CN117860688B - Direct-compression mannitol particles and preparation method thereof - Google Patents
Direct-compression mannitol particles and preparation method thereof Download PDFInfo
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- CN117860688B CN117860688B CN202410275111.7A CN202410275111A CN117860688B CN 117860688 B CN117860688 B CN 117860688B CN 202410275111 A CN202410275111 A CN 202410275111A CN 117860688 B CN117860688 B CN 117860688B
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- deionized water
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- 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 title claims abstract description 60
- 229930195725 Mannitol Natural products 0.000 title claims abstract description 60
- 239000000594 mannitol Substances 0.000 title claims abstract description 60
- 235000010355 mannitol Nutrition 0.000 title claims abstract description 60
- 239000002245 particle Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000007907 direct compression Methods 0.000 title claims abstract description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000000741 silica gel Substances 0.000 claims abstract description 37
- 239000008367 deionised water Substances 0.000 claims abstract description 35
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 35
- 238000001035 drying Methods 0.000 claims abstract description 35
- 229920002472 Starch Polymers 0.000 claims abstract description 34
- 239000008107 starch Substances 0.000 claims abstract description 34
- 235000019698 starch Nutrition 0.000 claims abstract description 34
- 239000002131 composite material Substances 0.000 claims abstract description 30
- 238000003756 stirring Methods 0.000 claims abstract description 29
- 238000002156 mixing Methods 0.000 claims abstract description 28
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000463 material Substances 0.000 claims abstract description 18
- 229910021487 silica fume Inorganic materials 0.000 claims abstract description 15
- 238000000498 ball milling Methods 0.000 claims abstract description 14
- 229920001592 potato starch Polymers 0.000 claims abstract description 13
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940075507 glyceryl monostearate Drugs 0.000 claims abstract description 11
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims abstract description 11
- 239000000661 sodium alginate Substances 0.000 claims abstract description 11
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 11
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 11
- 239000000843 powder Substances 0.000 claims description 50
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- 238000002791 soaking Methods 0.000 claims description 26
- 229910002027 silica gel Inorganic materials 0.000 claims description 24
- 229930006000 Sucrose Natural products 0.000 claims description 12
- 239000000194 fatty acid Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000005720 sucrose Substances 0.000 claims description 12
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims 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 description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 8
- 229930195729 fatty acid Natural products 0.000 claims description 8
- -1 fatty acid ester Chemical class 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001027 hydrothermal synthesis Methods 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000010355 oscillation Effects 0.000 claims 2
- 239000008187 granular material Substances 0.000 abstract description 10
- 239000003826 tablet Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 8
- 238000007873 sieving Methods 0.000 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000005054 agglomeration Methods 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000004368 Modified starch Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 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
- A61K9/14—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
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- 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
- A61K9/1611—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
- A61K9/14—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
-
- 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
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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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- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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Abstract
The invention provides a direct-compression mannitol granule and a preparation method thereof, belonging to the technical field of mannitol granules; the preparation method comprises the steps of preparing composite starch, modified micro silica gel, mixing materials and drying; adding deionized water and glyceryl monostearate into potato starch, stirring at 56-60 ℃ for 1.5-1.8h, drying after stirring, mixing with sodium alginate, performing ball milling for 25-30min at 142-150rpm and a ball-material ratio of 6-10:1, and obtaining composite starch after ball milling; the prepared direct compression mannitol particles have good fluidity, high hardness, low friability and short disintegration time limit after being used for tabletting, and still keep higher hardness and lower friability after absorbing water.
Description
Technical Field
The invention belongs to the technical field of mannitol particles, and particularly relates to a direct compression mannitol particle and a preparation method thereof.
Background
Mannitol is hexaol, absorbs heat when dissolved, has sweet taste and comfortable feeling to oral cavity, so that mannitol is widely applied to the manufacture of chewable tablets such as sobering-up drugs, mouth coolants and the like, and granules are used as excipients for direct tabletting; mannitol produced by crystallization is needle-shaped crystals, has poor fluidity, has a tight and firm crystal structure, cannot be directly used for tabletting, and has slower dissolution rate than granules.
