阅读说明：本技术 一种葡萄糖酸钙二水合物 (Calcium gluconate dihydrate ) 是由 王明 于 2019-10-18 设计创作，主要内容包括：本发明公开了一种葡萄糖酸钙二水合物及制法,该化合物用粉末X射线衍射测定法测定,以2θ±0.2°衍射角表示在8.03°,9.06°,17.30°,20.78°,22.47°处显示出特征衍射峰。本发明制备的葡萄糖酸钙二水合物具有热稳定性好、水中溶解速度快、含量高的优点,而且工艺简单,收率高,重复性强,适合于工业化生产。(The invention discloses a calcium gluconate dihydrate and a preparation method thereof, wherein the compound shows characteristic diffraction peaks at 8.03 degrees, 9.06 degrees, 17.30 degrees, 20.78 degrees and 22.47 degrees as shown by 2 theta +/-0.2 degrees diffraction angle measured by a powder X-ray diffraction measuring method. The calcium gluconate dihydrate prepared by the method has the advantages of good thermal stability, high dissolution speed in water and high content, and is simple in process, high in yield, strong in repeatability and suitable for industrial production.)

1. The calcium gluconate dihydrate is characterized in that the molecular formula of the calcium gluconate compound is C₁₂H₂₂CaO₁₄·2H₂O, molecular weight of 466.40, structural formula shown in formula (I), as shown below,

2. the calcium gluconate dihydrate according to claim 1, which has an X-ray powder diffraction pattern as measured by powder X-ray diffractometry at diffraction angles of 2 θ ± 0.2 ° as shown in FIG. 1, and which shows characteristic diffraction peaks at 8.03 °, 9.06 °, 17.30 °, 20.78 ° and 22.47 °.

3. The method for producing calcium gluconate dihydrate according to claim 1 or 2, characterized by comprising the steps of:

(1) dissolving gluconolactone in water, adding calcium hydroxide in batches, heating to reflux for 4-6 hours, filtering while hot, concentrating the filtrate to half, cooling, stirring, crystallizing for 12-14 hours, filtering, and drying at 60 ℃ under reduced pressure to obtain a crude product of calcium gluconate;

(2) dissolving the calcium gluconate crude product in water, controlling the water temperature to be 80-95 ℃, and preparing into a 5-15% aqueous solution;

(3) adding activated carbon, heating to 80-95 ℃, decoloring for 1-2 hours, performing hot filtration, cooling the filtrate, stirring, gradually precipitating crystals, standing for 6-8 hours, filtering, and washing with cold water;

(4) and drying the crystal obtained by filtering under reduced pressure to obtain the calcium gluconate dihydrate.

4. The preparation method according to claim 3, wherein calcium hydroxide in an amount of 20% of the total amount of gluconolactone is added in three times in step (1), heated to 80 ℃ to reflux for 5 hours, and stirred at 0-15 ℃ for crystallization for 12 hours.

5. The method according to claim 3, wherein the water temperature in the step (2) is controlled to 90 ℃ to prepare a 10% aqueous solution.

6. The process according to claim 3, wherein in the step (3), activated carbon is added in an amount of 4% by weight based on the total weight of the solution, the temperature is raised to 90 ℃, the mixture is stirred and adsorbed for 1.4 hours, the crystals are gradually precipitated by heat filtration at a temperature of 0 to 10 ℃ and a stirring speed of 500 to 600r/m, and the mixture is allowed to stand for 7 hours.

7. The method according to claim 3, wherein the drying under reduced pressure in the step (4) is carried out at 45 to 60 ℃ for 30 to 50 min.

8. A pharmaceutical composition characterized by comprising the calcium gluconate dihydrate according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.

9. A pharmaceutical composition characterized by comprising the calcium gluconate dihydrate prepared according to any one of claims 3 to 7 and a pharmaceutically acceptable excipient.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to calcium gluconate dihydrate and a preparation method thereof.

