CN104402705A - Spherical calcium citrate, and preparation method and application thereof - Google Patents

Spherical calcium citrate, and preparation method and application thereof Download PDF

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Publication number
CN104402705A
CN104402705A CN201410612039.9A CN201410612039A CN104402705A CN 104402705 A CN104402705 A CN 104402705A CN 201410612039 A CN201410612039 A CN 201410612039A CN 104402705 A CN104402705 A CN 104402705A
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citrate
lime
preparation
spherical
calcium citrate
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CN104402705B (en
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李峻峰
钟良兆
侯毅
赖雪飞
邱克辉
李冠玉
黄露梅
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Chengdu Univeristy of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compounds Of Alkaline-Earth Elements, Aluminum Or Rare-Earth Metals (AREA)
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Abstract

The invention belongs to the field of calcium citrate, and concretely relates to spherical calcium citrate, and a preparation method and application thereof. The provided calcium citrate is spherical, has the diameter of 10-100 mu m and has the specific surface area of 1-80 m<2>/g determined by a BET method. The prepared spherical calcium citrate is calcium citrate with a new morphology never reported before, calcium citrate, which is extremely good in biocompatibility, is endowed with new performances, and the application scope of calcium citrate is expanded. The foreseeable thing is that if the morphology of calcium citrate can be effectively controlled and calcium citrate powders with diversified morphologies can be obtained, calcium citrate powders with different properties can be obtained and the application fields of calcium citrate can be expanded.