With the development of medical technology, mannitol particles prepared by further improving crystalline mannitol are available at present, and can be used in a direct tabletting production process;
The Chinese patent with the application number 2013101542243 discloses a preparation method of mannitol granules capable of being directly pressed, and specifically discloses a method for crushing mannitol to obtain powder, performing top-spraying granulation on the powder by adopting a fluidized bed, and granulating and sieving by taking an adhesive aqueous solution as top-spraying slurry;
The method can not realize continuous production, and the prepared mannitol particles have low purity, so that the application of the product is limited, and in the tablet inspection, the disintegration time is still longer and the dissolution of the main medicine is influenced although the requirements on friability and hardness can be met;
The Chinese patent with the application number 2023108065164 discloses a preparation method of mannitol particles, and specifically discloses a preparation method of auxiliary agents by adopting xylitol, modified starch and modified microcrystalline cellulose, and then mixing the auxiliary agents with mannitol, and carrying out vacuum drying, crushing and sieving to obtain the mannitol particles;
The mannitol particles prepared by the method have high purity, improve hardness, reduce friability and shorten disintegration time, but adopt microcrystalline cellulose components, have high cost and poor taste, and the prepared tablets have reduced hardness after water absorption in the storage process, thereby increasing friability and influencing usability.
Therefore, the direct-compression mannitol particles and the preparation method thereof are provided, and the following technical problems need to be solved simultaneously:
1. high-cost raw materials such as microcrystalline cellulose and the like are avoided;
2. The tablet prepared from the granules has high hardness, low friability and short disintegration time;
3. the tablets still have better hardness and lower friability after water absorption during storage.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides the direct compression mannitol granules and the preparation method thereof, high-cost raw materials such as microcrystalline cellulose and the like are avoided, the tablet prepared from the granules has high hardness, low friability and short disintegration time, and the tablet still has better hardness and lower friability after water absorption in the storage process.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of direct compression mannitol particles comprises the steps of preparing composite starch, modified micro silica gel, mixing and drying; the specific operation is as follows:
1. preparation of composite starch
Adding deionized water and glyceryl monostearate into potato starch, stirring at 56-60deg.C for 1.5-1.8 hr, drying after stirring, mixing with sodium alginate, ball milling for 25-30min at 142-150rpm and ball material ratio of 6-10:1, and ball milling to obtain composite starch;
the mass ratio of the potato starch to the sodium alginate to the deionized water to the glyceryl monostearate is 62-66:1.5-1.7:112-120:0.24-0.28;
2. Modified micro powder silica gel
Mixing sucrose mono fatty acid ester with deionized water to obtain a soaking solution, soaking micro powder silica gel in 2-4 times of the soaking solution at 54-58 ℃ for 37-43min, drying after soaking, heating to 70-74 ℃ at the rate of 0.4-0.6 ℃/min, adding 3-5 times of absolute ethyl alcohol, stirring for 1.0-1.2h, drying after stirring, adding citric acid, placing in a microwave hydrothermal synthesizer for hydrothermal reaction for 1.1-1.3h at 120-124 ℃, washing and drying after reaction, and obtaining modified micro powder silica gel;
the mass ratio of the sucrose fatty acid monoester to the deionized water is 2.2-2.6:83-87;
the mass ratio of the micro silica gel to the citric acid is 1:1.5-2.
