CN115463099B - Cefprozil dry suspension and preparation method thereof - Google Patents
Cefprozil dry suspension and preparation method thereof Download PDFInfo
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- CN115463099B CN115463099B CN202211284911.2A CN202211284911A CN115463099B CN 115463099 B CN115463099 B CN 115463099B CN 202211284911 A CN202211284911 A CN 202211284911A CN 115463099 B CN115463099 B CN 115463099B
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- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 title claims abstract description 38
- 229960002580 cefprozil Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000000725 suspension Substances 0.000 title claims abstract description 23
- 238000002156 mixing Methods 0.000 claims abstract description 55
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 42
- 238000003756 stirring Methods 0.000 claims abstract description 37
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 22
- 229930006000 Sucrose Natural products 0.000 claims abstract description 22
- 239000005720 sucrose Substances 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
- 239000011780 sodium chloride Substances 0.000 claims abstract description 21
- 239000007779 soft material Substances 0.000 claims abstract description 20
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 19
- 238000001035 drying Methods 0.000 claims abstract description 19
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 17
- 229930195725 Mannitol Natural products 0.000 claims abstract description 17
- 239000000594 mannitol Substances 0.000 claims abstract description 17
- 235000010355 mannitol Nutrition 0.000 claims abstract description 17
- 108010011485 Aspartame Proteins 0.000 claims abstract description 16
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 16
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000605 aspartame Substances 0.000 claims abstract description 16
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims abstract description 16
- 235000010357 aspartame Nutrition 0.000 claims abstract description 16
- 229960003438 aspartame Drugs 0.000 claims abstract description 16
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 16
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 16
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 16
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims abstract description 16
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 229960002668 sodium chloride Drugs 0.000 claims abstract description 11
- 235000002639 sodium chloride Nutrition 0.000 claims abstract description 11
- 238000005303 weighing Methods 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 11
- 239000008187 granular material Substances 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 7
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 26
- 238000004090 dissolution Methods 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 3
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- WMTZPTDZOUFHEI-UHFFFAOYSA-N FL-120B Natural products C1=CC=C2C(=O)C(C3=C(N4C#N)C(C5(OC5C3O)C)OC(=O)C(C)C)=C4C(=O)C2=C1O WMTZPTDZOUFHEI-UHFFFAOYSA-N 0.000 description 3
- RPARKPVSEAVPID-XAPVIXHLSA-N [(3R,4R,6R,7S)-9-diazo-3,13-dihydroxy-6-methyl-11,18-dioxo-5-oxapentacyclo[8.8.0.02,8.04,6.012,17]octadeca-1(10),2(8),12(17),13,15-pentaen-7-yl] 2-methylpropanoate Chemical compound CC(C)C(=O)O[C@H]1c2c([C@@H](O)[C@H]3O[C@]13C)c1c(c2=[N+]=[N-])c(=O)c2c(O)cccc2c1=O RPARKPVSEAVPID-XAPVIXHLSA-N 0.000 description 3
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- 229910001220 stainless steel Inorganic materials 0.000 description 3
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- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- ALYUMNAHLSSTOU-PFBPGKLMSA-N (6r,7r)-7-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-prop-1-enyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C=CC)C(O)=O)=CC=C(O)C=C1 ALYUMNAHLSSTOU-PFBPGKLMSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 102100028717 Cytosolic 5'-nucleotidase 3A Human genes 0.000 description 1
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61P31/04—Antibacterial agents
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Abstract
The invention discloses a preparation method of cefprozil dry suspension, which belongs to the technical field of pharmaceutical preparations and comprises the following steps: (1) weighing raw materials: cefprozil, sucrose, mannitol, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, sodium chloride, aspartame and essence; (2) Mixing cefprozil, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame and sodium chloride to obtain a premix A; (3) Adding sucrose and mannitol into the premix A, and mixing to obtain a premix B; (4) Adding water into the premix B, stirring and mixing to prepare a soft material, granulating the soft material and drying; and (5) adding essence into the particles obtained by drying, and uniformly mixing. The cefprozil dry suspension prepared by the invention can improve the quality stability while ensuring the dissolution rate of the medicament.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a cefprozil dry suspension and application thereof.
