Preparation method of spherical calcium citrate crystal with adjustable particle size

Abstract

This invention belongs to the field of biochemical engineering, specifically relating to a method for preparing spherical calcium citrate crystals with controllable particle size. The preparation method includes the following steps: (1) preparing a citric acid-water solution with a concentration of 0.01–0.2 g / mL and a calcium carbonate-water suspension with a concentration of 0.01–0.3 g / mL; (2) adding the calcium carbonate-water suspension dropwise to the citric acid-water solution, stirring and crystallizing until the pH reaches 3.5–5, to obtain spherical calcium citrate particles. The particle size control of calcium citrate in this invention is achieved by controlling the reaction temperature and the droplet acceleration rate of the calcium carbonate suspension, resulting in spherical calcium citrate particles with an average particle size range of 30–170 micrometers and more uniform particle size. The product particles have good uniformity, high flowability, and an angle of repose between 28° and 32°. The preparation process of this invention is simple, green, environmentally friendly, and pollution-free.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of bio-chemical industry, and particularly relates to a preparation method of spherical calcium citrate crystal with adjustable particle size. BACKGROUND

[0002] Calcium is an essential element for human body, and participates in the whole life process of human body. A sufficient amount of calcium is required to be taken in every day to maintain normal metabolism of human body and effectively avoid the occurrence of body diseases.

[0003] Calcium citrate (CAS: 813-94-5) is a kind of organic calcium with good biocompatibility, and does not neutralize gastric acid, does not irritate the gastrointestinal tract, and has certain degree of disadvantages compared with inorganic calcium. Calcium citrate is a more ideal food calcium supplement.

[0004] The calcium citrate products obtained on the market have irregular morphology and uneven particle size distribution, which affects the taste of the calcium citrate products as food additives or calcium supplements. It is necessary to control the crystallization process to obtain calcium citrate with good morphology and more uniform particle size distribution. CN104529754A provides a preparation method of amorphous calcium citrate; CN104355991A provides a preparation method of calcium citrate with fibrous morphology. CN104402705A provides a preparation method of spherical calcium citrate, but the preparation method is relatively complex, the prepared spherical particles are self-assembled from flaky crystals, freezing drying is required to ensure the stability of the spherical crystals, the particle size of the spherical product is not uniform, and the required production raw materials are expensive, which is not conducive to industrialization. In the present application, calcium carbonate is added to the dropwise addition of citric acid, the dropwise addition rate is controlled to obtain spherical calcium citrate products with uniform particle size distribution, more stable morphology and compactness, and different particle sizes of calcium citrate products are obtained by controlling the temperature according to the product requirements. SUMMARY

[0005] The market demand for calcium citrate with high bioavailability advantage will continue to rise over time. Since calcium citrate is often used for daily high-end calcium supplementation, including calcium tablet formulations, mixed with other food raw materials such as infant formula milk powder, health products, beverages, dairy products, etc., it is required that the calcium citrate particles have better flowability, compounding property, suspensibility, excellent texture and other food functions, so as to meet the market quality requirements of food. The product morphology and particle size distribution are important indicators of the current calcium citrate product, and excellent taste requires high flowability, small particle size and narrow particle size distribution of spherical products to eliminate dryness and grit feeling during eating; high flowability products are required for tabletting formulations to reduce adhesion and residue on the tablet press. However, the calcium citrate produced in the industry at present is prone to agglomeration, resulting in uneven morphology and particle size distribution, which seriously affects its market value. In order to overcome the technical problems of the prior art, the present application provides a method for preparing stable and controllable particle size spherical calcium citrate, which reduces the difficulty of downstream processing and reduces the production energy consumption and dust pollution of the product. The calcium citrate product obtained by the process has uniform particle size distribution, stable morphology, no agglomeration, good flowability, low production cost, simple process, green and environmentally friendly, and can realize large-scale production.

[0006] The technical scheme of the present application is as follows:

[0007] (1) preparing a citric acid-water solution with a concentration of 0.03-0.2 g / mL and a calcium carbonate-water suspension with a concentration of 0.03-0.3 g / mL;

[0008] (2) adding the calcium carbonate-water suspension dropwise into the citric acid-water solution, stirring and reacting to crystallize until the pH is 3.5-5, to obtain spherical calcium citrate particles.

[0009] The calcium carbonate suspension is added dropwise into the prepared citric acid solution at a certain dropwise rate, the whole process is stirred to ensure complete reaction, and the experiment is ended 0.3-1 h (such as 0.3 h, 0.5 h, 0.8 h, 1 h, etc.) after the addition of the calcium carbonate suspension is completed, to obtain spherical calcium citrate particles.

