CN117297102A - Preparation method of ferrous fumarate granules with uniform particle size - Google Patents
Preparation method of ferrous fumarate granules with uniform particle size Download PDFInfo
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- CN117297102A CN117297102A CN202311086576.XA CN202311086576A CN117297102A CN 117297102 A CN117297102 A CN 117297102A CN 202311086576 A CN202311086576 A CN 202311086576A CN 117297102 A CN117297102 A CN 117297102A
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- ferrous fumarate
- granules
- stirring
- shearing
- soft material
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- 239000008187 granular material Substances 0.000 title claims abstract description 98
- 239000002245 particle Substances 0.000 title claims abstract description 85
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 title claims abstract description 52
- 229960000225 ferrous fumarate Drugs 0.000 title claims abstract description 52
- 235000002332 ferrous fumarate Nutrition 0.000 title claims abstract description 52
- 239000011773 ferrous fumarate Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000007779 soft material Substances 0.000 claims abstract description 42
- 238000003756 stirring Methods 0.000 claims abstract description 42
- 238000010008 shearing Methods 0.000 claims abstract description 37
- 239000000080 wetting agent Substances 0.000 claims abstract description 30
- 239000000945 filler Substances 0.000 claims abstract description 25
- 238000001035 drying Methods 0.000 claims abstract description 13
- 229920001353 Dextrin Polymers 0.000 claims abstract description 10
- 239000004375 Dextrin Substances 0.000 claims abstract description 10
- 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 10
- 229930006000 Sucrose Natural products 0.000 claims abstract description 10
- 235000019425 dextrin Nutrition 0.000 claims abstract description 10
- 239000005720 sucrose Substances 0.000 claims abstract description 10
- 239000000796 flavoring agent Substances 0.000 claims abstract description 7
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 4
- 239000000600 sorbitol Substances 0.000 claims abstract description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims abstract description 3
- 229920002472 Starch Polymers 0.000 claims abstract description 3
- 239000008107 starch Substances 0.000 claims abstract description 3
- 235000019698 starch Nutrition 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- 239000008213 purified water Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 10
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 7
- 230000003179 granulation Effects 0.000 claims description 7
- 229940095686 granule product Drugs 0.000 claims description 4
- 235000005976 Citrus sinensis Nutrition 0.000 claims description 2
- 240000002319 Citrus sinensis Species 0.000 claims description 2
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims 1
- 239000000843 powder Substances 0.000 abstract description 15
- 235000013305 food Nutrition 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 22
- 238000009826 distribution Methods 0.000 description 17
- 238000007873 sieving Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 11
- 241000220223 Fragaria Species 0.000 description 9
- 238000012216 screening Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 210000002506 abnormal erythrocyte Anatomy 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000011362 coarse particle Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000004503 fine granule Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000009818 secondary granulation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/16—Inorganic salts, minerals or trace elements
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen as heteroatom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
- A23L29/35—Degradation products of starch, e.g. hydrolysates, dextrins; Enzymatically modified starches
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
- A23L29/37—Sugar alcohols
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/20—Agglomerating; Granulating; Tabletting
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal 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
- A61K9/14—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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- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- 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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- 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
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
The invention relates to the field of health-care food processing, in particular to a preparation method of ferrous fumarate granules with uniform particle size, which comprises the following steps: A. mixing ferrous fumarate, a filler A and a flavoring agent in a wet granulator at a low speed, adding part of wetting agent, and stirring and shearing at a low speed to obtain a soft material A; B. adding a filler B into the soft material A, and stirring and shearing at a low speed to obtain a soft material B; C. adding the rest wetting agent into the soft material B for three times, and stirring at a low speed, shearing and granulating after each addition to obtain wet granules; D. drying the wet granules to obtain ferrous fumarate granule products; the filling agent A comprises one or more of sucrose, sorbitol and starch; the filler B comprises one or more of dextrin and microcrystalline cellulose. The invention solves the problems of more fine powder and poor formability of ferrous fumarate granules.
Description
Technical Field
The invention relates to the field of health-care food processing, in particular to a preparation method of ferrous fumarate granules with uniform particle size.
Background
Ferrous fumarate is a commonly used iron supplement and is widely used for treating iron deficiency anemia and other related diseases. Iron deficiency anemia is one of the common diseases worldwide, and is characterized by low hemoglobin content and abnormal erythrocyte morphology. Ferrous fumarate supplements the iron reserves of the body by providing iron elements, promotes the generation and repair of red blood cells, thereby improving anemia symptoms and improving the life quality of patients.
