Calcium carbonate d3 effervescent granules and process for their preparation

Abstract

The present application relates to a kind of calcium carbonate D3 effervescent granules and its preparation method, belong to biological medicine preparation technical field.The present application utilizes calcium carbonate and anhydrous citric acid to prepare granule A, utilizes vitamin D3 and alkali source to prepare basic granule B, then granule A, granule B are mixed with acid source again to obtain calcium carbonate D3 effervescent granules;The present application of calcium carbonate D3 effervescent granules meets water and causes acid-base neutralization reaction, quickly forms suspension;The present application of calcium carbonate D3 effervescent granules does not contain ethanol aqueous solution, anhydrous ethanol, isopropanol and other organic solvents, product safety is higher, production cost is lower;Calcium carbonate D3 effervescent granules accelerate 6 months, character is stable, does not occur acid-base reaction, does not produce carbon dioxide gas, stability is good, solve the effervescent granule in the process of placement, prone to acid-base reaction, produce carbon dioxide, the problem of affecting product quality.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical preparation technology, and in particular to a calcium carbonate D3 effervescent granule and its preparation method. Background Technology

[0002] Calcium is one of the essential nutrients for the human body and is the most abundant mineral element, playing vital physiological functions. Calcium carbonate contains approximately 40% elemental calcium (i.e., pure calcium that can be absorbed by the body), the highest content among all calcium supplement forms. Furthermore, calcium carbonate is inexpensive and safe to use, making it the preferred raw material for calcium supplements both domestically and internationally. Vitamin D3 promotes calcium absorption, and compound preparations containing both vitamin D and calcium carbonate are ideal supplements—efficient and convenient.

[0003] Calcium carbonate is a type of calcium supplement that relies on stomach acid for absorption, making it highly dependent on stomach acid – this is its most prominent drawback. It only dissolves effectively in an acidic environment. For individuals with insufficient stomach acid secretion (such as the elderly, those taking antacids long-term, and patients with atrophic gastritis), the absorption rate of calcium carbonate will be significantly reduced, leading to indigestion, bloating, and other adverse reactions. Calcium carbonate D3 effervescent granules address these issues. The acidic components (such as citric acid and tartaric acid) in the effervescent granules react with the alkaline components in water, dissolving to form a weakly acidic solution, thus reducing dependence on stomach acid to some extent. For individuals with insufficient stomach acid secretion, this ensures the dissolution and subsequent absorption of calcium carbonate, thereby improving bioavailability. The effervescent granules enter the stomach in solution form, distributing evenly and reducing irritation to the gastric mucosa, effectively minimizing common side effects such as belching, constipation, and bloating. While ordinary calcium carbonate tablets have a rough, "lime-like" taste, effervescent granules, when dissolved in water, form a slightly cloudy, fruit-flavored beverage with a sweet and sour taste, masking the unpleasant taste of calcium carbonate itself.

[0004] However, this formulation also has some shortcomings, such as its sensitivity to moisture and its susceptibility to acid-base reactions during storage, producing carbon dioxide and causing the packaging bag to bulge. Current technologies mostly use ethanol in the production process to reduce water content; however, ethanol is a flammable and explosive liquid, posing a risk of danger and increasing costs during use. For example, the preparation process of calcium carbonate effervescent granules disclosed in patent CN102225070A is as follows: (1) Dissolve the binder in an ethanol solution to prepare a binder ethanol solution; (2) Dissolve the vitamin D-β-cyclodextrin inclusion complex in 15-25% binder ethanol solution and add it to calcium carbonate, mix well, and then add 40-50% binder ethanol solution, mix and granulate to obtain alkaline granules; (3) Add the remaining binder ethanol solution to an acidic foaming agent, granulate to obtain acidic granules; (4) Mix the above alkaline granules and acidic granules to obtain calcium carbonate effervescent granules. The method used in this patent is to granulate acidic granules and alkaline granules separately, but this method uses an ethanol solution, which increases the cost of the product and poses a significant safety risk during production. For example, the calcium carbonate vitamin D3 composition in patent CN113952358A includes the following components: vitamin D3 powder, calcium carbonate, filler, binder, pH adjuster, ethanol and purified water. The preparation method of this patent also requires the use of an ethanol solution. The three-dimensional calcium self-emulsifying effervescent composition of patent CN112741841A requires the use of solvents such as ethanol in its preparation, which also increases costs and poses significant safety risks during the production process. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a calcium carbonate D3 effervescent granule with better stability and its preparation method.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides calcium carbonate D3 effervescent granules, comprising granules A, granules B and an acid source, wherein granules A are obtained by granulation of a mixture A containing calcium carbonate and anhydrous citric acid, and granules B are obtained by granulation of a mixture B containing vitamin D3, an alkali source, filler b and binder b. The anhydrous citric acid has a particle size of 30-100 mesh; The filler b is rice starch or corn starch, and the adhesive b is rice starch or corn starch; The acid source is an organic acid in the effervescent granules, excluding anhydrous citric acid.