[0010] The molar ratio of the two reactants in step (1) is calcium carbonate: citric acid = 1.3-1.47:1, to ensure that the final pH is between 3.5 and 5.

[0011] The dropwise rate of the calcium carbonate suspension in step (2) is calculated according to the absolute dropwise rate (i.e. dropwise time), which is 30-180 min.

[0012] Preferably, the dropwise time at different temperatures is respectively: 150-180 min at 20℃; 100-130 min at 40℃; 50-70 min at 60℃; 30-40 min at 80℃.

[0013] The stirring rate in the step (2) is maintained at 200-350 rpm (for example, 200 rpm, 250 rpm, 300 rpm, 350 rpm).

[0014] The particle size of the spherical product in the step (2) can be adjusted by changing the reaction temperature: as the temperature increases, the reaction rate and the growth rate of calcium citrate crystals increase, and a spherical product with large particle size is obtained. When the reaction temperature is controlled between 20, 40, 60, 80℃, the average particle size (D v (50)) is 29.6 microns, 68.1 microns, 116 microns, and 173 microns, respectively.

[0015] The preparation method further comprises sequentially performing solid-liquid separation and drying on the substance obtained by reaction crystallization. The solid-liquid separation method is vacuum filtration. The drying method adopts normal pressure drying, the temperature is 50-55℃ (for example, 50℃, 55℃, etc.), and the drying time is 12-24h (for example, 12h, 16h, 20h, 24h, etc.).

[0016] The spherical calcium citrate product has high flowability, and the rest angle is between 28° and 32°. The test standard of the rest angle is GB / T11986-1989. The Span number representing the particle size distribution is calculated as formula (1), wherein d 90 , d 10 , and d 50 represent the particle sizes of 10%, 50%, and 90% of the cumulative particle size distribution, respectively. The smaller the Span number value, the more uniform the particle size distribution.

[0017] Span=(d 90 -d 10 ) / d 50 (1)

[0018] Further analysis, the application also provides the application of the above-mentioned spherical calcium citrate product: it can be applied in the field of food, including as a tabletting preparation and a food calcium fortifier, etc. The spherical product has better powder performance, which improves the tabletting performance of the calcium supplement product and the taste as a food calcium fortifier.

[0019] Compared with the current preparation method of calcium citrate, the method has the following beneficial effects:

[0020] a) The crystal morphology of calcium citrate obtained by the method is spherical, which greatly improves the product powder performance such as morphology and flowability compared with other morphologies (for example: fibrous, massive, powdery), and is also more conducive to the downstream processing of the product.

[0021] b) The spherical calcium citrate product prepared by the method has higher stability, so compared with the currently self-assembled spherical crystals, it has the advantages of better particle size distribution and not easy to break, further simplifying the product post-processing process, and the better particle size distribution and uniform morphology as a food additive will have better taste.

[0022] c) The method effectively creates a temperature-controlled calcium citrate crystal nucleation and growth reaction crystallization system, which has the advantages of low raw material price, simple process parameter control, and no by-product generation compared to the reported preparation process of spherical calcium citrate. The particle size of the spherical particles obtained by the method is controlled based on the reaction temperature, and the corresponding reaction temperature can be selected according to the product requirements. Providing a solid process scheme will promote calcium citrate to enter the ranks of high-end calcium supplements. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 : SEM photo of spherical calcium citrate in Example 1 of the present application (scale is 20 microns);

[0024] Figure 2 : SEM photo of spherical calcium citrate in Example 2 of the present application (scale is 50 microns);

[0025] Figure 3 : SEM photo of spherical calcium citrate in Example 3 of the present application (scale is 100 microns);

[0026] Figure 4 : SEM photo of spherical calcium citrate in Example 4 of the present application (scale is 100 microns);

[0027] Figure 5 : Particle size characterization chart of Example 1, 2, 3, 4 of the present application using Malvern 3000.

[0028] Figure 6 : XRD pattern of calcium citrate prepared in the present application. DETAILED DESCRIPTION

[0029] Example 1:

[0030] (1) At 20℃, prepare a 0.03g / mL citric acid-water mixed solution, stir until the citric acid is completely dissolved in water. Prepare a 0.03g / mL calcium carbonate-water suspension, stir until the calcium carbonate is suspended in water. The molar ratio of calcium carbonate to citric acid is 1.4:1;

[0031] (2) The calcium carbonate suspension was added into the citric acid solution at the same dropping rate within 1.5 h, and the reaction temperature was controlled at 20°C. A stirring rate of 250 rpm was maintained until 1.5 h after the end of the calcium carbonate suspension dropping, so that the solid particles nucleated and grew into stable spherical particles.