Description

Spherical citrate of lime and its preparation method and application
Technical field
The invention belongs to citrate of lime field, be specifically related to a kind of spherical citrate of lime and its preparation method and application.
Background technology
Citrate of lime is the extraordinary organic calcium salt of a kind of biocompatibility, due to its be easily absorbed by the body, nontoxic advantage, citrate of lime through being often used as calsium supplement, calcium deficiency illness such as treatment osteoporosis etc.Citrate of lime is generally obtained by calcium hydroxide and citric acid neutralization titration or calcium carbonate and citric acid reactions, pays attention to the cheap cheapness of raw material, to commercially produce, but does not control the pattern of citrate of lime and crystallization.As Chinese patent application 200710021894.2 " one utilizes potato slag method for extracting soluble calcium citrate ", be utilize black-koji mould to ferment to potato slag, obtain citric acid, then react with calcium carbonate; Chinese patent application 201010237025.5 " a kind of method being prepared citrate of lime by oyster shells and scallop shell " utilizes calcium carbonate contained in comparatively cheap oyster shells and scallop shell for raw material is to prepare citrate of lime.The feature of these methods is that raw material sources are extensive, low price, is suitable for large-scale industrial production, focuses on cost.
In recent years owing to noticing the characteristic of nontoxic easy degraded in the biocompatibility that citrate of lime is good and human body, someone attempts citrate of lime as bone renovating material.As the people such as Ding Xiuming utilize in the biological characteristics of citrate of lime " the simulated body fluid infusion method evaluate " natural oyster shells after crushed with citric acid reactions, then through grinding, sieve, obtain citrate of lime particle.Wear star in " development of biotype citrate of lime bone material and correlative study " be also utilize oyster shells as calcium source and citric acid reactions to citrate of lime, obtain the citrate of lime particle of applicable size through screening.
The shape of the citrate of lime of current use is sheet, Powdered, and there is no the relevant report of spherical citrate of lime.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of spherical citrate of lime, this citrate of lime can be used as common citrate of lime and uses, in addition, because it forms globosity by sheet citrate of lime, there is high-specific surface area, new performance given by the material fabulous for this biocompatibility of citrate of lime, by the range of application of expansion citrate of lime.
The invention provides a kind of spherical citrate of lime, its diameter is 10-100 μm (micron), and described citrate of lime is 1 ~ 80m based on the specific surface area that BET method measures 2/ g.
Preferably, described citrate of lime is 1 ~ 51m based on the specific surface area that BET method measures 2/ g.
Preferably, the diameter of described spherical citrate of lime is 30-60 μm.
Further, above-mentioned spherical citrate of lime is formed by the self-assembly of sheet citrate of lime.
Present invention also offers the preparation method of above-mentioned spherical citrate of lime, the mixing that water-soluble Ca salt and water-soluble citrate added water obtains the mixed aqueous solution of calcium salt and Citrate trianion, the mixed aqueous solution of calcium salt and Citrate trianion in 40-99 DEG C of heated and stirred 2min-30min, by obtained solidliquid mixture solid-liquid separation, washing and drying obtain spherical citrate of lime; Wherein, in the mixed aqueous solution of calcium salt and Citrate trianion, in molar ratio, Gai Li ︰ citrate > 2.5 ︰ 2.
Preferably, in the mixed aqueous solution of calcium salt and Citrate trianion, in molar ratio, Gai Li ︰ citrate=2.8 ~ 3.2 ︰ 2.
Described water-soluble Ca salt is at least one in calcium chloride, nitrocalcite.
Described water-soluble citrate is at least one in trisodium citrate, citric acid tri potassium, Triammonium citrate.
Preferably, in the preparation method of described spherical citrate of lime, heated and stirred speed is 5-60 rev/min.
Further, in above-mentioned spherical citrate of lime preparation method, after heated and stirred, before gained solidliquid mixture solid-liquid separation, room temperature is cooled to.
Preferably, in the preparation method of described spherical citrate of lime, cryodesiccated method is adopted.
Further, the invention provides the application of above-mentioned spherical citrate of lime: the spherical citrate of lime of gained of the present invention has all purposes (as calsium supplement, foodstuff additive etc.) of existing citrate of lime, in addition, because it is for spherical and have high-specific surface area, it also can be used to: drug release, Bone Defect Repari etc.
Beneficial effect of the present invention:
The spherical citrate of lime that the present invention prepares, this is the new pattern of the citrate of lime of no one's report in the past, and new performance given by the material fabulous for this biocompatibility of citrate of lime, will expand the range of application of citrate of lime.Can predict, if the pattern of citrate of lime effectively can be controlled, thus obtain the diversified citrate of lime powder of pattern, then can obtain citrate of lime powder of different nature and will the Application Areas of citrate of lime be expanded.
