CN112190561B - Preparation method of amoxicillin and clavulanate potassium tablets - Google Patents
Preparation method of amoxicillin and clavulanate potassium tablets Download PDFInfo
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- CN112190561B CN112190561B CN202011190105.XA CN202011190105A CN112190561B CN 112190561 B CN112190561 B CN 112190561B CN 202011190105 A CN202011190105 A CN 202011190105A CN 112190561 B CN112190561 B CN 112190561B
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- amoxicillin
- mixed powder
- clavulanate
- potassium
- powder
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- 229960003022 amoxicillin Drugs 0.000 title claims abstract description 75
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 title claims abstract description 75
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 title claims abstract description 75
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 title claims abstract description 60
- 229940038649 clavulanate potassium Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000011812 mixed powder Substances 0.000 claims abstract description 51
- 238000000576 coating method Methods 0.000 claims abstract description 37
- 239000000843 powder Substances 0.000 claims abstract description 36
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 33
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 33
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 33
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 33
- 239000011248 coating agent Substances 0.000 claims abstract description 32
- 238000002156 mixing Methods 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 230000000694 effects Effects 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 12
- 229920002472 Starch Polymers 0.000 claims abstract description 9
- 239000011734 sodium Substances 0.000 claims abstract description 9
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 9
- 239000008107 starch Substances 0.000 claims abstract description 9
- 235000019698 starch Nutrition 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 8
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims abstract description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 6
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims description 19
- 238000005485 electric heating Methods 0.000 claims description 17
- 238000007873 sieving Methods 0.000 claims description 12
- 238000005303 weighing Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000005461 lubrication Methods 0.000 claims description 4
- 230000002572 peristaltic effect Effects 0.000 claims description 3
- 238000010981 drying operation Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229940090805 clavulanate Drugs 0.000 claims 1
- 230000001050 lubricating effect Effects 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 10
- 238000004090 dissolution Methods 0.000 abstract description 10
- 239000002904 solvent Substances 0.000 abstract description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 abstract description 4
- 229960003324 clavulanic acid Drugs 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 229940083542 sodium Drugs 0.000 abstract description 4
- 239000011259 mixed solution Substances 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 34
- 230000000052 comparative effect Effects 0.000 description 23
- 230000008569 process Effects 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000007908 dry granulation Methods 0.000 description 5
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000428 dust Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 241000588655 Moraxella catarrhalis Species 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000009702 powder compression Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000009475 tablet pressing Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses a preparation method of an amoxicillin and clavulanate potassium tablet, which comprises the following steps: mixing and drying amoxicillin heavy powder, microcrystalline cellulose and colloidal silicon dioxide until the water activity of the mixed powder is less than 0.05aW to obtain mixed powder I; adding a mixed raw material of potassium clavulanate and microcrystalline cellulose, carboxymethyl starch sodium, colloidal silicon dioxide and microcrystalline cellulose into the mixed powder I, and mixing to obtain mixed powder II; adding magnesium stearate into the mixed powder II, and mixing to obtain mixed powder II; directly tabletting the mixed powder III to obtain amoxicillin and clavulanate potassium tablets; taking the compressed amoxicillin potassium clavulanate tablets as tablet core coatings to obtain finished amoxicillin potassium clavulanate tablets; wherein the mass ratio of amoxicillin to clavulanic acid is 7:1, and the coating solvent is a mixed solution of isopropanol and dichloromethane. The invention obtains the amoxicillin and clavulanate potassium tablet product with good stability and dissolution rate by improving the combination relationship of the components and the preparation process.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of an amoxicillin potassium clavulanate tablet.
Background
The amoxicillin and clavulanate potassium is suitable for the lower respiratory tract infection, otitis media and nasosinusitis caused by beta-lactamase Haemophilus influenzae and Moraxella catarrhalis; staphylococcus aureus producing beta-lactamase and bacteria of Enterobacteriaceae such as Escherichia coli and Klebsiella causing urinary tract and skin soft tissue infection; it can also be used for treating mild and moderate infection caused by enterococcus. The product can also be used for treating various infections caused by non-enzyme-producing strains in the bacteria.