[0032] (3) The calcium citrate particles were obtained by vacuum filtration, washing with water, and drying at 50°C under normal pressure for 24 h.

[0033] The SEM image of the product (SEM model HITACHI, TM3000, Japan) is shown in Figure 1 ; and the XRD pattern of the product (XRD model R-AXIS-RAPID, Rigaku, Japan) is shown in Figure 6 ; Figure 5 The average particle size of the spherical calcium citrate product was 29.6 microns, the Span number was 0.87, and the rest angle was 32°.

[0034] Example 2:

[0035] (1) A 0.01 g / mL citric acid-water mixed solution was prepared at 40°C, and stirred until the citric acid was completely dissolved in water. A 0.01 g / mL calcium carbonate-water suspension was prepared, and stirred until the calcium carbonate was suspended in water. The molar ratio of calcium carbonate to citric acid was 1.42:1.

[0036] (2) The calcium carbonate suspension was added into the citric acid solution at the same dropping rate within 1 h, and the reaction temperature was controlled at 40°C. A stirring rate of 300 rpm was maintained until 0.5 h after the end of the calcium carbonate suspension dropping, so that the solid particles nucleated and grew into stable spherical particles.

[0037] (3) The calcium citrate particles were obtained by vacuum filtration, washing with water, and drying at 50°C under normal pressure for 16 h.

[0038] The SEM image of the product is shown in Figure 2 ; Figure 5 The average particle size of the spherical calcium citrate product was 68.1 microns, the Span number was 0.90, and the rest angle was 31°, and the test method was the same as in Example 1.

[0039] Example 3:

[0040] (1) A 0.15 g / mL citric acid-water mixed solution was prepared at 60°C, and stirred until the citric acid was completely dissolved in water. A 0.3 g / mL calcium carbonate-water suspension was prepared, and stirred until the calcium carbonate was suspended in water. The molar ratio of calcium carbonate to citric acid was 1.47:1.

[0041] (2) The calcium carbonate suspension was added into the citric acid solution at the same dropping rate within 0.8 h, the reaction temperature was controlled at 60 °C, and the stirring rate was maintained at 300 rpm until 0.5 h after the end of dropping the calcium carbonate suspension, so as to make the solid particles nucleate and grow into stable spherical particles;

[0042] (3) The dried calcium citrate particles were obtained by vacuum filtration, washing with water, and drying at 55 °C under normal pressure for 12 h.

[0043] The SEM morphology characterization graph of the product (SEM model HITACHI, TM3000, Japan) is shown in Figure 3 ; Figure 5 The average particle size of the spherical calcium citrate product was 116 microns, the Span number was 0.81, and the rest angle was 30°. The test method was the same as that of Example 1.

[0044] Example 4:

[0045] (1) A 0.1 g / mL citric acid-water mixed solution was prepared at 80 °C and stirred until the citric acid was completely dissolved in water. A 0.5 g / mL calcium carbonate-water suspension was prepared and stirred until the calcium carbonate was suspended in water, and the molar ratio of calcium carbonate to citric acid was 1.45:1.

[0046] (2) The calcium carbonate suspension was added into the citric acid solution at the same dropping rate within 0.8 h, the reaction temperature was controlled at 80 °C, and the stirring rate was maintained at 250 rpm until 0.5 h after the end of dropping the calcium carbonate suspension, so as to make the solid particles nucleate and grow into stable spherical particles;

[0047] (3) The dried calcium citrate particles were obtained by vacuum filtration, washing with water, and drying at 50 °C under normal pressure for 16 h.

[0048] The SEM morphology characterization graph of the product (SEM model HITACHI, TM3000, Japan) is shown in Figure 4 ; Figure 5 The average particle size of the spherical calcium citrate product was 173 microns, the Span number was 0.77, and the rest angle was 28°. The test method was the same as that of Example 1.

[0049] Comparative Example 1:

[0050] The difference from Example 1 was only that the dropping rate of the calcium carbonate suspension was changed, and the dropping time was reduced from the original 1.5 h to 0.2 h.

[0051] The average particle size of the product particles was 53 microns, the Span number was 1.26, and the rest angle was 46°. The product was severely agglomerated, and the sphericity was poor. The test method was the same as that of Example 1.

[0052] Comparative Example 2:

[0053] The difference from Example 1 is that the calcium carbonate suspension and the citric acid concentration are both changed to 0.3 g / mL, and other experimental conditions are ensured to be the same as in Example 1.

[0054] A large number of fine crystals appear in the product, causing the solution in the crystallizer to gradually gel until the stirring paddle can no longer stir the suspended matter in the crystallizer. The product characterization morphology appears spherical, short rod-shaped and needle-shaped, and the product rest angle is 48°.

