved material and the binder for granulation, and then drying and granulating to obtain intermediate material particles; S4) mixing the intermediate material particles with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate, and tableting and drying to obtain measartan potassium tablets. The present invention optimizes the preparation process of measartan potassium tablets, strictly controls each production link, improves production efficiency, reduces production cost, reduces the impurity content in the drug, improves the stability of the drug, solves the problem of storage difficulties, and improves production safety. DETAILED DESCRIPTION
[0041] In order to further illustrate the present invention, the following is a detailed description in conjunction with the embodiments. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.
[0042] All raw materials of the present invention have no particular limitation on their sources, and can be purchased from the market or prepared according to conventional methods known to those skilled in the art.
[0043] Example 1
[0044] Prescription (80mg 100,000 tablets / 40mg 200,000 tablets)
[0045] Table 1
[0046]
[0047] Production operation steps
[0048] 1) Sieving: First, pass the mannitol through a 40-mesh sieve to remove clumps and collect them in a PE bag. Then, pass the prescribed amount of mesartan potassium and mannitol through a 30-mesh sieve together. Collect the sieved materials, weigh them, seal them, and set them aside.
[0049] 2) Preparation of adhesive: Add the prescribed amount of DL-tartaric acid and sodium hydroxide to the prescribed amount of purified water, stir to dissolve, then add the prescribed amount of hydroxypropyl cellulose, stir to dissolve, and set aside.
[0050] 3) Granulation: Add the sieved mesartan potassium and mannitol to the fluidized bed for preheating, set the air inlet temperature to above 60°C for preheating for 10 to 20 minutes, and use a binder for granulation. The atomization pressure is 0.1 to 0.3 MPa, adjust the fan frequency and spray frequency, and the material temperature is above 25°C.
[0051] 4) Drying: After granulation, adjust the inlet air temperature to 60℃ for drying, and dry until the material temperature is 40-50℃ (moisture content is less than 1.0%) before discharging.
[0052] 5) Whole grain: sieve with 40 mesh.
[0053] 6) Total mixing: Add the whole granulated material into the hopper mixer, add the prescribed amount of croscarmellose sodium and microcrystalline cellulose, premix for 5 minutes, then add the prescribed amount of magnesium stearate and mix for 10 minutes.
[0054] 7) Tablet pressing: pressure 9~21KN, tablet pressing speed 8-21r / min, hardness of plain tablets 40N~100N, tablet weight difference is within the range of ±5% of the target tablet weight.
[0055] 8) Drying: temperature 40°C, vacuum degree 0.1 mbar, reduced pressure drying, drying until the moisture content is less than 0.5%.
[0056] 9) Packaging.
[0057] The test results show that the obtained lasartan potassium tablets are white tablets with a total impurity content of only 0.16%. The average solubility of lasartan potassium is 96%, and the tablet drying loss is 0.72%, which shows high stability.
[0058] The above embodiments are only used to help understand the method and core idea of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims
1. A preparation process of Asartan Potassium Tablets, comprising the following steps: S1) firstly sieving mannitol for a first time to remove agglomerated particles; then mixing the sieved mannitol and mesartan potassium and sieving for a second time to obtain a sieved material; S2) dissolving DL-tartaric acid, sodium hydroxide and hydroxypropyl cellulose in pure water to obtain an adhesive; S3) mixing the sieved material and the binder to form granules, and then drying and granulating to obtain intermediate material granules; S4) mixing the intermediate material granules with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate, tableting and drying to obtain mesartan potassium tablets.
2. The preparation process according to claim 1, characterized in that: The mass ratios of the mesartan potassium, mannitol, DL-tartaric acid, sodium hydroxide, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, and cross-linked sodium carboxymethyl cellulose are (20-25): (50-55): (0.9-1.3): (0.2-0.6): (2.8-3.2): (8-12): (1.0-2.0): (7-8).
3. The preparation process according to claim 2, characterized in that: The mass ratio of mesartan potassium, mannitol, DL-tartaric acid, sodium hydroxide, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, and cross-linked sodium carboxymethyl cellulose is 23.7:52.6:1.1:0.4:3.0:10.0:1.5:7.
7.
4. The preparation process according to claim 1, characterized in that: The first screening is a 40-mesh sieve; the second screening is a 30-mesh sieve.
5. The preparation process according to claim 1, characterized in that: The step S2) is specifically as follows: DL-tartaric acid and sodium hydroxide are dissolved in pure water, and then hydroxypropyl cellulose is added and dissolved to obtain an adhesive.
6. The preparation process according to claim 1, characterized in that: In the step S3), the granulation is specifically: Add the sieved mesartan potassium and mannitol into the fluidized bed for preheating, set the air inlet temperature to above 60°C for preheating for 10 to 20 minutes, and use a binder for granulation; The atomization pressure of the granulation is 0.1-0.3 MPa, and the material temperature is above 25°C.
7. The preparation process according to claim 1, characterized in that: In the step S3), the drying temperature is 50-60°C; The drying specifically includes drying until the material temperature is 40-50° C. and the moisture content is less than 1.0%.
8. The preparation process according to claim 1, characterized in that: In the step S3), the granulation is performed by 40-mesh sieve granulation.
9. The preparation process according to claim 1, characterized in that: The mixing in step S4) is specifically as follows: First, the intermediate material particles obtained in step S3) are premixed with cross-linked sodium carboxymethyl cellulose and microcrystalline cellulose for 3 to 8 minutes, and then magnesium stearate is added and mixed for 8 to 12 minutes.
10. The preparation process according to claim 1, characterized in that: In the step S4), the tableting pressure is 9-21 KN, and the tableting speed is 8-21 r / min; The drying temperature is 30-50°C, and the drying vacuum degree is 0.1 mbar; The drying step is drying until the moisture content of the tablet is less than 0.5%.