The dry granulation and tabletting method is widely applied to the preparation of the compound amoxicillin and clavulanate potassium tablet, but the tablet produced by the dry granulation and tabletting method has the crystal form transformation and activity reduction caused by high pressure and high temperature, the stability of the tablet is influenced, and the improvement of the stability of the tablet is always the key work of various research breakthroughs; and the dry granulation tabletting method has more overall procedures and is more complicated to operate.
Although the direct powder compression method avoids the granulation process, the method has the outstanding advantages of time and energy saving, simple and convenient process, less working procedures, suitability for medicines with unstable moist heat and the like; but also has the defects of poor powder flowability, large tablet weight difference, easy cracking caused by powder tabletting and the like, and the appearance of the tablet is not ideal, so that the application of the process is limited to a certain extent; in addition, the amoxicillin and clavulanate potassium tablet obtained by directly tabletting conventional powder has the defects of poor stability, slower dissolution than a reference preparation and the like.
Disclosure of Invention
Aiming at the technical problems, the invention provides a preparation method of amoxicillin and clavulanate potassium tablets for solving the problems, the invention adopts a direct powder tabletting method to prepare the tablets, and the granulation process is not needed, so that the working procedures are saved; by improving the material adding sequence, improving the coating preparation formula and strictly detecting the water activity of the intermediate process, the fluidity of the material is effectively improved, tabletting and forming are facilitated, and the obtained amoxicillin and clavulanate potassium tablets are good in stability and high in medicinal value.
The invention is realized by the following technical scheme:
a preparation method of amoxicillin and clavulanate potassium tablets comprises the following steps:
step 1, mixing and drying amoxicillin heavy powder, microcrystalline cellulose and colloidal silicon dioxide until the water activity of the mixed powder is less than 0.05aW to obtain mixed powder I;
step 2, adding a mixed raw material of potassium clavulanate and microcrystalline cellulose, carboxymethyl starch sodium, colloidal silicon dioxide and microcrystalline cellulose into the mixed powder I, and mixing to obtain mixed powder II;
step 3, adding magnesium stearate into the mixed powder II, and mixing to obtain mixed powder III;
step 4, directly tabletting the mixed powder III to obtain amoxicillin and clavulanate potassium tablets;
step 5, taking the compressed amoxicillin potassium clavulanate tablets as tablet core coatings to obtain finished amoxicillin potassium clavulanate tablets;
wherein the mass ratio of amoxicillin to clavulanic acid is 7:1, and the coating solvent is a mixed solution of isopropanol and dichloromethane.
In the prior art, potassium clavulanate is mainly sensitive to moisture, so if the influence of moisture on the potassium clavulanate is reduced, the stability of the potassium clavulanate is greatly improved; the amoxicillin content in the preparation is high, and due to the poor flowability of the medicinal powder, the direct tabletting is difficult, the dry granulation process is complex, and the dust is large, so that the research and development of the amoxicillin tablet which is simple to operate, can ensure that the product has good compressibility and the finished tablet has good stability is of great significance.
The invention does not adopt a conventional wet method or dry method granulation and tabletting method, but adopts powder direct tabletting to prepare the amoxicillin and clavulanate potassium gastric-soluble common tablet, mixes the amoxicillin, microcrystalline cellulose (used as a filling agent) and colloidal silicon dioxide (used as a flow aid) in advance and dries the amoxicillin, microcrystalline cellulose and colloidal silicon dioxide in advance through material combination and creative batch mixing, and strictly controls the water activity of the mixed powder to be less than 0.05 aW; then adding the potassium clavulanate and microcrystalline cellulose mixed raw material, carboxymethyl starch sodium, colloidal silicon dioxide and microcrystalline cellulose into the mixed powder, and further mixing the powder uniformly. In addition, the mixing sequence of the materials is improved, the water activity is selectively controlled, the coating material is also improved, the anhydrous environment is fully guaranteed, the finally obtained amoxicillin potassium clavulanate tablet has very good stability, the powder before tabletting has good fluidity, the compressibility is guaranteed, and the prepared tablet product has good appearance and smooth and clean tablet surface.
As a preferred scheme, in the step 1, a double-cone electric heating vacuum dryer is adopted to simultaneously perform mixing and drying operations; setting the temperature of a cylinder body of the cylinder body to 35 ℃; the rotating speed of the cylinder body is 5 rpm; opening in vacuum; and in the vacuum drying process, sampling and detecting the water activity of the mixed powder, and stopping when the water activity of the mixed powder is less than 0.05aW to obtain mixed powder I.