Background

Calcium gluconate (calcium gluconate) is calcium salt of gluconic acid and has a molecular formula of C₁₂H₂₂CaO₁₄·H₂O, molecular weight 448.40, is white crystal or powder, odorless and tasteless, easily dissolves in boiling water, slowly dissolves in water, and does not dissolve in anhydrous alcohol, chloroform or diethyl ether. The calcium gluconate has important application in the aspects of medicine, food, chemical engineering and the like, particularly in the aspect of medicine, the calcium gluconate is beneficial to the formation of bone and maintains the normality and excitability of nerves and muscles, is important organic calcium, is clinically used as a calcium supplement and becomes a preferred product for calcium supplement of people; also can be used as raw material for producing other gluconate (zinc gluconate, ferric gluconate, etc.) and glucono delta-lactone. The structural formula is as follows:

the production process of calcium gluconate mainly comprises three parts of preparing gluconic acid by oxidizing glucose, neutralizing the gluconic acid and calcium to obtain the calcium gluconate, and finally refining. The quality requirement of the calcium gluconate for injection is high, starch is used as a raw material in the prior art, the refining process is slightly different, the quality of the produced calcium gluconate hardly reaches the standard of the calcium gluconate for injection, and particularly, the calcium gluconate has unqualified clarity, PH, content and the like and needs to be dissolved in boiling water.

In patent CN201810245150.7, a method for continuously cooling and rapidly crystallizing calcium gluconate is disclosed, which mainly includes the steps of dissolving, oxidizing, concentrating, filtering, decolorizing, performing kinetic crystallization, drying, etc., and the invention describes the preparation method of calcium gluconate in detail, but the description of the continuous cooling crystallization system and process is unclear.

Patent 201410543277.9 discloses a vacuum flash cooling continuous crystallization device, which uses a self-evaporator and a three-stage vacuum flash crystallizer as main equipment for cooling continuous crystallization, wherein the self-evaporator needs to be connected with a cooling system, the surface cooler occupies a large area and has low cooling efficiency, and the system has the defects of complex system, huge equipment and the like.

In patent CN201910294514.5, a system and a process for continuous crystallization of calcium gluconate are disclosed, comprising an MVR evaporator, a three-stage vacuum flash crystallizer, a steam jet vacuum pump, a hybrid condenser, a heat exchanger, a slurry tank, a centrifuge, a granulator and a dryer, wherein although the crystallization effect is good, the system is still huge and the operation of the system is complex.

Patent CN201810547582.3 discloses a calcium gluconate injection and its preparation method, wherein the preparation method comprises boiling water for injection, adding calcium gluconate, stirring for dissolving, and keeping boiling state; slowly adding lactic acid/calcium hydroxide clarified liquid under boiling, stirring for dissolving, and keeping a first-stage boiling state; adjusting the pH value with dilute hydrochloric acid; then adding medicinal active carbon and sodium hydroxide solution to adjust the pH value; adding water for injection, stirring, standing, removing carbon, adjusting pH with dilute hydrochloric acid, adding water for injection to full volume, stirring, filtering, refluxing, and cooling to room temperature; and (5) encapsulating and sterilizing. The pH value is adjusted repeatedly, the industrial production operation is not easy, and the labor cost is increased.

The calcium gluconate raw material on the market at present is mainly monohydrate, has poor stability of raw material medicine, is easy to dissolve in boiling water, has low content and complex process, and is not convenient for industrial production and storage. The inventor prepares the calcium gluconate dihydrate containing 2 crystal waters different from the prior art by taking the existing gluconolactone as a raw material through a large number of experiments, and finds that the calcium gluconate dihydrate has the advantages of good thermal stability, high dissolution speed in water and high content through the experiments, and the calcium gluconate dihydrate is simple in process, high in yield and strong in repeatability and is suitable for industrial production.

Disclosure of Invention

The invention aims to develop and prepare a novel calcium gluconate compound product, and solves the problems of poor stability, easy dissolution in boiling water, low content and the like of calcium gluconate raw material medicines in the current market. In order to solve the problems, the invention prepares the calcium gluconate dihydrate.