3. Mixing material
Mixing composite starch, modified micro powder silica gel, low-substituted hydroxypropyl cellulose and deionized water to obtain auxiliary materials, uniformly stirring, adding mannitol powder, performing ultrasonic vibration treatment, controlling the ultrasonic power to be 43-47W, the ultrasonic frequency to be 62-67kHz, and the ultrasonic time to be 10-14min, and obtaining a mixture after ultrasonic vibration is finished;
The grain size of the mannitol powder is 110-130 meshes;
The mass ratio of the composite starch, the modified micro powder silica gel, the low-substituted hydroxypropyl cellulose and the deionized water is 1.7-2.2:0.3-0.5:1.3-1.7:176-195;
the mass ratio of the auxiliary materials to mannitol powder is 85-90:28-33.
4. Drying
And (3) performing centrifugal spray drying on the mixture, controlling the air inlet temperature to be 214-221 ℃, the air outlet temperature to be 118-122 ℃, the rotating speed of an atomizer to be 35-39Hz, crushing after the drying is finished, and sieving to obtain the direct-pressure mannitol particles.
The direct compression mannitol particles are prepared by the preparation method.
Compared with the prior art, the invention has the following beneficial effects:
1. According to the invention, the superfine silica powder is modified, firstly, the mixed solution of sucrose mono-fatty acid ester and deionized water is adopted to soak so as to promote dispersion of the superfine silica powder, avoid aggregation among particles, and then citric acid is adopted to treat, so that carboxyl of the citric acid is bonded with hydroxyl on the surface of the superfine silica powder, agglomeration among the superfine silica powder is avoided, on one hand, the performance of the glidant can be more effectively exerted, and the fluidity of the particles is ensured; on the other hand, the mannitol can be uniformly mixed with other components, so that the stability of mannitol particles is ensured, the tablet can still keep higher hardness after absorbing water, and the friability is reduced; the composite starch prepared by adopting the method of combining heat treatment and ball milling treatment has the advantages that on one hand, the fluidity and the compressibility are improved, on the other hand, the crystalline structure of the starch is damaged, the number of free hydroxyl groups is increased, the tablet after tabletting is easy to absorb moisture and disintegrate, the disintegrating property is improved, mannitol particles prepared by combining the composite starch with specific modified micro powder silica gel have good fluidity and good compressibility, and the tablet prepared after tabletting has short disintegrating time limit, high hardness, low friability and excellent stability;
2. the direct-compression mannitol particles prepared by the method have good fluidity and repose angle of 26-29 degrees;
3. Adding 1% of magnesium stearate into the direct compression mannitol granules prepared by the method, uniformly mixing, tabletting under 13kN, wherein the hardness of the prepared tablets is 134-138N, the friability is 0.08-0.11%, and the disintegration time is 37-39s;
standing the tablet at 38deg.C under 67% humidity for 7 days to obtain tablet with hardness of 128-133N and friability of 0.10-0.15%.
Detailed Description
For a clearer understanding of the technical features, objects and effects of the present invention, specific embodiments of the present invention will be described.
Example 1 preparation method of direct compression mannitol particles
1. Preparation of composite starch
Adding deionized water and glyceryl monostearate into potato starch, stirring at 58 ℃ for 1.7h, drying after stirring, mixing with sodium alginate, performing ball milling for 28min at 146rpm, and obtaining composite starch after ball milling;
The mass ratio of the potato starch to the sodium alginate to the deionized water to the glyceryl monostearate is 64:1.6:117:0.26;
2. Modified micro powder silica gel
Mixing sucrose mono fatty acid ester with deionized water to obtain a soaking solution, soaking micro powder silica gel in the soaking solution with the volume of 3 times, wherein the soaking temperature is 56 ℃, the soaking time is 40min, drying after the soaking, then heating to 72 ℃ at the speed of 0.5 ℃/min, adding absolute ethyl alcohol with the volume of 4 times, stirring for 1.1h, drying after the stirring, adding citric acid, performing hydrothermal reaction in a microwave hydrothermal synthesizer for 1.2h, and the reaction temperature is 122 ℃, and washing and drying after the reaction is finished to obtain modified micro powder silica gel;
The mass ratio of the sucrose mono-fatty acid ester to the deionized water is 2.4:85;
The mass ratio of the micro silica gel to the citric acid is 1:1.8.