As a preferable scheme:
in the step 1: the diameter of the amoxicillin heavy powder particles is 30-60 meshes, and the amoxicillin heavy powder particles and the microcrystalline cellulose and the colloidal silicon dioxide are mixed with the amoxicillin heavy powder after passing through a 30-mesh sieve; wherein the amoxicillin heavy powder has a bulk density of 0.45g/ml to 0.70g/ml, a tapping density of not less than 0.65g/ml and good fluidity;
in the step 2, the sodium carboxymethyl starch and the colloidal silicon dioxide are sieved by a 30-mesh sieve and then added into the mixed powder I, a mixture of the potassium clavulanate and the microcrystalline cellulose according to the mass ratio of 1:1 and the microcrystalline cellulose are taken, and the sodium clavulanate and the microcrystalline cellulose are sieved by a 40-mesh sieve and then added into the materials for further mixing;
in the step 3, the magnesium stearate is sieved by a 60-mesh sieve, and then the mixed powder II is added and mixed.
Preferably, in the step 4, the tabletting parameters are as follows: the weight of the tablet is (1.345 +/-0.05) g, and the allowable deviation range value of the weight of the tablet is +/-3.7 percent; the thickness of the sheet is 7.50mm-7.60 mm; in the step 5, the coating is increased by 3 percent.
Preferably, in the step 5, Opadry white OY-S-7300-CN is adopted as the coating powder, and the coating solution is prepared according to the mass ratio of the coating powder to isopropanol to dichloromethane of 1:10: 10.
Preferably, the coating formulation method comprises the following steps: firstly, mixing isopropanol and dichloromethane, then adding coating powder under the condition of stirring, and after stirring, sieving by a 60-mesh sieve to obtain a coating solution.
Preferably, during the coating process, the parameters of the coating machine are set as follows: the air inlet temperature is 35 ℃; the material temperature is 30-32 ℃, and the rotation speed of a peristaltic pump is 15 rpm; the rotation speed of the main machine is 5 rpm.
The invention has the following advantages and beneficial effects:
in the prior art, potassium clavulanate is mainly sensitive to moisture, so if the influence of moisture on the potassium clavulanate is reduced, the stability of the potassium clavulanate is greatly improved; the amoxicillin content in the preparation is high, and due to the poor flowability of the medicinal powder, the direct tabletting is difficult, the dry granulation process is complex, and the dust is large, so that the research and development of the amoxicillin tablet which is simple to operate, can ensure that the product has good compressibility and the finished tablet has good stability is of great significance.
The invention does not adopt a conventional wet method or dry method granulation and tabletting method, but adopts powder direct tabletting to prepare the amoxicillin and clavulanate potassium gastric-soluble common tablet, mixes the amoxicillin, microcrystalline cellulose (used as a filling agent) and colloidal silicon dioxide (used as a flow aid) in advance and dries the amoxicillin, microcrystalline cellulose and colloidal silicon dioxide in advance through material combination and creative batch mixing, and strictly controls the water activity of the mixed powder to be less than 0.05 aW; then adding the potassium clavulanate and microcrystalline cellulose mixed raw material, carboxymethyl starch sodium, colloidal silicon dioxide and microcrystalline cellulose into the mixed powder, and further mixing the powder uniformly. In addition, the mixing sequence of the materials is improved, the water activity is selectively controlled, the coating material is also improved, the anhydrous environment is fully guaranteed, the finally obtained amoxicillin potassium clavulanate tablet has very good stability, the powder before tabletting has good fluidity, the compressibility is guaranteed, and the prepared tablet product has good appearance and smooth and clean tablet surface.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not used as limitations of the present invention.
Example 1
The embodiment provides a preparation method of an amoxicillin potassium clavulanate tablet, which comprises the following specific steps:
step 1, drying treatment
Sieving the amoxicillin heavy powder, weighing 2510g of amoxicillin which can pass through a 30-mesh sieve and be intercepted by a 60-mesh sieve, and adding the weighed amoxicillin into a double-cone electric heating vacuum dryer; then 17.46g of microcrystalline cellulose and 7.49g of colloidal silicon dioxide are weighed, and the two are sieved by a 30-mesh sieve and then poured into a double-cone electric heating vacuum drying machine to be mixed and dried with amoxicillin heavy powder. The double-cone electric heating vacuum drier is arranged as follows: the temperature of the cylinder body is 35 ℃; the rotating speed of the cylinder body is 5 rpm; the vacuum is turned on. And in the vacuum drying process, sampling every 30min to detect the water activity of the mixed powder, and stopping when the water activity of the mixed powder is less than 0.05aW to obtain mixed powder I.
