CN112552167A - Preparation method of calcium gluconate - Google Patents
Preparation method of calcium gluconate Download PDFInfo
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- CN112552167A CN112552167A CN202011636435.7A CN202011636435A CN112552167A CN 112552167 A CN112552167 A CN 112552167A CN 202011636435 A CN202011636435 A CN 202011636435A CN 112552167 A CN112552167 A CN 112552167A
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- temperature
- calcium gluconate
- crystallization
- stirring
- calcium
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- 229960004494 calcium gluconate Drugs 0.000 title claims abstract description 25
- 239000004227 calcium gluconate Substances 0.000 title claims abstract description 25
- 235000013927 calcium gluconate Nutrition 0.000 title claims abstract description 25
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 18
- 238000003756 stirring Methods 0.000 claims abstract description 12
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims abstract description 9
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims abstract description 4
- 239000012065 filter cake Substances 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 15
- 230000008025 crystallization Effects 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 238000005054 agglomeration Methods 0.000 abstract description 2
- 230000002776 aggregation Effects 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000007581 slurry coating method Methods 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- GZCGUPFRVQAUEE-VANKVMQKSA-N aldehydo-L-glucose Chemical compound OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)C=O GZCGUPFRVQAUEE-VANKVMQKSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940040682 calcium gluconate monohydrate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- XLNFVCRGJZBQGX-XRDLMGPZSA-L calcium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate;hydrate Chemical compound O.[Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O XLNFVCRGJZBQGX-XRDLMGPZSA-L 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of calcium gluconate, which comprises the following steps: reacting gluconic acid-delta-lactone with calcium carbonate at the temperature of 80-90 ℃ to obtain a calcium gluconate aqueous solution, adding medicinal activated carbon, and preserving heat at the temperature of 80-90 ℃ for 30 min. ② filtering while hot, cooling the filtrate to 30-40 ℃, adding seed crystal, cooling to 10-20 ℃, stirring and crystallizing at the temperature with the frequency of 20 plus or minus 1Hz for 8-12 h. Thirdly, centrifugal filtration is carried out, and the finished product of the calcium gluconate is obtained after crushing and drying of a filter cake. According to the invention, a large number of experiments show that the temperature in the crystallization kettle can be ensured to be uniform and stable by controlling the temperature of stirring crystallization and the stirring frequency, so that the problems of crystallization agglomeration, crystallization slurry coating, large supersaturation degree and the like are solved, the crystallization efficiency is obviously improved, and the reaction yield is greatly improved.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of calcium gluconate.
Background
Calcium gluconate (also known as calcium gluconate monohydrate) is an organic calcium salt with chemical formula C12H24O15Ca, white crystalline or granular powder, with melting point of 201 deg.C (decomposition), odorless, tasteless, and easily soluble in boiling water (20 g/100)mL) and is slightly soluble in cold water (3 g/100mL, 20 ℃) and insoluble in an organic solvent such as ethanol or diethyl ether. The aqueous solution was neutral (pH about 6-7). The calcium gluconate is mainly used as calcium enhancer, nutrient, buffering agent, solidifying agent and chelating agent of food.
At present, the method for preparing calcium gluconate mainly comprises the following two types:
(1) glucose oxidation method: that is, glucose and calcium carbonate are used as starting materials, and calcium gluconate is prepared by reaction in the presence of glucose oxidase and catalase [ see Chinese patent document CN106399404A, etc. ].
(2) Hydrolysis of gluconic acid-delta-lactone: namely, gluconic acid-delta-lactone is used as a starting material, is heated and dissolved to obtain gluconic acid, and then reacts with calcium carbonate to obtain calcium gluconate [ see Chinese patent document CN101434532A, etc. ].
At present, the biggest problems in the preparation of calcium gluconate are as follows: the yield is not high, and is usually only about 70%.
The main reasons for the low yield are as follows: the crystallization effect is not ideal, and the crystallization mother liquor contains a large amount of products.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of calcium gluconate with higher product purity and higher reaction yield.
The technical scheme for realizing the purpose of the invention is as follows: a preparation method of calcium gluconate comprises the following steps:
reacting gluconic acid-delta-lactone with calcium carbonate at the temperature of 80-90 ℃ to obtain a calcium gluconate aqueous solution, adding medicinal activated carbon, and preserving heat at the temperature of 80-90 ℃ for 30 min.
② filtering while hot, cooling the filtrate to 30-40 ℃, adding seed crystal, cooling to 10-20 ℃, stirring and crystallizing at the temperature with the frequency of 20 plus or minus 1Hz for 8-12 h.
Thirdly, centrifugal filtration is carried out, and the finished product of the calcium gluconate is obtained after crushing and drying of a filter cake.
In the third step, the molar ratio of the gluconic acid-delta-lactone to the calcium carbonate is 1: 0.4-1: 0.6, and preferably 1: 0.5.
And the drying in the third step is boiling drying, the temperature is 60-75 ℃, and the time is 1-3 h.
The invention has the following positive effects: according to the invention, a large number of experiments show that the temperature in the crystallization kettle can be ensured to be uniform and stable by controlling the temperature of stirring crystallization and the stirring frequency, so that the problems of crystallization agglomeration, crystallization slurry coating, large supersaturation degree and the like are solved, the crystallization efficiency is obviously improved, and the reaction yield is greatly improved.
Detailed Description
(example 1)
The preparation method of calcium gluconate of the embodiment comprises the following steps:
adding 700L of purified water into a reaction kettle, starting stirring, adding 89kg (0.50 kmol) of gluconic acid-delta-lactone, adding 25kg (0.25 kmol) of calcium carbonate after complete stirring and dissolution, supplementing the purified water to reach the total volume of 850L, heating to 85 +/-1 ℃, and stirring for reaction for 1.5h to obtain a calcium gluconate aqueous solution. Then adding 1kg of 50-mesh medicinal activated carbon at one time under stirring, and keeping the temperature at 85 +/-1 ℃ for decoloring for 30 min.