3. Mixing material
Mixing composite starch, modified micro powder silica gel, low-substituted hydroxypropyl cellulose and deionized water to obtain auxiliary materials, uniformly stirring, adding mannitol powder, performing ultrasonic vibration treatment, controlling the ultrasonic power to be 45W, the ultrasonic frequency to be 64kHz, the ultrasonic time to be 12min, and obtaining a mixture after ultrasonic vibration is finished;
the grain size of the mannitol powder is 120 meshes;
the mass ratio of the composite starch to the modified micro silica gel to the low-substituted hydroxypropyl cellulose to the deionized water is 2.0:0.4:1.5:187;
The mass ratio of the auxiliary materials to mannitol powder is 87:31.
4. Drying
And (3) performing centrifugal spray drying on the mixture, controlling the air inlet temperature to be 218 ℃, the air outlet temperature to be 120 ℃, the rotating speed of an atomizer to be 37Hz, crushing after the drying is finished, and sieving to obtain the direct-pressure mannitol particles.
Example 2 preparation method of direct compression mannitol particles
1. Preparation of composite starch
Adding deionized water and glyceryl monostearate into potato starch, stirring at 56 ℃ for 1.5 hours, drying after stirring, mixing with sodium alginate, performing ball milling for 25 minutes at 142rpm, and obtaining composite starch after ball milling;
the mass ratio of the potato starch to the sodium alginate to the deionized water to the glyceryl monostearate is 62:1.5:112:0.24;
2. Modified micro powder silica gel
Mixing sucrose mono fatty acid ester with deionized water to obtain a soaking solution, soaking micro powder silica gel in 2 times of the soaking solution at a temperature of 54 ℃ for 37min, drying after soaking, heating to 70 ℃ at a speed of 0.4 ℃/min, adding 3 times of absolute ethyl alcohol, stirring for 1.0h, drying after stirring, adding citric acid, performing hydrothermal reaction in a microwave hydrothermal synthesizer for 1.1h at a reaction temperature of 120 ℃, and washing and drying after the reaction is finished to obtain modified micro powder silica gel;
the mass ratio of the sucrose mono-fatty acid ester to the deionized water is 2.2:83;
The mass ratio of the micro silica gel to the citric acid is 1:1.5.
3. Mixing material
Mixing composite starch, modified micro powder silica gel, low-substituted hydroxypropyl cellulose and deionized water to obtain auxiliary materials, uniformly stirring, adding mannitol powder, performing ultrasonic vibration treatment, controlling the ultrasonic power to be 43W, controlling the ultrasonic frequency to be 62kHz, controlling the ultrasonic time to be 10min, and obtaining a mixture after ultrasonic vibration is finished;
the grain size of the mannitol powder is 110 meshes;
The mass ratio of the composite starch to the modified micro silica gel to the low-substituted hydroxypropyl cellulose to the deionized water is 1.7:0.3:1.3:176;
the mass ratio of the auxiliary materials to mannitol powder is 85:28.
4. Drying
And (3) performing centrifugal spray drying on the mixture, controlling the air inlet temperature to be 214 ℃, the air outlet temperature to be 118 ℃, the rotating speed of an atomizer to be 35Hz, crushing after the drying is finished, and sieving to obtain the direct-pressure mannitol particles.