Step 2, pre-lubrication treatment
Weighing 12.39g of sodium carboxymethyl starch and 7.43g of colloidal silicon dioxide, sieving the two materials with a 30-mesh sieve, and adding the sieved materials into a double-cone electric heating vacuum dryer filled with mixed powder I; then, 754.61g of potassium clavulanate, 754.61g of microcrystalline cellulose (the mass ratio of the two is 1:1) and 17.31g of microcrystalline cellulose are weighed, and the potassium clavulanate, the microcrystalline cellulose and the microcrystalline cellulose are sieved by a 40-mesh sieve and then are added into a double-cone electric heating vacuum drier for mixing. The double-cone electric heating vacuum drier is arranged as follows: heating the cylinder to close; the rotating speed of the cylinder body is 5 rpm; the vacuum is turned off. Mixing for 30min to obtain mixed powder II.
Step 3, lubrication treatment
Weighing 24.73g of magnesium stearate, sieving with a 60-mesh sieve, adding into a double-cone electric heating vacuum drying machine, and mixing with the mixed powder II. The double-cone electric heating vacuum drier is arranged as follows: heating the cylinder to close; the rotating speed of the cylinder body is 5 rpm; the vacuum is turned off. Mixing for 3min to obtain mixed powder III.
Step 4, tabletting
Tabletting by using the mixed powder III, wherein the rotating speed of a tabletting machine is 6rpm, and the tabletting parameters are as follows: the weight of the tablet is 1.345 g; the thickness of the sheet is 7.50mm-7.60 mm.
Step 5, coating
1) Preparing coating liquid
Coating liquid is prepared by mixing IPA and DCM in a mass ratio of 1:10:10 of IPA to DCM, then slowly adding the coating powder while stirring, stirring for 1h, and then sieving with a 60-mesh sieve to obtain the coating liquid;
2) coating film
Taking the compressed amoxicillin potassium clavulanate tablets as tablet core coatings, wherein a coating machine is set as follows: the air inlet temperature is 35 ℃; the material temperature is 30-32 ℃, the rotating speed of a peristaltic pump is 15 rpm; the rotation speed of the main machine is 5 rpm. The coating is finished until the tablet core is increased to 1.385g (3 percent of weight).
Comparative example 1
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: in the step 1, the drying treatment is stopped when the water activity of the mixed powder is controlled to be 0.2 aW.
Comparative example 2
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: in the step 1, the drying treatment is carried out to control the water content to be less than 10% by mass.
Comparative example 3
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: simultaneously adding amoxicillin heavy powder, potassium clavulanate, sodium carboxymethyl starch, all microcrystalline cellulose and colloidal silicon dioxide into a double-cone electric heating vacuum drying machine for mixing to obtain mixed powder I, namely adding the materials in batches and in sequence; then adding magnesium stearate into the mixed powder I and mixing to obtain mixed powder II; and (3) directly tabletting the mixed powder II to obtain the amoxicillin and clavulanate potassium tablets.
Comparative example 4
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: the sequence of step 2 and step 1 is changed:
step 1, pre-lubrication treatment
Weighing 12.39g of sodium carboxymethyl starch and 7.43g of colloidal silicon dioxide, sieving the two materials with a 30-mesh sieve, and adding the sieved materials into a double-cone electric heating vacuum dryer filled with mixed powder I; then, 754.61g of potassium clavulanate, 754.61g of microcrystalline cellulose (the mass ratio of the two is 1:1) and 17.31g of microcrystalline cellulose are weighed, and the potassium clavulanate, the microcrystalline cellulose and the microcrystalline cellulose are sieved by a 40-mesh sieve and then are added into a double-cone electric heating vacuum drier for mixing. The double-cone electric heating vacuum drier is arranged as follows: heating the cylinder to close; the rotating speed of the cylinder body is 5 rpm; the vacuum is turned off. Mixing for 30min to obtain mixed powder I.