The granule is prepared by mixing the medicine with proper auxiliary materials, and can be generally divided into soluble granule, suspension granule and effervescent granule, if the particle size is in the range of 105-500 microns, the granule can also be called as fine granule, and the granule is mainly characterized by convenient oral administration, adjustable dosage, rapid absorption and the like. Therefore, the granule is widely used in the field of pharmaceutical preparations, especially in cases where special requirements are imposed on the release and absorption of the drug in the gastrointestinal tract.
However, some technical problems are often faced in preparing ferrous fumarate granules. One of them is that the particle size is not satisfactory, and often there is a problem of more fines. This may lead to reduced uniformity and stability of the particles, which in turn affects the solubility and bioavailability of the drug. In addition, the problem of poor formability is also present when preparing ferrous fumarate granules. The formability of the granules is very important for preparing high quality granules. Poor formability may lead to granules that are difficult to form a uniform granular structure during the formulation process, increasing difficulty and non-uniformity of preparation.
Disclosure of Invention
The invention aims to provide an improved preparation method of ferrous fumarate particles, which aims to solve the problems of more fine powder and poor formability. The invention can improve the physical property and the forming quality of the granule by changing the adding sequence of the filling agent and the types of the wetting agent, and realize better granule size distribution and stability. The preparation method is beneficial to improving the preparation efficiency and quality of ferrous fumarate granules, thereby better meeting the requirements of the pharmaceutical industry.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of ferrous fumarate granules with uniform particle size comprises the following steps:
A. mixing ferrous fumarate, a filler A and a flavoring agent in a wet granulator at a low speed, adding part of wetting agent, and stirring and shearing at a low speed to obtain a soft material A;
B. adding a filler B into the soft material A, and stirring and shearing at a low speed to obtain a soft material B;
C. adding the rest wetting agent into the soft material B for three times, stirring at a low speed and shearing and granulating after each addition to obtain wet granules;
D. drying the wet granules to obtain ferrous fumarate granule products;
the filling agent A comprises one or more of sucrose, sorbitol and starch; the filler B comprises one or more of dextrin and microcrystalline cellulose.
Preferably, the wetting agent comprises one or more of purified water and ethanol.
Preferably, the wetting agent comprises purified water or 10% -40% ethanol solution.
Preferably, the wetting agent comprises purified water or a 10% ethanol solution.
Preferably, in the step A, the low-speed stirring and mixing comprises stirring at 500rpm for 1-3 min, and the low-speed stirring and shearing comprises stirring and shearing at 1500rpm for 5-10 min; in the step B, the low-speed stirring and shearing comprises stirring and shearing for 5-10 min at 1500 rpm; in the step C, the low-speed stirring, shearing and granulating comprises stirring and shearing at 1500rpm for 5-10 min; in the step D, the drying temperature is 60-65 ℃, and the moisture of the particles is controlled within 5.0%.
The first stirring step in the step A mainly mixes the materials uniformly, and the time can be adjusted according to the addition amount of the actual materials.
Preferably, in the step C, the soft material is lightly held and agglomerated and dispersed after each granulation.
Preferably, in step C, the wet granules are sieved through a 14 mesh sieve; in step D, the ferrous fumarate granule product is sized with a 10 mesh screen.
In the step C, the granulator is stirred at a low speed, and a proper amount of wetting agent is added; stirring and shearing at low speed after each addition, granulating to obtain soft materials, slightly holding to form clusters, dispersing while touching, sieving with a 14 mesh sieve, and measuring wet granule moisture.
In the step D, after the dry particles are obtained, the dry particles are sieved and granulated by a 10-mesh sieve, and indexes such as moisture and granularity of the dry particles are measured, and the yield is calculated.
Preferably, the mass ratio of the ferrous fumarate to the filler A to the filler B to the wetting agent to the flavoring agent is 1:20-23:8-14:3-5:0.1-0.2; the flavoring agent comprises one or more of strawberry essence, sweet orange essence and steviosin.
Preferably, in the step A, the mass of the wetting agent is 45% -65% of the total dosage of the wetting agent.
In the step A, firstly, 45% -65% of wetting agent accounting for the total dosage is added, the total weight of the granules is about 9% -10%, the obtained soft material A in the proportion is moderate, the soft material A is not too dry and loose or too wet and has too high viscosity, and then, the rest wetting agent is added for granulation in a distribution manner, so that a uniform and compact granule structure can be formed.
The ferrous fumarate granule product obtained by the preparation method of the ferrous fumarate granule with uniform particle size.
Compared with the prior art, the implementation of the invention has the following beneficial effects:
1. reducing the generation of fine powder: the method and the technology of the invention aim at improving the problem of more fine powder in the preparation process of ferrous fumarate granules. The invention can effectively reduce the generation rate of fine powder by changing the addition sequence of the filler and the types of the wetting agent and optimizing the process conditions. This will improve the homogeneity and stability of the granule and increase the solubility and bioavailability of the drug.