Example 3 preparation method of direct compression mannitol particles
1. Preparation of composite starch
Adding deionized water and glyceryl monostearate into potato starch, stirring at 60 ℃ for 1.8 hours, drying after stirring, mixing with sodium alginate, performing ball milling for 30 minutes at 150rpm, and obtaining composite starch after ball milling;
The mass ratio of the potato starch to the sodium alginate to the deionized water to the glyceryl monostearate is 66:1.7:120:0.28;
2. Modified micro powder silica gel
Mixing sucrose mono fatty acid ester with deionized water to obtain a soaking solution, soaking micro powder silica gel in the soaking solution with the volume of 4 times, wherein the soaking temperature is 58 ℃, the soaking time is 43min, drying after the soaking, then heating to 74 ℃ at the speed of 0.6 ℃/min, adding absolute ethyl alcohol with the volume of 5 times, stirring for 1.2h, drying after the stirring, adding citric acid, performing hydrothermal reaction in a microwave hydrothermal synthesizer for 1.3h, and the reaction temperature is 124 ℃, and washing and drying after the reaction is finished to obtain modified micro powder silica gel;
the mass ratio of the sucrose fatty acid monoester to the deionized water is 2.6:87;
The mass ratio of the micro silica gel to the citric acid is 1:2.
3. Mixing material
Mixing composite starch, modified micro powder silica gel, low-substituted hydroxypropyl cellulose and deionized water to obtain auxiliary materials, uniformly stirring, adding mannitol powder, performing ultrasonic vibration treatment, controlling the ultrasonic power to be 47W, the ultrasonic frequency to be 67kHz, the ultrasonic time to be 14min, and obtaining a mixture after ultrasonic vibration is finished;
The grain size of the mannitol powder is 130 meshes;
The mass ratio of the composite starch to the modified micro silica gel to the low-substituted hydroxypropyl cellulose to the deionized water is 2.2:0.5:1.7:195;
the mass ratio of the auxiliary materials to mannitol powder is 90:33.
4. Drying
And (3) performing centrifugal spray drying on the mixture, controlling the air inlet temperature to be 221 ℃, the air outlet temperature to be 122 ℃, and the rotating speed of an atomizer to be 39Hz, crushing after the drying is finished, and sieving to obtain the direct-pressure mannitol particles.
Comparative example 1
Based on example 1, the modification was that,
The preparation method of the composite starch is replaced by the following steps: adding deionized water into potato starch, stirring at 58 ℃ for 1.7h, and drying after stirring to obtain composite starch; the mass ratio of the potato starch to the deionized water is 64:117;
The rest of the operations are the same.
Comparative example 2
The procedure of example 1 was followed except that the modified silica fume was directly used without any treatment, and the procedure for preparing the modified silica fume was omitted.
Performance detection
The straight-press mannitol particles prepared in examples 1-3 and comparative examples 1-2 were subjected to a flow property test by injecting the product from the hopper opening into a plane and measuring the powder to form the base angle of a cone, i.e., angle of repose; the test results were as follows:
from the above data, it is clear that comparative examples 1-2 have a large angle of repose, i.e., poor flowability.
Product application
1% Magnesium stearate was added to the direct compression mannitol granules prepared in examples 1 to 3 and comparative examples 1 to 2, respectively, and after uniform mixing, tabletting was performed at 13kN, and then tablet detection was performed, with the following results:
The tablets were left to stand for 7d in an environment at 38℃and 67% humidity, and the hardness and friability of the tablets were again tested, with the following results:
According to the invention, the superfine silica powder is modified, firstly, the mixed solution of sucrose mono-fatty acid ester and deionized water is adopted to soak so as to promote dispersion of the superfine silica powder, avoid aggregation among particles, and then citric acid is adopted to treat, so that carboxyl of the citric acid is bonded with hydroxyl on the surface of the superfine silica powder, agglomeration among the superfine silica powder is avoided, on one hand, the performance of the glidant can be more effectively exerted, and the fluidity of the particles is ensured; on the other hand, the mannitol can be uniformly mixed with other components, so that the stability of mannitol particles is ensured, the tablet can still keep higher hardness after absorbing water, and the friability is reduced; the composite starch prepared by adopting the method combining heat treatment and ball milling treatment has the advantages that on one hand, the fluidity and the compressibility are improved, on the other hand, the crystalline structure of the starch is damaged, the number of free hydroxyl groups is increased, the tablet after tabletting is easy to absorb moisture and disintegrate, the disintegrating property is improved, mannitol particles prepared by combining the composite starch with specific modified micro powder silica gel have good fluidity and good compressibility, and the tablet prepared after tabletting has short disintegrating time limit, high hardness, low friability and excellent stability.