Accompanying drawing illustrates:
Fig. 1 is the SEM photo of the spherical citrate of lime of preparation in the embodiment of the present invention 1.
Fig. 2 be in the embodiment of the present invention 3 preparation spherical citrate of lime under × 1500 magnifications SEM photo.
Fig. 3 be in the embodiment of the present invention 3 preparation spherical citrate of lime under × 3000 magnifications SEM photo.
Fig. 4 is the drug release patterns figure of the spherical citrate of lime of test example 1 gained of the present invention.
Fig. 5 is the XRD figure of the spherical citrate of lime of preparation in the embodiment of the present invention 1.
Embodiment:
The invention provides a kind of spherical citrate of lime, its diameter is 10-100 μm (micron), and described citrate of lime is 1 ~ 80m based on the specific surface area that BET method measures 2/ g.
Preferably, the diameter of described spherical citrate of lime is 30-60 μm.
Above-mentioned spherical citrate of lime is formed by the self-assembly of sheet citrate of lime.Detailed process is: first heat calcium salt-Citrate trianion mixing solutions, separate out sheet citrate of lime, the size of this sheet citrate of lime is about 10-30nm × 20-1000nm × 30-2000nm, these flaps due to self with the group in electrostatic or citrate of lime as OH-, O-Ca-O, hydrogen bond etc. attract each other near formed coacervate, also because flap belongs to nano material, due to the surfactivity that it is higher, nano material easily reunion balling-up, can spontaneous reunion balling-up in the solution so heat rear sheet citrate of lime of separating out to reduce surface energy.
Present invention also offers the preparation method of above-mentioned spherical citrate of lime, the mixing that water-soluble Ca salt and water-soluble citrate added water obtains the mixed aqueous solution of calcium salt and Citrate trianion, the mixed aqueous solution of calcium salt and Citrate trianion in 40-99 DEG C of heated and stirred 2min-30min, by obtained solidliquid mixture solid-liquid separation, washing and drying obtain spherical citrate of lime; Wherein, in the mixed aqueous solution of calcium salt and Citrate trianion, in molar ratio, Gai Li ︰ citrate > 2.5 ︰ 2; Preferably, Gai Li ︰ citrate=2.8 ~ 8 ︰ 2; Preferred, Gai Li ︰ citrate=2.8 ~ 3.2 ︰ 2.
In the present invention, can separate out citrate of lime in calcium salt-citrate solution more than 40 degree, because calcium salt, Citrate trianion all use water dissolution, therefore temperature generally can not exceed the boiling point of water; If temperature is too low, than being easier to the sheet citrate of lime forming dispersion, the effect of reunion balling-up is bad.In addition, heat-up time is shorter, and the self-assembly microspheres of formation is less, and the time, longer microballoon was larger.And find in experiment, heat-up time is long, and sheet citrate of lime can change strip into by sheet gradually, and therefore the time is not more than 30min.
Preferably, in above-mentioned preparation method, Gai Li ︰ citrate=2.8 ~ 8 ︰ 2.
Preferably, in the mixed aqueous solution of calcium salt and Citrate trianion, in molar ratio, Gai Li ︰ citrate=2.8 ~ 3.2 ︰ 2.
Preferably, in the preparation method of described spherical citrate of lime, heated and stirred speed is 5-60 rev/min.
Stir the external force mainly making sheet citrate of lime obtain the outside upset provided, make assembling more neat, can not seem disorderly and unsystematic; Stirring velocity may make sheet citrate of lime easily be adsorbed in wall of container or bottom too slowly, reduces balling-up efficiency; Then self-assembly microspheres may be broken up, 5-60 rev/min too soon.
Preferably, in the preparation method of described spherical citrate of lime, cryodesiccated method is adopted.
The present invention can separate out the calcium citrate microparticles of sheet when being and utilizing Citrate trianion and calcium salt to heat at the temperature of 40-99 DEG C, under the molecular linkage in these particulates and electrostatic interaction, sheet citrate of lime can be agglomerated into the microballoon of certain pattern automatically.Because the time is longer, the citrate of lime microballoon of reunion can be larger, therefore, can control water bath time to reach the object controlling citrate of lime self-assembly microspheres size.Microsphere diameter about 5 microns when heating 2 minutes, microsphere diameter about 10 microns when 5 minutes, when 30 minutes, microsphere diameter can reach about 30 microns.Because taking-up can have surplus heat after the short periods such as water-bath 2min, now citrate of lime still can continue to separate out, and after heating completes, preferably adds cold water immediately cool.In addition, lump because vacuum-drying easily makes calcium citrate powder reunite, therefore drying means preferably selects lyophilize.
Further, the invention provides the application of above-mentioned spherical citrate of lime: the spherical citrate of lime of gained of the present invention has all purposes (as calsium supplement, foodstuff additive etc.) of existing citrate of lime, in addition, because it is spherical, it also can be used to: drug release, Bone Defect Repari etc.