[0055] Comparative Example 3:

[0056] The difference from Example 3 is that the stirring rate of the reaction crystallization is changed to 600 rpm, and other experimental conditions are ensured to be the same as in Example 3.

[0057] Short flaky and spherical crystals appear in the product, and the surface of the spherical crystals is found to have traces of polishing by electron microscopy. The average particle size of the product is reduced to 84 microns, and the particle size shows a bimodal distribution with a very uneven size distribution.

[0058] Comparative Example 4:

[0059] The CN104402705A patent application proposes a water-soluble calcium salt and citrate mixed reaction crystallization to obtain self-assembled agglomerated spherical particles and dispersed flaky crystals that are unable to be electrostatically attracted and agglomerated. The product particle size distribution is 10-100 microns (large spherical crystals, small dispersed flaky crystals).

[0060] From the comparison of Example 1 and Comparative Example 1, it can be seen that when the reaction calcium carbonate suspension dropwise addition time is too short, the product appears to be agglomerated, the sphericity is poor, the flowability is reduced, and the average particle size is significantly increased. This is because the dropwise addition rate is too fast, resulting in too short a dropwise addition time, an increased supersaturation degree, and an increased crystal growth site, which promotes the formation of cauliflower-shaped spherical crystals (agglomerated crystals) while reducing the powder performance of the product.

[0061] From the comparison of Example 1 and Comparative Example 2, it can be seen that when the initial concentration of the reactant components in the solution exceeds the limited range of the present application, an abnormal paste phenomenon occurs, which seriously affects the mass transfer and the flowability of the system, and greatly prolongs the subsequent solid-liquid separation and drying time. The product morphology observed by microscopy shows spherical and short rod-shaped, so if the paste abnormality occurs, it will seriously affect the process efficiency and the powder performance of the product.

[0062] By comparing example 3 and comparative example 3, it can be seen that when the stirring speed of the reaction operation exceeds the limited range of the application, the shear force in each position of the system changes. The spherulites composed of long plate-like crystals are broken by the larger shear force during the growth process, resulting in a large amount of broken crystals in the product, the particle size changes, and the quality of the calcium citrate product is seriously affected.

[0063] By comparing examples 1-4 and comparative example 4, it can be seen that the application adopts the reaction crystallization of citric acid and calcium carbonate, and adjusts the dropping speed to obtain spherulites with uniform particle size distribution, uniform morphology and stability, which improves the powder performance of the spherulites and is beneficial to realize industrialization.

[0064] The application discloses and proposes a preparation method of spheroidal calcium citrate with adjustable particle size, and those skilled in the art can obtain calcium citrate products with good spheroidality by referring to the content of the application, selecting the temperature, the concentration of citric acid and calcium carbonate, the dropping speed and the residence time under the reaction crystallization system, and adjusting the key parameter of temperature to obtain spheroidal calcium citrates with different particle sizes. The method of the application has been described through preferred examples, and relevant skilled persons can obviously modify or appropriately change and combine the method and product described in the application without departing from the content, spirit and range of the application, so as to realize the application. It should be particularly pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are regarded as being included in the spirit, range and content of the application.

Claims

1. A method for preparing spherical calcium citrate crystals with controllable particle size, characterized in that, The preparation method comprises the following steps: (1) preparing a citric acid-water solution with a concentration of 0.03-0.2 g / mL and a calcium carbonate-water suspension with a concentration of 0.03-0.3 g / mL; (2) adding the calcium carbonate-water suspension into the citric acid-water solution, stirring and reacting to crystallize at 20-80 ℃ until the pH is 3.5-5, to obtain spherical calcium citrate particles; In step (1), the molar ratio of calcium carbonate in the calcium carbonate-water suspension to citric acid in the citric acid-water solution is (1.3-1.47):1; In step (2), the stirring rate is 200-350 rpm; In step (2), the ripening time after the reactants are added dropwise is 0.3-1 h.

2. The preparation method according to claim 1, characterized in that, In step (2), the dropwise adding time is 30-180 min.

3. The preparation method according to claim 1, characterized in that, The dropwise adding time at different temperatures is as follows: 150-180 min at 20 ℃, 100-130 min at 40 ℃, 50-70 min at 60 ℃, and 30-40 min at 80 ℃.

4. The method of claim 1, wherein, Step (2) further comprises sequentially performing solid-liquid separation, washing, and drying on the product obtained by reaction and crystallization.

5. The production method according to claim 4, characterized by, The solid-liquid separation mode is vacuum filtration.

6. The preparation method according to claim 4, characterized in that, The drying mode is normal pressure drying, the drying temperature is 50-55 ℃, and the drying time is 12-24 h.

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