Step 2, drying treatment
Sieving the amoxicillin heavy powder, weighing 2510g of amoxicillin which can pass through a 30-mesh sieve and be intercepted by a 60-mesh sieve, adding into a double-cone electric heating vacuum drying machine, and mixing with the mixed powder I; then, 17.46g of microcrystalline cellulose and 7.49g of colloidal silicon dioxide are weighed, and the two are sieved by a 30-mesh sieve and then poured into a double-cone electric heating vacuum drying machine to be mixed and dried with the mixture of the amoxicillin heavy powder and the mixed powder I. The double-cone electric heating vacuum drier is arranged as follows: the temperature of the cylinder body is 35 ℃; the rotating speed of the cylinder body is 5 rpm; the vacuum is turned on. And in the vacuum drying process, sampling every 30min to detect the water activity of the mixed powder, and stopping until the water activity of the mixed powder is less than 0.05aW to obtain mixed powder II.
Comparative example 5
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: the coating solvent adopts absolute ethyl alcohol.
Comparative example 6
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: the coating solvent adopts isopropanol.
Comparative example 7
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: the coating solvent adopts dichloromethane.
Comparative example 8
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: the ratio of amoxicillin to clavulanic acid is 8: 1.
Comparative example 9
Based on the preparation method of amoxicillin and clavulanate potassium tablets provided in example 1, the difference is that: the ratio of amoxicillin to clavulanic acid is 4: 1.
Water Activity and Angle of repose detection
1. Water activity determination
The instrument was calibrated at six points with the activity standard solution provided with the water activity meter prior to the experiment. About 1.0g of sample is taken and placed in a sample box equipped with a water activity meter, the sample box is placed in a sample bin of the instrument in an open state for 20min, and the measurement is started after the balance. Each sample was measured 2 times, and the average value was taken and the measurement temperature was 25 ℃.
In example 1 and comparative examples 1 and 3 to 9, the water activity test was determined by the method described above.
2. Method for measuring angle of repose
A powder sample was taken, and the angle of repose was measured by the fixed cone bottom method, the cone bottom diameter (2R) was 5.42cm, the height of the powder particle stack was measured, and the angle of repose α, α ═ arctg (h/R) was calculated. The powders before tableting in example 1 and comparative examples 1 to 4 and comparative examples 8 to 9 were tested for flowability, and the results are shown in table 1:
TABLE 1
| Sample (I) | Example 1 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 8 | Comparative example 9 |
| Angle of repose | 28° | 30° | 31° | 38° | 40° | 33° | 35° |
The mixed powder III provided by the embodiment 1 has good fluidity, good compressibility and smooth tablet pressing, and the obtained tablet product has smooth surface and no undesirable phenomena such as cracking and the like. Comparative examples 1, 2 and 8 have better fluidity, and the surface of the tablet product is smooth; comparative examples 3, 4 and 9 had poor flowability and compressibility, the powder was too dry, and the finished tablets had rough and unsmooth surfaces.
Secondly, stability and dissolution rate detection
1. Method for high-humidity accelerated stability experiment
Samples were taken and placed in a climatic chamber with the experimental temperature (25 +/-2) DEG C and the relative humidity (75 +/-5)% to carry out a high-humidity acceleration experiment, and the samples were not taken for measurement at 0, 2, 5, 10, 24, 48 and 120h respectively from the beginning of the lofting.
The related substances of amoxicillin and potassium clavulanate at 24 months are taken as indexes for investigation.
2. Dissolution determination
According to a dissolution rate determination method of amoxicillin potassium clavulanate tablets (second part of version 2010 of Chinese pharmacopoeia), samples are taken, according to a dissolution rate determination method (second part of appendix X C of second part of version 2010 of Chinese pharmacopoeia), 900mL of water is taken as a medium, the water temperature is 37 ℃, the rotating speed is 75r/min, the operation is carried out according to the method, 10mL of solution is taken after 30min, the solution is filtered, 10uL of subsequent filtrate is taken and injected into a chromatograph, and the chromatogram is recorded; and precisely weighing appropriate amount of amoxicillin reference substance and potassium clavulanate reference substance, dissolving in water to obtain solution containing amoxicillin 0.67mg in each 1mL, and determining by the same method to obtain reference substance. And calculating the dissolution amount of amoxicillin and potassium clavulanate in each tablet.