The invention also provides a calcium gluconate dihydrate and a preparation method thereof.

The invention also provides a pharmaceutical composition containing the calcium gluconate dihydrate.

The technical scheme of the invention is as follows:

calcium gluconate dihydrate with molecular formula of C₁₂H₂₂CaO₁₄·2H₂O, molecular weight of 466.40, structural formula shown below,

the calcium gluconate dihydrate is measured by a powder X-ray diffraction measurement method, and an X-ray powder diffraction pattern expressed by a 2 theta +/-0.2 DEG diffraction angle is shown in figure 1, and characteristic diffraction peaks are shown at 8.03 DEG, 9.06 DEG, 17.30 DEG, 20.78 DEG and 22.47 deg.

A preparation method of calcium gluconate dihydrate specifically comprises the following steps:

(1) dissolving gluconolactone in water, adding calcium hydroxide in batches, heating to reflux for 4-6 hours, filtering while hot, concentrating the filtrate to half, cooling, stirring, crystallizing for 12-14 hours, filtering, and drying at 60 ℃ under reduced pressure to obtain a crude product of calcium gluconate;

(2) dissolving the calcium gluconate crude product in water, controlling the water temperature to be 80-95 ℃, and preparing into a 5-15% aqueous solution;

(3) adding activated carbon, heating to 80-95 ℃, decoloring for 1-2 hours, performing hot filtration, cooling the filtrate, stirring, gradually precipitating crystals, standing for 6-8 hours, filtering, and washing with cold water;

(4) and drying the crystal obtained by filtering under reduced pressure to obtain the calcium gluconate dihydrate.

In a preferred embodiment of the invention, calcium hydroxide accounting for 20% of the total amount of the gluconolactone is added in three times in the step (1), the mixture is heated to 80 ℃ to reflux for 5 hours, and stirred and crystallized at 0-15 ℃ for 12 hours.

As a preferred embodiment of the present invention, the water temperature in step (2) is controlled to 90 ℃ to prepare a 10% aqueous solution.

In a preferred embodiment of the present invention, in step (3), activated carbon in an amount of 4% by weight of the total solution is added, the temperature is raised to 90 ℃, and the mixture is stirred and adsorbed for 1.4 hours, followed by heat filtration. Gradually precipitating crystals at the temperature of 0-10 ℃ and the stirring speed of 500-600 r/m, and standing for 7 hours.

In a preferred embodiment of the present invention, the reduced pressure drying condition in step (4) is reduced pressure drying at 45-60 ℃ for 30-50 min.

A pharmaceutical composition comprising the calcium gluconate dihydrate of the present invention and a pharmaceutically acceptable excipient.

The pharmaceutical composition also contains calcium hydroxide and lactic acid.

The pharmaceutical composition is sterile injection prepared from calcium gluconate, calcium hydroxide and lactic acid. The specification contained 10 ml: 1g and 10 ml: 0.5 g.

Compared with the prior art, the invention has the following advantages:

1. the calcium gluconate dihydrate provided by the invention has high content, good thermal stability and high dissolution speed in water.

2. The preparation method of the calcium gluconate dihydrate provided by the invention has the advantages of simple process, high yield and strong repeatability, and is suitable for industrial production.

3. The pharmaceutical composition containing the calcium gluconate dihydrate provided by the invention has good stability, so that the medication safety and effectiveness are improved, and the incidence rate of adverse reactions is reduced.

Drawings

Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:

FIG. 1X-ray powder diffraction pattern of calcium gluconate dihydrate.

Detailed Description

The following examples are further illustrative of the present invention and are in no way intended to limit the scope of the invention. The present invention is further illustrated in detail below with reference to examples, but it should be understood by those skilled in the art that the present invention is not limited to these examples and the preparation method used. Also, equivalent substitutions, combinations, improvements or modifications of the invention may be made by those skilled in the art based on the description of the invention, but these are included in the scope of the invention.