Embodiment 1
Take 0.8670 gram of CaCl respectively 2, 1.4854 grams of Na 3c 6h 5o 72H 2o, respectively adds 20ml water dissolution in beaker; By Na 3c 6h 5o 72H 2o solution adds CaCl 2, stir; The beaker that mixing solutions is housed is put into water-bath, and bath temperature is 75 degrees Celsius, and stirring velocity is set to 20r/min; Take out beaker after 2 minutes, in beaker, add distilled water be cooled to room temperature (due to comparatively slow from 75 degree of naturally cooling times, the 2min of relative water-bath is oversize, terminates just to add cold water lower the temperature rapidly for making to be swift in response); Filter, solid-liquid separation, gets solids wash 3 postlyophilizations, can obtain the spherical citrate of lime of self-assembly, and its SEM schemes as shown in Figure 1; Its diameter is 10-20 micron.Its specific surface area uses the test of BET method to be 1.737m 2/ g.The XRD figure of gained citrate of lime as shown in Figure 5.
Embodiment 2
Take 0.8670 gram of CaCl respectively 2, 1.4854 grams of Na 3c 6h 5o 72H 2o, respectively adds 20ml water dissolution in beaker; By Na 3c 6h 5o 72H 2o solution adds CaCl 2solution, stirs; The beaker that mixing solutions is housed is put into water-bath, and bath temperature is 75 degrees Celsius, and stirring velocity is set to 20r/min; Take out beaker after 5 minutes, in beaker, add distilled water be cooled to room temperature; Filter, solid-liquid separation, gets solids wash 3 postlyophilizations, can obtain the spherical citrate of lime of self-assembly, and scheming its diameter known by its SEM is 10-20 micron.Its specific surface area uses the test of BET method to be 50.824m 2/ g.
Embodiment 3
Take 0.8670 gram of CaCl respectively 2, 1.4854 grams of Na 3c 6h 5o 72H 2o, respectively adds 20ml water dissolution in beaker; By Na 3c 6h 5o 72H 2o solution adds CaCl 2solution, stirs; The beaker that mixing solutions is housed is put into water-bath, and bath temperature is 75 degrees Celsius, and stirring velocity is set to 5r/min; Take out beaker after 20 minutes, in beaker, add distilled water be cooled to room temperature; Filter, solid-liquid separation, gets solids wash 3 postlyophilizations, can obtain the spherical citrate of lime of self-assembly, and its SEM schemes as shown in Figures 2 and 3; Its diameter is 30-60 micron.Its specific surface area uses the test of BET method to be 25.093m 2/ g.
Embodiment 4
Take 0.8670 gram of CaCl respectively 2, 1.4854 grams of Na 3c 6h 5o 72H 2o, respectively adds 20ml water dissolution in beaker; By Na 3c 6h 5o 72H 2o solution adds CaCl 2solution, stirs; The beaker that mixing solutions is housed is put into water-bath, and bath temperature is 75 degrees Celsius, and stirring velocity is set to 5r/min; Take out beaker after 30 minutes, in beaker, add distilled water be cooled to room temperature; Filter, solid-liquid separation, gets solids wash 3 postlyophilizations, can obtain the spherical citrate of lime of self-assembly, and scheming its diameter known by SEM is 30-60 micron.Its specific surface area uses the test of BET method to be 5.132m 2/ g.
Test example 1
Get 0.8670 gram of CaCl respectively 2, 1.4854 grams of Na 3c 6h 5o 72H 2o, respectively adds 20ml water dissolution in beaker, by Na 3c 6h 5o 72H 2o solution adds CaCl 2solution, added in mixing solutions by 0.2g berberine hydrochloride after stirring and stir, other steps are with embodiment 2.By the release conditions of UV spectrophotometer measuring berberine hydrochloride, drug release patterns as shown in Figure 4.As seen from Figure 4:
The release of medicine in citrate of lime microballoon can be divided into three phases: the first stage is 0-30min, and subordinate phase is 30-60min, and the phase III is 60-90min, and after 90min, medicine discharges substantially completely; First stage Chinese traditional medicine release rate is very fast, releases the medicine of about 71.5% in 30min; The release rate of subordinate phase medicine becomes relatively milder, this stage only release about 10.7% medicine; Phase III drug releasing rate accelerate, release rate lower than the first stage higher than subordinate phase, this stage release about 17.8% medicine.
This drug release patterns is relevant with the unique texture of citrate of lime; Because medicine carrying microballoons is formed by the self-assembly of sheet citrate of lime, the specific surface area of microballoon extexine is large, large with the contact surface of solution, thus when starting, drug releasing rate is very fast; Subordinate phase may be that the specific surface area of microballoon internal layer is less, and the medicine of parcel and solution contact surface amass less thus release rate is slack-off; And along with extexine in the solution soak time increase and come off gradually, come out by internal layer, the quickening of drug releasing rate that internal layer wrap up is until discharge completely.
To release rate, the present invention requires that drug effect is larger faster, because the specific surface area of this spherical citrate of lime is larger, medicine is attached in the performance of sheet citrate of lime, medicine and environmental exposure area large, thus the release rate of medicine is larger, visible, the spherical citrate of lime of gained of the present invention can for needs release rate faster medicine a kind of well carrier is provided.