Background
Cefprozil is (6R, 7R) -3-propenyl-7- [ (R) -2-amino-2- (4-hydroxyphenyl) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-hydrate, belonging to beta-lactam antibiotics. The action mechanism of the antibacterial agent is similar to that of other cephalosporins, the antibacterial agent mainly plays an antibacterial role by blocking bacterial cell wall biosynthesis, and the antibacterial agent has stronger activity against gram-negative bacillus and stability against gram-negative bacillus beta-lactamase than the first-generation cephalosporins, so that the antibacterial agent has good application prospect.
The cefprozil is prepared into a dry suspension, so that the dry suspension is convenient to carry, good in stability and convenient to take; however, the instant dry suspension is required to be rapidly dissolved and also required to have proper physical stability, so how to provide a preparation method capable of ensuring the dissolution effect and stability of the cefprozil dry suspension is a technical problem to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the invention provides a preparation method of cefprozil dry suspension, which can improve the stability of the product and can not influence the dissolution efficiency of the product.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a preparation method of cefprozil dry suspension comprises the following steps:
(1) Weighing the following raw materials in parts by weight:
12-14 parts of cefprozil, 50-60 parts of sucrose, 25-35 parts of mannitol, 0.1-0.7 part of sodium carboxymethyl cellulose, 0.2-0.5 part of microcrystalline cellulose, 0.3-0.8 part of colloidal silicon dioxide, 0.2-0.7 part of sodium chloride, 0.1-0.5 part of aspartame and 0.1-0.2 part of essence;
(2) Mixing cefprozil, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame and sodium chloride to obtain a premix A;
(3) Adding sucrose and mannitol into the premix A, and mixing to obtain a premix B;
(4) Adding water into the premix B, wherein the water adding amount is related to the production batch, the average dosage of the premix B to a single dosage is 25-55 mu L according to the batch, stirring and mixing the premix B to prepare a soft material, granulating the soft material, and drying the soft material;
(5) Adding essence into the dried granules, and mixing uniformly.
According to the invention, cefprozil, sucrose, mannitol, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, sodium chloride and aspartame are compounded in a specific proportion, and are mixed and granulated in a specific sequence, so that the obtained cefprozil dry suspension has good stability and high drug dissolution speed, and is suitable for large-scale production;
in addition, because the proportion of mannitol and sucrose in the prescription is relatively high and the proportion of other components is small, the cefprozil, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame, sodium chloride, mannitol and sucrose are not mixed together, but cefprozil, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame and sodium chloride are mixed first, mannitol and sucrose are added, so that the situation of uneven mixing is prevented, and according to the general consideration of preparation research, the materials with large proportion are mixed together after the small proportion is uniformly mixed, and the risk of uneven mixing can be reduced.
Preferably, in the step (1),
sodium chloride is sieved by a 40-mesh sieve, colloidal silica is sieved by a 20-mesh sieve, and sucrose is sieved by a 80-mesh sieve.
Preferably, in the step (2),
the rotation speed is 20+/-1 r/min during mixing, and the mixing time is 15+/-1 min.
Preferably, in the step 3), a wet granulator is used for mixing, the rotation speed of a stirring paddle is 20+/-2 r/min, the rotation speed of a cutter is 22+/-3 r/min, and the mixing is 15+/-1 min.
Preferably, in the step (4),
stirring, mixing and granulating by using a wet granulator:
stirring paddle rotation speed: 30+/-2 r/min, the rotating speed of the cutter is 30+/-3 r/min, and the mixing is 45+/-5 s; checking the granulating condition, if the granulating is unqualified, continuously adding a proper amount of water, and then stirring at the rotating speed of a stirring paddle: 30+/-2 r/min, the rotating speed of the cutter is 30+/-3 r/min, and the mixing is 45+/-5 s; after the preparation of the soft material is completed, a discharge port of a wet granulator is opened, the prepared soft material is granulated by a 20-mesh screen, and the granulated material is fed to a boiling granulating dryer for drying by a vacuum feeding system.
The fine powder prepared by too small particle size has more particles, and the later fluidity is poor, so that the inner package is affected; the particle size is too large, the prepared particles are larger, the drying in the drying step is not facilitated, and experiments show that 20 meshes are the most suitable in the process.
Preferably, in the step (4),
drying with boiling granulating drier at air inlet temperature of 45+ -15deg.C, air outlet temperature of 40+ -10deg.C, material temperature of less than or equal to 50deg.C, and drying for 45+ -1 min.
Preferably, in the step (5),
the mixing rotating speed is 15+/-1 r/min, and the mixing is 45+/-1 min.
In conclusion, the cefprozil dry suspension prepared by the method has stable quality and high dissolution rate, and is suitable for large-scale production.