The results are shown in tables 2 and 3:
table 2 test results of finished tablets prepared in example 1 and comparative examples 1 to 9 on day 0
Table 3 test results of finished tablets prepared in example 1 and comparative examples 1 to 9 after 6 months
The dissolution rate of the tablet prepared in the embodiment 1 of the invention reaches 100% within 10min after detection within 0 day; after 6 months, the dissolution rate reaches 100% within 15 min.
Third, determination of disintegration time limit
The samples were tested for disintegration time limit (appendix XA of second part of the version 2010 of Chinese pharmacopoeia), water was used as disintegration medium, the temperature was 21 ℃, disintegration was completed within 3min, and the test results are shown in Table 4:
TABLE 4 disintegration time of tablets prepared in example 1 and comparative examples 1 to 9
The amoxicillin potassium clavulanate tablet sample prepared by the embodiment has a faster disintegration rate, and is beneficial to the improvement of subsequent dissolution rate.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (4)
1. A preparation method of amoxicillin and clavulanate potassium tablets is characterized by comprising the following steps:
step 1, drying treatment:
sieving amoxicillin heavy powder, weighing 2510g amoxicillin which can pass through a 30-mesh sieve and is intercepted by a 60-mesh sieve, weighing 17.46g microcrystalline cellulose and 7.49g colloidal silicon dioxide, and sieving the amoxicillin heavy powder and the colloidal silicon dioxide with the 30-mesh sieve; adding amoxicillin heavy powder, microcrystalline cellulose and colloidal silicon dioxide into a dryer, mixing and drying until the water activity of the mixed powder is less than 0.05aW to obtain mixed powder I;
step 2, pre-lubrication treatment:
weighing 12.39g of sodium carboxymethyl starch and 7.43g of colloidal silicon dioxide, sieving the two materials with a 30-mesh sieve, and adding the sieved materials into a dryer filled with mixed powder I; then 754.61g of potassium clavulanate and 17.31g of microcrystalline cellulose are weighed, and the two are sieved by a 40-mesh sieve and then are added into a drier to be mixed to obtain mixed powder II; the mass ratio of the potassium clavulanate to the microcrystalline cellulose is 1: 1;
step 3, lubricating treatment:
weighing 24.73g of magnesium stearate, sieving with a 60-mesh sieve, adding into a drier, and mixing with the mixed powder II to obtain mixed powder III;
and 4, tabletting:
tabletting by using mixed powder III, wherein the tabletting parameters are as follows: the weight of the tablet is 1.345 g; the thickness of the sheet is 7.50mm-7.60 mm;
step 5, coating:
1) preparing coating liquid
Coating liquid is prepared by mixing IPA and DCM in a mass ratio of 1:10:10 of IPA to DCM, then slowly adding the coating powder while stirring, stirring for 1h, and then sieving with a 60-mesh sieve to obtain the coating liquid;
2) coating film
Taking the compressed amoxicillin potassium clavulanate tablets as tablet core coatings, and finishing the coating until the weight of the tablet core is increased to 1.385 g.
2. The process for preparing potassium amoxicillin and clavulanate tablets as claimed in claim 1, wherein in step 1, a double-cone electric heating vacuum drier is used to perform the mixing and drying operations simultaneously; setting the temperature of a cylinder body of the cylinder body to 35 ℃; the rotating speed of the cylinder body is 5 rpm; the vacuum is turned on.
3. The process for preparing amoxicillin and clavulanate potassium tablets as claimed in claim 1, wherein in step 1: the amoxicillin heavy powder has a bulk density of 0.45-0.70 g/ml and a tapped density of not less than 0.65 g/ml.
4. The process for preparing amoxicillin and potassium clavulanate tablets as claimed in claim 1, wherein during coating, the coating machine parameters are set as follows: the air inlet temperature is 35 ℃; the material temperature is 30-32 ℃, and the rotation speed of a peristaltic pump is 15 rpm; the rotation speed of the main machine is 5 rpm.
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Application publication date: 20210108 Assignee: CHENGDU JINGFU PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Assignor: SICHUAN PHARMACEUTICAL Inc. Contract record no.: X2024980005562 Denomination of invention: A preparation method for amoxicillin and potassium clavulanate tablets Granted publication date: 20220201 License type: Common License Record date: 20240510 |