2. Improving the forming performance of the particles: the invention also provides a solution to the problem of poor formability in the preparation process of the granules. The moldability of the granules can be improved by optimizing the formulation and proportions of filler and wetting agent and by employing appropriate process steps. This will help to form a uniform, compact particle structure, improving the consistency and controllability of the manufacturing process.
3. The quality and the stability of the granule are improved: by the technical improvement of the invention, the physical property and chemical stability of the granule are improved. The particle size distribution of the particles is more uniform, and the drug ingredients are better wrapped in the particles, so that the solubility and bioavailability of the drug are improved, and the curative effect and the therapeutic effect of the drug are enhanced.
Drawings
FIG. 1 is a graph showing the comparison of samples obtained in examples and comparative examples.
Detailed Description
The present invention will be further described in detail below with reference to the accompanying drawings, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, so that those skilled in the art can better understand the present invention and implement the present invention, but the present invention is not limited thereto. Modifications and substitutions to methods, procedures, or conditions of the present invention without departing from the spirit and nature of the invention are intended to be within the scope of the present invention. The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated.
Example 1
Ferrous fumarate particles, made by the following method:
1) 45g of ferrous fumarate, 1000g of sucrose and 5g of strawberry essence are mixed in a wet granulator at a low speed of 500rpm for 3min, 100g of 10% ethanol solution is added, and the mixture is stirred and sheared at a low speed of 1500rpm for 5min, and the soft material state is checked;
2) Adding 450g of dextrin into the soft material, stirring and shearing at a low speed of 1500rpm for 5min, adding a proper amount of 10% ethanol solution for three times, stirring and shearing at a low speed of 1500rpm for 5min after each addition, granulating until the soft material is slightly held into clusters, dispersing when touched, sieving with a 14-mesh sieve, and measuring the moisture of wet particles;
3) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
4) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Example 2
Ferrous fumarate particles, made by the following method:
1) Mixing ferrous fumarate 45g, sucrose 1000g and strawberry essence 5g in a wet granulator at a low speed of 500rpm for 3min, adding purified water 100g, stirring at a low speed of 1500rpm and shearing for 5min, and checking the soft material state;
2) Adding 450g of dextrin into the soft material, stirring and shearing at a low speed of 1500rpm for 5min, adding a proper amount of purified water for three times, stirring and shearing at a low speed of 1500rpm for 5min after each addition, granulating until the soft material is slightly held into clusters, dispersing when touched, sieving with a 14-mesh sieve, and measuring the moisture of wet granules;
3) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
4) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Example 3
Ferrous fumarate particles, made by the following method:
1) 45g of ferrous fumarate, 950g of sorbitol and 5g of strawberry essence are mixed in a wet granulator at a low speed of 500rpm for 3min, then 100g of purified water is added, and the mixture is stirred and sheared at a low speed of 1500rpm for 5min, and the soft material state is checked;
2) Adding 500g of microcrystalline cellulose into a soft material, stirring and shearing at a low speed of 1500rpm for 5min, adding a proper amount of purified water three times, stirring and shearing at a low speed of 1500rpm for 5min after each addition, granulating until the soft material is slightly held into clusters, dispersing when the soft material is touched, screening the clusters by a 14-mesh sieve, and measuring the moisture of wet particles;
3) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
4) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Comparative example 1
Ferrous fumarate particles, made by the following method:
1) 45g of ferrous fumarate, 450g of dextrin and 5g of strawberry essence are mixed in a wet granulator at a low speed of 500rpm for 3min, 90g of 10% ethanol solution is added, and the mixture is stirred and sheared at a low speed of 1500rpm for 5min, and the soft material state is checked;
2) Adding 1000g of sucrose into the soft material, stirring and shearing at a low speed of 1500rpm for 5min, adding a proper amount of 10% ethanol solution for three times, stirring and shearing at a low speed of 1500rpm for 5min after each addition, granulating until the soft material is slightly held into clusters, dispersing when touching, sieving with a 14-mesh sieve, and measuring the moisture of wet particles;
3) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
4) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Comparative example 2
Ferrous fumarate particles, made by the following method:
1) 45g of ferrous fumarate, 1000g of sucrose and 5g of strawberry essence are mixed in a wet granulator at a low speed of 500rpm for 3min, 100g of 20% ethanol solution is added, and the mixture is stirred and sheared at a low speed of 1500rpm for 5min, and the soft material state is checked;
2) Adding 450g of dextrin into the soft material, stirring and shearing at a low speed of 1500rpm for 5min, adding a proper amount of 20% ethanol solution for three times, stirring and shearing at a low speed of 1500rpm for 5min after each addition, granulating until the soft material is slightly held into clusters, dispersing when touching, sieving with a 14-mesh sieve, and measuring the moisture of wet particles;
3) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
4) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Comparative example 3
Ferrous fumarate particles, made by the following method:
1) 45g of ferrous fumarate, 1000g of sucrose and 5g of strawberry essence are mixed in a wet granulator at a low speed of 500rpm for 3min, 100g of 30% ethanol solution is added, and the mixture is stirred and sheared at a low speed of 1500rpm for 5min, and the soft material state is checked;
2) Adding 450g of dextrin into the soft material, stirring and shearing at a low speed of 1500rpm for 5min, adding a proper amount of 30% ethanol solution for three times, stirring and shearing at a low speed of 1500rpm for 5min after each addition, granulating until the soft material is lightly held into clusters, dispersing when the soft material is touched, sieving with a 14-mesh sieve, and measuring the moisture of wet particles;
3) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
4) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Comparative example 4
Ferrous fumarate particles, made by the following method:
1) 45g of ferrous fumarate, 1000g of sucrose and 5g of strawberry essence are mixed in a wet granulator at a low speed of 500rpm for 3min, 100g of 40% ethanol solution is added, and the mixture is stirred and sheared at a low speed of 1500rpm for 5min, and the soft material state is checked;
2) Adding 450g of dextrin into the soft material, stirring and shearing at a low speed of 1500rpm for 5min, adding a proper amount of 40% ethanol solution for three times, stirring and shearing at a low speed of 1500rpm for 5min after each addition, granulating until the soft material is slightly held into clusters, dispersing when touched, sieving with a 14-mesh sieve, and measuring the moisture of wet particles;
3) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
4) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Comparative example 5
Ferrous fumarate particles, made by the following method:
1) 45g of ferrous fumarate, 1000g of sucrose, 450g of dextrin and 5g of strawberry essence are stirred and mixed in a wet granulator at a low speed of 500rpm for 5min, 172.50g of wetting agent (10% ethanol solution) which is equal to that of the embodiment 1 is added, the mixture is stirred and sheared at a low speed of 1500rpm for 5min, then the mixture is stopped and stirred manually, the operation is carried out for 4 times, and finally the mixture is screened by a swing granulator with a 14-mesh sieve, so that the moisture of wet granules is measured;
2) Drying the wet particles at 65 ℃ to control the moisture of the particles to be less than 5.0%;
3) 100g of dry granules are firstly taken for checking the granularity of the granules (the second method of the pharmacopoeia general rule 0982, double screening method). Then, the granules were sized with a 10-mesh sieve, the size distribution of 100g of the granules was checked (pharmacopoeia general rule 0982 second method mechanical sieving method), the moisture content of the dry granules was measured, and indexes such as yield were calculated.
Effect example 1
Summarizing experimental results:
TABLE 1
* The granule according to the rule of Chinese pharmacopoeia 2020 is checked according to the particle size and particle size distribution determination method (double sieving method of general rule 0982), and the sum of the first sieve (2 mm) and the fifth sieve (180 μm) cannot exceed 15%.
TABLE 2
| Lot number retention rate | No. two sieves (24 mesh) | Sieve No. four (65 mesh) | Five-size screen (80 mesh) | Six sieves (100 mesh) |
| Example 1 | 9.68 | 87.78 | 1.89 | 0.65 |
| Example 2 | 10.25 | 85.83 | 2.25 | 1.67 |
| Example 3 | 10.57 | 85.11 | 2.28 | 2.04 |
| Comparative example 1 | 11.05 | 76.40 | 7.31 | 5.24 |
| Comparative example 2 | 13.58 | 77.33 | 5.85 | 3.24 |
| Comparative example 3 | 14.05 | 75.96 | 5.52 | 4.47 |
| Comparative example 4 | 14.27 | 75.74 | 5.38 | 5.09 |
| Comparative example 5 | 21.48 | 68.05 | 4.97 | 4.28 |
* The powder grades are as follows:
as shown in table 1, table 2 and fig. 1, the particle size and particle size distribution of the particles of comparative example 1 and comparative example 1 revealed that the particle size of the granules was affected by the order of addition of the filler, as shown by the high powder fraction and low fine powder fraction and low finest powder fraction in the particles of example 1. In combination with the particle size and particle size distribution of the granules of examples 1 to 3, it is not difficult to find that the method for preparing the granules in the invention is to pre-granulate the materials with saccharides or sugar alcohols which are easy to induce viscosity by wetting agents, and then add other fillers for granulating again.