Drawings
FIG. 1 shows the impurity profile of example 4;
FIG. 2 shows the dissolution profile of the dissolution medium of example 4 at pH 1.0.
Detailed Description
Example 1
A preparation method of cefprozil dry suspension comprises the following steps:
(1) Weighing the following raw materials in parts by weight:
12.5 parts of cefprozil, 55 parts of sucrose, 30.1 parts of mannitol, 0.5 part of sodium carboxymethyl cellulose, 0.4 part of microcrystalline cellulose, 0.5 part of colloidal silicon dioxide, 0.4 part of sodium chloride, 0.4 part of aspartame and 0.2 part of strawberry essence; wherein, sodium chloride is sieved by a 40-mesh sieve, colloidal silicon dioxide is sieved by a 20-mesh sieve, and sucrose is sieved by a 80-mesh sieve.
(2) Sequentially adding cefprozil, sodium carboxymethylcellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame and sodium chloride into a multidirectional motion mixer (model: HD-200 in Winzhou, pharmaceutical equipment factory), closing a barrel cover, adjusting the rotating speed to 20+/-1 r/min, starting the mixer, mixing for 15+/-1 min, and discharging the mixture into a turnover barrel of an inner sleeve nontoxic plastic bag to obtain a premix A.
(3) Pouring the premix A, sucrose and mannitol into a high-efficiency wet granulator (model: HZ-250B of Chongqing south pharmaceutical machinery factory), starting a stirring paddle and a cutter to stir for 15+/-1 min, wherein the rotating speed of the stirring paddle is 20+/-2 r/min, and the rotating speed of the cutter is 22+/-2 r/min, so as to obtain the premix B.
(4) Adding purified water into the premix B, stirring, adding a proper amount of purified water according to the wetting condition, averaging to a single dosage of 25-55 mu L, starting a stirring paddle and a cutter for stirring while adding, wherein the rotating speed of the stirring paddle is 30+/-2 r/min, the rotating speed of the cutter is 30+/-3 r/min, and mixing for 45+/-5 s to prepare a soft material.
After the preparation of the soft material is completed, a discharge port of a wet granulator is opened, and the prepared soft material is granulated by a 20-mesh screen.
The prepared granules are sucked into a boiling granulating dryer (model FL-120B of Chongqing south pharmaceutical machinery factory) for drying, the air inlet temperature is adjusted to be 45+/-15 ℃, the air outlet temperature is adjusted to be 40+/-10 ℃, the material temperature is not more than 50 ℃, and the drying is performed for 45+/-1 min.
And (3) finishing the dried particles by using a vibrating screen, confirming that the mesh number of the screen is 20 meshes before using the vibrating screen, and loading the prepared particles into a mixing barrel for total mixing.
(5) And (3) pouring the granules prepared in the step (4) and the strawberry essence into an automatic lifting hopper mixer (HZD-1500, model number: manufactured by Zhejiang Galan pharmaceutical equipment Co., ltd.), closing a barrel cover, adjusting the rotating speed to 15+/-1 r/min, starting the machine, mixing for 45+/-1 min, and discharging into a stainless steel rotary barrel internally sleeved with a nontoxic plastic bag.
(6) And (5) taking the qualified particles prepared in the step (5), and carrying out inner wrapping by using a particle automatic filling and packaging machine.
Example 2
A preparation method of cefprozil dry suspension comprises the following steps:
(1) Weighing the following raw materials in parts by weight:
12 parts of cefprozil, 60 parts of sucrose, 25 parts of mannitol, 0.7 part of sodium carboxymethyl cellulose, 0.5 part of microcrystalline cellulose, 0.8 part of colloidal silicon dioxide, 0.7 part of sodium chloride, 0.1 part of aspartame and 0.2 part of strawberry essence; wherein, sodium chloride is sieved by a 40-mesh sieve, colloidal silicon dioxide is sieved by a 20-mesh sieve, and sucrose is sieved by a 80-mesh sieve.
(2) Sequentially adding cefprozil, sodium carboxymethylcellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame and sodium chloride into a multidirectional motion mixer (model: HD-200 in Winzhou, pharmaceutical equipment factory), closing a barrel cover, adjusting the rotating speed to 20+/-1 r/min, starting the mixer, mixing for 15+/-1 min, and discharging the mixture into a turnover barrel of an inner sleeve nontoxic plastic bag to obtain a premix A.