Claims (9)

1. citrate of lime, is characterized in that, described citrate of lime is spherical, and its diameter is 10-100 μm, and described citrate of lime is 1 ~ 80m based on the specific surface area that BET method measures 2/ g.
2. citrate of lime according to claim 1, is characterized in that, the diameter of described citrate of lime is 30 ~ 60 μm, and specific surface area is 1 ~ 51m 2/ g.
3. citrate of lime according to claim 1 and 2, is characterized in that, described spherical citrate of lime is formed by the self-assembly of sheet citrate of lime.
4. the preparation method of the citrate of lime described in any one of claims 1 to 3, it is characterized in that, the mixing that water-soluble Ca salt and water-soluble citrate added water obtains the mixed aqueous solution of calcium salt and Citrate trianion, the mixed aqueous solution of calcium salt and Citrate trianion in 40 ~ 99 DEG C of heated and stirred 2min-30min, by obtained solidliquid mixture solid-liquid separation, washing and drying obtain spherical citrate of lime; Wherein, in the mixed aqueous solution of calcium salt and Citrate trianion, in molar ratio, Gai Li ︰ citrate > 2.5 ︰ 2.
5. the preparation method of citrate of lime according to claim 3, is characterized in that, Gai Li ︰ citrate=2.8 ~ 3.2 ︰ 2.
6. the preparation method of the citrate of lime according to claim 4 or 5, is characterized in that, heated and stirred speed is 5 ~ 60 revs/min.
7. the preparation method of the citrate of lime according to any one of claim 4 ~ 6, is characterized in that, described water-soluble Ca salt is at least one in calcium chloride, nitrocalcite; Described water-soluble citrate is at least one in trisodium citrate, citric acid tri potassium, Triammonium citrate.
8. the purposes of citrate of lime in drug release, Bone Defect Repari, described citrate of lime is the citrate of lime described in any one of claims 1 to 3, or the citrate of lime obtained for the preparation method described in any one of claim 4 ~ 7.
9. a drug release carrier, it adopts the citrate of lime described in any one of claims 1 to 3, or the citrate of lime obtained for the preparation method described in any one of claim 4 ~ 7.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218694A (en) * 2018-01-30 2018-06-29 日照金禾博源生化有限公司 A kind of preparation method of ultra-fine calcium citrate
CN108853516A (en) * 2018-07-07 2018-11-23 成都迈德克科技有限公司 A kind of functional load medicine calcium citrate
CN115572222A (en) * 2022-08-11 2023-01-06 山东金禾保健品有限公司 Preparation method and application of calcium citrate spherical crystal

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CN1073333A (en) * 1991-12-20 1993-06-23 卡夫通用食品有限公司 Aqueous calcium citrate compositions
CN1261793A (en) * 1997-07-01 2000-08-02 美国辉瑞有限公司 Sertraline salts and substained-release dosage forms of sertraline
CN101185772A (en) * 2007-12-12 2008-05-28 彭磊 Human body hard tissue filling renovation material containing calcium citrate
CN101553204A (en) * 2006-12-04 2009-10-07 苏佩努斯制药公司 Enhanced immediate release formulations of topiramate
CN102334690A (en) * 2010-07-27 2012-02-01 河北农业大学 Method for preparing calcium citrate with oyster shells and fan shells
CN102921036A (en) * 2012-10-11 2013-02-13 海南医学院 Method for preparing marine environment-friendly calcium citrate hard tissue repair material

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1073333A (en) * 1991-12-20 1993-06-23 卡夫通用食品有限公司 Aqueous calcium citrate compositions
CN1261793A (en) * 1997-07-01 2000-08-02 美国辉瑞有限公司 Sertraline salts and substained-release dosage forms of sertraline
CN101553204A (en) * 2006-12-04 2009-10-07 苏佩努斯制药公司 Enhanced immediate release formulations of topiramate
CN101185772A (en) * 2007-12-12 2008-05-28 彭磊 Human body hard tissue filling renovation material containing calcium citrate
CN102334690A (en) * 2010-07-27 2012-02-01 河北农业大学 Method for preparing calcium citrate with oyster shells and fan shells
CN102921036A (en) * 2012-10-11 2013-02-13 海南医学院 Method for preparing marine environment-friendly calcium citrate hard tissue repair material

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218694A (en) * 2018-01-30 2018-06-29 日照金禾博源生化有限公司 A kind of preparation method of ultra-fine calcium citrate
CN108218694B (en) * 2018-01-30 2020-12-25 日照金禾博源生化有限公司 Preparation method of superfine calcium citrate
CN108853516A (en) * 2018-07-07 2018-11-23 成都迈德克科技有限公司 A kind of functional load medicine calcium citrate
CN108853516B (en) * 2018-07-07 2023-01-06 成都迈德克科技有限公司 Functional medicine-carrying calcium citrate
CN115572222A (en) * 2022-08-11 2023-01-06 山东金禾保健品有限公司 Preparation method and application of calcium citrate spherical crystal
CN115572222B (en) * 2022-08-11 2024-05-10 山东金禾保健品有限公司 Preparation method and application of spherical calcium citrate crystal

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