② filtering while hot, cooling the filtrate to 35 plus or minus 1 ℃, adding 2kg of seed crystal, then cooling to 15 plus or minus 1 ℃, maintaining the temperature and stirring at the frequency of 20 plus or minus 1Hz for crystallization for 10 hours.
Thirdly, centrifugal filtration is carried out, and 106.6kg of calcium gluconate is obtained after filter cakes are crushed and boiled and dried for 2 hours at 70 ℃, the yield is 95.2 percent, and the purity (HPLC) is 98.9 percent.
(examples 2 to 3)
The preparation method of each example is substantially the same as that of example 1 except that see table 1.
(comparative examples 1 to 4)
The comparative examples were prepared in substantially the same manner as in example 1 except that the process is shown in Table 1.
TABLE 1
| Crystallization temperature | Time of crystallization | Frequency of agitation | Weight (D) | Yield of | Purity of | |
| Example 1 | 15±1℃ | 10h | 20±1Hz | 106.6kg | 95.2% | 99.5% |
| Example 2 | 12±1℃ | 12h | 20±1Hz | 104.9kg | 93.7% | 99.2% |
| Example 3 | 18±1℃ | 8h | 20±1Hz | 103.9kg | 92.8% | 99.0% |
| Comparative example 1 | 25±1℃ | 5h | 20±1Hz | 79.9kg | 71.3% | 98.2% |
| Comparative example 2 | 25±1℃ | 10h | 20±1Hz | 88.3kg | 78.8% | 98.8% |
| Comparative example 3 | 15±1℃ | 10h | 30±1Hz | 75.3kg | 67.2% | 96.5% |
| Comparative example 4 | 15±1℃ | 10h | 10±1Hz | 70.2kg | 62.7% | 95.7% |
Claims (4)
1. A preparation method of calcium gluconate comprises the following steps:
reacting gluconic acid-delta-lactone with calcium carbonate at the temperature of 80-90 ℃ to obtain a calcium gluconate aqueous solution, adding medicinal activated carbon, and preserving heat at the temperature of 80-90 ℃ for 30 min;
secondly, filtering while the solution is hot, cooling the filtrate to 30-40 ℃, adding seed crystals, cooling to 10-20 ℃, and stirring and crystallizing at the temperature for 8-12 hours at the frequency of 20 +/-1 Hz;
thirdly, centrifugal filtration is carried out, and the finished product of the calcium gluconate is obtained after crushing and drying of a filter cake.
2. The method for preparing calcium gluconate according to claim 1, wherein: in the third step, the molar ratio of the gluconic acid-delta-lactone to the calcium carbonate is 1: 0.4-1: 0.6.
3. The method for preparing calcium gluconate according to claim 2, wherein: in the step (c), the molar ratio of the gluconic acid-delta-lactone to the calcium carbonate is 1: 0.5.
4. The method of producing calcium gluconate according to any one of claims 1 to 3, wherein: and the drying in the third step is boiling drying, the temperature is 60-75 ℃, and the time is 1-3 h.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011636435.7A CN112552167B (en) | 2020-12-31 | 2020-12-31 | Preparation method of calcium gluconate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011636435.7A CN112552167B (en) | 2020-12-31 | 2020-12-31 | Preparation method of calcium gluconate |
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| Publication Number | Publication Date |
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| CN112552167A true CN112552167A (en) | 2021-03-26 |
| CN112552167B CN112552167B (en) | 2024-03-22 |
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|---|---|---|---|
| CN202011636435.7A Active CN112552167B (en) | 2020-12-31 | 2020-12-31 | Preparation method of calcium gluconate |
Country Status (1)
| Country | Link |
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| CN (1) | CN112552167B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115154415A (en) * | 2022-08-04 | 2022-10-11 | 山东新华制药股份有限公司 | Preparation method of calcium gluconate injection |
| CN115522228A (en) * | 2022-04-25 | 2022-12-27 | 江苏双盛锌业股份有限公司 | Energy-saving environment-friendly high-purity zinc powder preparation method and preparation equipment |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0254486A1 (en) * | 1986-07-18 | 1988-01-27 | Stabra AG | Preparation of metal gluconates |
| JPH0523137A (en) * | 1991-07-19 | 1993-02-02 | Toyo Ratsushiyan Seiyaku Kk | Instantly soluble pasty calcium pharmaceutical and its production |
| RU2058294C1 (en) * | 1994-02-21 | 1996-04-20 | Акционерное общество "Курский комбинат лекарственных средств" | Method for production of calcium gluconate |
| US20050032894A1 (en) * | 2002-06-27 | 2005-02-10 | Buendia Manuel Torres | Method for manufacturing calcium gluconolcatate compositions, processes and uses |
| CN106987608A (en) * | 2017-06-02 | 2017-07-28 | 四川仁安药业有限责任公司 | A kind of crystallization in motion of calcium gluconae |
| CN108611378A (en) * | 2018-03-23 | 2018-10-02 | 连云港瑞邦药业有限公司 | A kind of continuous cooling rapid crystallization method of calcium gluconate |
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-
2020
- 2020-12-31 CN CN202011636435.7A patent/CN112552167B/en active Active
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115522228A (en) * | 2022-04-25 | 2022-12-27 | 江苏双盛锌业股份有限公司 | Energy-saving environment-friendly high-purity zinc powder preparation method and preparation equipment |
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| CN115154415B (en) * | 2022-08-04 | 2024-03-08 | 山东新华制药股份有限公司 | Preparation method of calcium gluconate injection |
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