(3) Pouring the premix A, sucrose and mannitol into a high-efficiency wet granulator (model: HZ-250B of Chongqing south pharmaceutical machinery factory), starting a stirring paddle and a cutter to stir for 15+/-1 min, wherein the rotating speed of the stirring paddle is 20+/-2 r/min, and the rotating speed of the cutter is 22+/-2 r/min, so as to obtain the premix B.
(4) Adding purified water into the premix B, stirring, adding a proper amount of purified water according to the wetting condition, averaging to a single dosage of 25-55 mu L, starting a stirring paddle and a cutter for stirring while adding, wherein the rotating speed of the stirring paddle is 30+/-2 r/min, the rotating speed of the cutter is 30+/-3 r/min, and mixing for 45+/-5 s to prepare a soft material.
After the preparation of the soft material is completed, a discharge port of a wet granulator is opened, and the prepared soft material is granulated by a 20-mesh screen.
The prepared granules are sucked into a boiling granulating dryer (model FL-120B of Chongqing south pharmaceutical machinery factory) for drying, the air inlet temperature is adjusted to be 45+/-15 ℃, the air outlet temperature is adjusted to be 40+/-10 ℃, the material temperature is not more than 50 ℃, and the drying is performed for 45+/-1 min.
And (3) finishing the dried particles by using a vibrating screen, confirming that the mesh number of the screen is 20 meshes before using the vibrating screen, and loading the prepared particles into a mixing barrel for total mixing.
(5) And (3) pouring the granules prepared in the step (4) and the strawberry essence into an automatic lifting hopper mixer (HZD-1500, model number: manufactured by Zhejiang Galan pharmaceutical equipment Co., ltd.), closing a barrel cover, adjusting the rotating speed to 15+/-1 r/min, starting the machine, mixing for 45+/-1 min, and discharging into a stainless steel rotary barrel internally sleeved with a nontoxic plastic bag.
(6) And (5) taking the qualified particles prepared in the step (5), and carrying out inner wrapping by using a particle automatic filling and packaging machine.
Example 3
A preparation method of cefprozil dry suspension comprises the following steps:
(1) Weighing the following raw materials in parts by weight:
14 parts of cefprozil, 50 parts of sucrose, 35 parts of mannitol, 0.1 part of sodium carboxymethyl cellulose, 0.2 part of microcrystalline cellulose, 0.3 part of colloidal silicon dioxide, 0.2 part of sodium chloride, 0.1 part of aspartame and 0.1 part of strawberry essence; wherein, sodium chloride is sieved by a 40-mesh sieve, colloidal silicon dioxide is sieved by a 20-mesh sieve, and sucrose is sieved by a 80-mesh sieve.
(2) Sequentially adding cefprozil, sodium carboxymethylcellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame and sodium chloride into a multidirectional motion mixer (model: HD-200 in Winzhou, pharmaceutical equipment factory), closing a barrel cover, adjusting the rotating speed to 20+/-1 r/min, starting the mixer, mixing for 15+/-1 min, and discharging the mixture into a turnover barrel of an inner sleeve nontoxic plastic bag to obtain a premix A.
(3) Pouring the premix A, sucrose and mannitol into a high-efficiency wet granulator (model: HZ-250B of Chongqing south pharmaceutical machinery factory), starting a stirring paddle and a cutter to stir for 15+/-1 min, wherein the rotating speed of the stirring paddle is 20+/-2 r/min, and the rotating speed of the cutter is 22+/-2 r/min, so as to obtain the premix B.
(4) Adding purified water into the premix B, stirring, adding a proper amount of purified water according to the wetting condition, averaging to a single dosage of 25-55 mu L, starting a stirring paddle and a cutter for stirring while adding, wherein the rotating speed of the stirring paddle is 30+/-2 r/min, the rotating speed of the cutter is 30+/-3 r/min, and mixing for 45+/-5 s to prepare a soft material.
After the preparation of the soft material is completed, a discharge port of a wet granulator is opened, and the prepared soft material is granulated by a 20-mesh screen.
The prepared granules are sucked into a boiling granulating dryer (model FL-120B of Chongqing south pharmaceutical machinery factory) for drying, the air inlet temperature is adjusted to be 45+/-15 ℃, the air outlet temperature is adjusted to be 40+/-10 ℃, the material temperature is not more than 50 ℃, and the drying is performed for 45+/-1 min.