According to the experimental result of the comparative example 1, the comparative example 1 only adopts a heat treatment method to prepare the composite starch, on one hand, the starch is easy to agglomerate, the fluidity is poor, the uniformity of the mixture can be affected in the mixing process, and the compressibility and the hardness of the tablet are further affected; on the other hand, starch still has a certain crystalline structure, so that the disintegration time limit is prolonged, the disintegration performance is influenced, and further, the prepared mannitol particles have poor fluidity, the tablet after tabletting has long disintegration time limit, high friability and low hardness;
from the experimental results of the aforementioned comparative example 2, it is apparent that comparative example 2 uses the micro silica gel without any treatment as a glidant, the micro silica gel is easy to aggregate, the dispersion property is poor, the mixing with other components is uneven, the properties of mannitol particles are unstable, and after being placed in a high humidity environment, the tablet absorbs water, so that the retention rate of hardness is low, and the friability increase rate is high.
The proportions described in the invention are mass proportions, and the percentages are mass percentages unless otherwise specified.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some of the technical features thereof. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (2)
1. The preparation method of the direct compression mannitol particles is characterized by comprising the steps of preparing composite starch, modified micro powder silica gel, mixing and drying;
Adding deionized water and glyceryl monostearate into potato starch, stirring at 56-60 ℃ for 1.5-1.8h, drying after stirring, mixing with sodium alginate, performing ball milling for 25-30min at 142-150rpm and a ball-material ratio of 6-10:1, and obtaining composite starch after ball milling;
the mass ratio of the potato starch to the sodium alginate to the deionized water to the glyceryl monostearate is 62-66:1.5-1.7:112-120:0.24-0.28;
The modified micro powder silica gel is prepared by mixing sucrose mono fatty acid ester with deionized water to prepare a soaking solution, soaking the micro powder silica gel in the soaking solution with the volume of 2-4 times, wherein the soaking temperature is 54-58 ℃, the soaking time is 37-43min, drying after the soaking, heating to 70-74 ℃ at the speed of 0.4-0.6 ℃/min, adding 3-5 times of absolute ethyl alcohol, stirring for 1.0-1.2h, drying after the stirring, adding citric acid, performing hydrothermal reaction in a microwave hydrothermal synthesizer for 1.1-1.3h, and washing and drying after the reaction is finished, thereby preparing the modified micro powder silica gel;
the mass ratio of the sucrose fatty acid monoester to the deionized water is 2.2-2.6:83-87;
The mass ratio of the micro silica gel to the citric acid is 1:1.5-2;
Mixing composite starch, modified micro silica gel, low-substituted hydroxypropyl cellulose and deionized water to prepare auxiliary materials, uniformly stirring, adding mannitol powder, then carrying out ultrasonic oscillation treatment, controlling the ultrasonic power to be 43-47W, the ultrasonic frequency to be 62-67kHz, the ultrasonic time to be 10-14min, and preparing a mixture after the ultrasonic oscillation is finished;
The grain size of the mannitol powder is 110-130 meshes;
The mass ratio of the composite starch, the modified micro powder silica gel, the low-substituted hydroxypropyl cellulose and the deionized water is 1.7-2.2:0.3-0.5:1.3-1.7:176-195;
the mass ratio of the auxiliary materials to mannitol powder is 85-90:28-33;
the drying step is that the mixture is subjected to centrifugal spray drying, the air inlet temperature is controlled to be 214-221 ℃, the air outlet temperature is controlled to be 118-122 ℃, the rotating speed of an atomizer is controlled to be 35-39Hz, and after the drying is finished, the mixture is crushed and sieved to obtain the direct-pressure mannitol particles.
2. The direct compression mannitol particles produced according to the production process of claim 1.
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