As shown in table 1, table 2 and fig. 1, by the particle sizes and particle size distribution of the particles of comparative example 1 and comparative example 2, comparative example 3 and comparative example 4, the higher the concentration of ethanol added when the filler addition order is the same, the more fine powder produced by the produced granules may be related to the decrease in tackiness after wetting with the increase in the concentration of ethanol. In combination with the particle size and particle size distribution of the particles of examples 1 and 2, it was found that the granulation effect of a 10% ethanol solution was better than that of purified water, and therefore the optimal wetting agent according to the present invention was a 10% ethanol solution.
As shown in table 1, table 2 and fig. 1, the medium-powder ratio and the fine-powder ratio of the particles of comparative example 5 were low and the finest-powder ratio was high by the particle size and particle size distribution of the particles of comparative example 1 and comparative example 5, and the yield of the particles was much lower than that of example 1, which means that the filler was added at one time and the wetting agent was slowly added at the later time, the filler and the wetting agent could not be uniformly mixed during the granulation, and the soft material portion was drier (more fine powder was generated) or wet (more coarse particles were caused by the adhesion of soft material, and more loss was caused during the granulation and the granulation), and the granules with uniform particle size could not be obtained. The appearance of each group of samples is shown in figure 1, the particles of the samples of the example group are obviously coarser than those of the samples of the comparative example group, and the samples of the comparative example group have more macroscopic small particles, so that the method for pre-granulating materials and saccharides or sugar alcohols which are easy to be sticky induced by wetting agents and adding other fillers for secondary granulation is feasible, the granularity of the granules can be obviously increased, and the generation of fine powder is reduced.
The foregoing disclosure is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, which is defined by the appended claims.
Claims (10)
1. The preparation method of the ferrous fumarate granules with uniform particle size is characterized by comprising the following steps:
A. mixing ferrous fumarate, a filler A and a flavoring agent in a wet granulator at a low speed, adding part of wetting agent, and stirring and shearing at a low speed to obtain a soft material A;
B. adding a filler B into the soft material A, and stirring and shearing at a low speed to obtain a soft material B;
C. adding the rest wetting agent into the soft material B for three times, stirring at a low speed and shearing and granulating after each addition to obtain wet granules;
D. drying the wet granules to obtain ferrous fumarate granule products;
the filling agent A comprises one or more of sucrose, sorbitol and starch; the filler B comprises one or more of dextrin and microcrystalline cellulose.
2. The method for preparing ferrous fumarate particles of uniform particle size of claim 1, wherein said wetting agent comprises one or more of purified water and ethanol.
3. The method for preparing ferrous fumarate particles of uniform size according to claim 1, wherein said wetting agent comprises purified water or 10% -40% ethanol solution.
4. The method for preparing ferrous fumarate particles of uniform particle size of claim 1, wherein said wetting agent comprises purified water or 10% ethanol solution.
5. The method for preparing ferrous fumarate particles of uniform particle size according to claim 1, wherein in step a, the low-speed stirring and mixing comprises stirring at 500rpm for 1-3 min, and the low-speed stirring and shearing comprises stirring and shearing at 1500rpm for 5-10 min; in the step B, the low-speed stirring and shearing comprises stirring and shearing for 5-10 min at 1500 rpm; in the step C, the low-speed stirring, shearing and granulating comprises stirring and shearing at 1500rpm for 5-10 min; in the step D, the drying temperature is 60-65 ℃, and the moisture of the particles is controlled within 5.0%.
6. The method for preparing ferrous fumarate particles of uniform size according to claim 1, wherein in step C, each granulation is carried out until the soft material is lightly held and agglomerated, and then dispersed.
7. The method for preparing ferrous fumarate granules of uniform particle size of claim 1, wherein in step C, the wet granules are sieved through a 14 mesh screen; in step D, the ferrous fumarate granule product is sized with a 10 mesh screen.
8. The method for preparing ferrous fumarate granules with uniform particle size according to claim 1, wherein the mass ratio of ferrous fumarate to filler a to filler B to wetting agent to flavoring agent comprises 1:20 to 23: 8-14: 3 to 5:0.1 to 0.2; the flavoring agent comprises one or more of strawberry essence, sweet orange essence and steviosin.
9. The method for preparing ferrous fumarate granules with uniform granule size according to claim 1, wherein in step a, the mass of the wetting agent added accounts for 45% -65% of the total amount of the wetting agent.
10. A ferrous fumarate granule product obtained by the method for preparing ferrous fumarate granules with uniform particle size according to claim 1.
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