And (3) finishing the dried particles by using a vibrating screen, confirming that the mesh number of the screen is 20 meshes before using the vibrating screen, and loading the prepared particles into a mixing barrel for total mixing.
(5) And (3) pouring the granules prepared in the step (4) and the strawberry essence into an automatic lifting hopper mixer (HZD-1500, model number: manufactured by Zhejiang Galan pharmaceutical equipment Co., ltd.), closing a barrel cover, adjusting the rotating speed to 15+/-1 r/min, starting the machine, mixing for 45+/-1 min, and discharging into a stainless steel rotary barrel internally sleeved with a nontoxic plastic bag.
(6) And (5) taking the qualified particles prepared in the step (5), and carrying out inner wrapping by using a particle automatic filling and packaging machine.
Example 4
Taking samples of examples 1, 2 and 3, respectively taking purified water and a pH1.0 hydrochloric acid solution as dissolution media for dissolution curve measurement, comparing the dissolution curves with a reference preparation (cefprozil dry suspension marketed by Lupin LTD in the United states, batch number: F701087), adopting a slurry method (second method of rule 0931 of four portions of Chinese pharmacopoeia 2010 version), taking 5ml of solution as a sample solution after 5min, 10min, 15min, 20min and 30min respectively, wherein the rotation speed is 50 revolutions per minute, and the volume of the medium is 900 ml. The dissolution (%) results are shown in table 1 and fig. 2.
TABLE 1
Samples of examples 1, 2 and 3 were taken, and impurity spectra were compared with a reference preparation (cefprozil dry suspension of Lupin LTD in the united states, lot number: F701087) using a DAD detector, and the results are shown in tables 2 to 3 and fig. 1, which show that the number and positions of the detected impurity peaks of the examples are substantially identical to those of the reference preparation, and the purity of each impurity peak is equivalent.
TABLE 2
TABLE 3 Table 3
The stability of the samples of examples 1, 2 and 3 was examined under accelerated conditions (40 ℃ + -2 ℃/75% + -5% RH) in comparison with a reference formulation (cefprozil dry suspension, lot number F701087, marketed by Lupin LTD in the United states), and the results showed that the stability of the samples of examples 1, 2 and 3 was substantially identical to the reference formulation.
TABLE 4 Table 4
Example 5
According to the prescription proportion and the preparation process of the above example 1, raw material medicines with different particle sizes are selected to prepare samples so as to examine the influence of the particle sizes of the raw materials on dissolution. Dissolution profile measurements were performed on each formulation aliquot using purified water as dissolution medium, and the results are shown in table 5, compared to the dissolution profile of the reference formulation. The research result shows that the average dissolution rate of the samples prepared from 5 batches of raw materials and the Lupin reference preparation in purified water for 15min is more than 85%, and the dissolution curve of the samples prepared from 5 batches of raw materials is similar to the dissolution curve of the reference preparation according to the dissolution curve similarity judgment standard in the general oral solid preparation dissolution curve measurement and comparison guidelines. Thus, the upper limit of the particle size was found to be D50:28.51. Mu.m, D90:70.48. Mu.m; the lower limit is D50:9.76 μm and D90:19.73 μm.
TABLE 5
| Formulation lot number | Corresponding raw material lot number | D50 | D90 |
| BX220513A | 2032202003 | 9.76 | 19.73 |
| BX220513B | 2032202002 | 10.55 | 22.52 |
| BX220513C | 2032111001 | 18.63 | 50.28 |
| BX220513D | BX220401(lab)03 | 23.03 | 57.28 |
| BX220513E | 2032110001 | 28.51 | 70.48 |
TABLE 6
| Sample of | 10min | 15min |
| Reference formulation (F701087) | 98.33 | 101.90 |
| BX220513A | 107.08 | 107.37 |
| BX220513B | 111.04 | 111.54 |
| BX220513C | 105.76 | 108.81 |
| BX220513D | 95.55 | 99.84 |
| BX220513E | 88.36 | 95.45 |
Example 6
According to the prescription proportion of the example 1 and the raw materials in the particle size range of the example 5, cefprozil, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame, sodium chloride, sucrose and mannitol are sequentially poured into a high-efficiency wet granulator without premixing, stirring paddles and cutters are started for 15+/-1 min, the rotating speed of the stirring paddles is 20+/-2 r/min, the rotating speed of the cutters is 22+/-2 r/min, mixing is carried out, and sampling is carried out in the mixing process, so that the mixing uniformity is checked. The rest of the preparation is the same as in example 1. The results of the uniformity of mixing examination are shown in Table 7, and show that all the materials were mixed together, the materials were not uniformly mixed, and the uniformity of mixing of the materials was not improved with the increase of the mixing time.
TABLE 7
Example 7
Sample preparation was performed according to the procedure of example 1, except that the cutter was not activated in step 3, according to the recipe of example 1 and the raw materials in the particle size range of example 5, and the other parameters were the same as in example 1. The results of the uniformity test are shown in Table 8, which shows that the cutter is not started in the step 3, and the materials are unevenly mixed. The results of the mixing uniformity inspection are shown in the following table.
TABLE 8
Example 8
Sample preparation was performed according to the procedure of example 1, with the raw materials in the recipe proportion of example 1 and the particle size range of example 5, but in step (4), the rotation speed of the stirring paddle was adjusted to 40r/min, the rotation speed of the cutter was adjusted to 40r/min, the mixing time was adjusted to 60s, and the other preparation parameters were the same as in example 1. The sample prepared by the process has excessive fine powder and loose particles, and influences the accuracy of the subsequent packaging process and the like.
Example 9
Sample preparation was performed according to the procedure of example 1, with the recipe of example 1 and the starting materials in the particle size range of example 5, but the particle drying temperature was adjusted at step (4) as follows: the air inlet temperature is 50+/-15 ℃, the air outlet temperature is 45+/-10 ℃, the material temperature is less than or equal to 55 ℃, the drying time is 40+/-1 min, and the other preparation parameters are the same as those of the example 1 for preparing the sample. The samples produced according to this process have a reduced content compared with example 1, a marked increase in the relevant substances and a detailed comparison is given in table 9.
TABLE 9
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to the embodiments described above will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. The preparation method of the cefprozil dry suspension is characterized by comprising the following steps of:
(1) Weighing the following raw materials in parts by weight:
12-14 parts of cefprozil, 50-60 parts of sucrose, 25-35 parts of mannitol, 0.1-0.7 part of sodium carboxymethyl cellulose, 0.2-0.5 part of microcrystalline cellulose, 0.3-0.8 part of colloidal silicon dioxide, 0.2-0.7 part of sodium chloride, 0.1-0.5 part of aspartame and 0.1-0.2 part of essence;
(2) Mixing cefprozil, sodium carboxymethyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, aspartame and sodium chloride to obtain a premix A;
(3) Adding sucrose and mannitol into the premix A, and mixing to obtain a premix B; mixing by using a wet granulator, wherein the rotating speed of a stirring paddle is 20+/-2 r/min, the rotating speed of a cutter is 22+/-3 r/min, and mixing is 15+/-1 min;
(4) Adding water into the premix B, stirring and mixing to prepare a soft material, granulating the soft material and drying; stirring, mixing and granulating by using a wet granulator: stirring paddle rotation speed: 30+/-2 r/min, the rotating speed of the cutter is 30+/-3 r/min, and the mixing is 45+/-5 s; checking the granulating condition, if the granulating is unqualified, continuously adding a proper amount of water, and then stirring at the rotating speed of a stirring paddle: 30+/-2 r/min, the rotating speed of the cutter is 30+/-3 r/min, and the mixing is 45+/-5 s; after the preparation of the soft material is completed, a discharge port of a wet granulator is opened, the prepared soft material is granulated by a 20-mesh screen, and the granulated material is fed to a boiling granulating dryer for drying by a vacuum feeding system; drying with boiling granulating drier at air inlet temperature of 45+ -15deg.C and air outlet temperature of 40+ -10deg.C, material temperature of less than or equal to 50deg.C for 45+ -1 min;
(5) Adding essence into the dried granules, and mixing uniformly.
2. The method for preparing cefprozil dry suspension according to claim 1, wherein the method is characterized in that,
in the step (1), the step of (a),
sodium chloride is sieved by a 40-mesh sieve, colloidal silica is sieved by a 20-mesh sieve, and sucrose is sieved by a 80-mesh sieve.
3. The method for preparing cefprozil dry suspension according to claim 1, wherein the method is characterized in that,
in the step (2), the step of (C),
the rotation speed is 20+/-1 r/min during mixing, and the mixing time is 15+/-1 min.
4. The method for preparing cefprozil dry suspension according to claim 1, wherein the method is characterized in that,
in the step (5), the step of (c),
the mixing rotating speed is 15+/-1 r/min, and the mixing is 45+/-1 min.
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