[0007] This invention utilizes calcium carbonate and anhydrous citric acid to prepare granules A, and vitamin D3 and an alkaline source to prepare alkaline granules B. Then, granules A and B are mixed with an acid source to obtain calcium carbonate D3 effervescent granules. The calcium carbonate D3 effervescent granules of this invention do not contain organic solvents such as ethanol, resulting in higher product safety. The calcium carbonate D3 effervescent granules remain stable after being placed at 60±2℃ for 30 days and under accelerated conditions at 40±2℃ and relative humidity RH 75±5% for 6 months, without undergoing acid-base reactions or producing carbon dioxide gas, demonstrating good stability.

[0008] In this invention, the calcium carbonate D3 effervescent granules require the use of specific fillers and binders for granule B. If other fillers and binders besides rice starch or corn starch are used, it will lead to incompatibility between the raw materials and excipients.

[0009] Compared to preparing acidic granules using an acid source, preparing alkaline granules using calcium carbonate, an alkaline source, and vitamin D3, and preparing calcium carbonate D3 effervescent granules by mixing acidic and alkaline granules, the calcium carbonate D3 effervescent granules of the present invention have higher stability.

[0010] Compared to preparing alkaline granules using calcium carbonate and an alkaline source, and preparing calcium carbonate D3 effervescent granules by mixing alkaline granules with an acid source and vitamin D3, the calcium carbonate D3 effervescent granules of the present invention also have higher stability.

[0011] This invention utilizes a mixture A containing calcium carbonate and anhydrous citric acid to granulate and prepares granules A, and a mixture B containing vitamin D3, an alkali source, filler b, and binder b to granulate and prepare granules B. By combining these with organic acids available for effervescent granules other than anhydrous citric acid, effervescent granules with better stability can be obtained. However, if anhydrous citric acid is used as the acid source in this invention and combined with granules A and B to prepare effervescent granules, the stability of the effervescent granules will be reduced.

[0012] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the anhydrous citric acid has a particle size of 50-100 mesh.

[0013] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass ratio of calcium carbonate to anhydrous citric acid in granule A is 30~40:40~55.

[0014] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass ratio of calcium carbonate to anhydrous citric acid in granule A is 30~35:50~55.

[0015] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass ratio of vitamin D3, alkali source, filler b and binder b in granule B is 0.1~0.2:3~5:3~6:0.1~0.2.

[0016] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass ratio of vitamin D3, alkali source, filler b and binder b in granule B is 0.1~0.15:3~4:4~5:0.1~0.15.

[0017] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mixture A further contains filler a and binder a; the mass ratio of calcium carbonate to filler a and binder a in the granules A is 30~40:3~6:0.3~0.6.

[0018] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass ratio of calcium carbonate to filler a and binder a in granule A is 30~35:3~4:0.4~0.5.

[0019] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the filler a includes one or more of corn starch, rice starch or maltodextrin; the binder a includes one or more of corn starch, rice starch or pregelatinized starch.

[0020] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the vitamin D3 is a vitamin D3 concentrate; the alkaline source includes potassium carbonate, potassium bicarbonate, sodium carbonate, or sodium bicarbonate.

[0021] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass percentage of calcium carbonate in the calcium carbonate D3 effervescent granules is 20%~40%; the mass ratio of calcium carbonate to vitamin D and acid source in the calcium carbonate D3 effervescent granules is 30~40:0.1~0.2:3~15.

[0022] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass percentage of calcium carbonate in the calcium carbonate D3 effervescent granules is 30%~35%; the mass ratio of calcium carbonate to vitamin D and acid source in the calcium carbonate D3 effervescent granules is 30~35:0.1~0.15:3~4.

[0023] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the acid source includes malic acid or tartaric acid.

[0024] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the acid source is malic acid; preferably, the malic acid is DL-malic acid.

[0025] As a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the calcium carbonate D3 effervescent granules further contain a flavoring agent, and the mass percentage of the flavoring agent in the calcium carbonate D3 effervescent granules is 0.05%~0.5%.

[0026] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the mass percentage of the flavoring agent in the calcium carbonate D3 effervescent granules is 0.1%.

[0027] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the flavoring agent includes one or more of sodium cyclohexylsulfamate, sodium saccharin, and flavoring.

[0028] In a preferred embodiment of the calcium carbonate D3 effervescent granules of the present invention, the vitamin D3 is a vitamin D3 concentrate. The vitamin D3 concentrate contains 100,000 IU / g of vitamin D3. The vitamin D3 concentrate is prepared according to the preparation method of vitamin D3 formulation in CN101951920A, and the preparation method of the vitamin D3 concentrate includes the following steps: (1) Aqueous phase preparation Sodium octenyl succinate starch, sucrose, sodium vitamin C, and water for injection were mixed at a mass ratio of 1096.5:264:60.0:2475.0 and stirred at 50-70°C until homogeneous to obtain the aqueous phase. (2) Preparation of oil phase Racemic α-tocopherol, vitamin D3, and medium-chain triglycerides were mixed in a mass ratio of 15.0:3.75:45.0 and stirred until dissolved to obtain the oil phase; the mass ratio of sodium vitamin C to vitamin D3 was 60.0:3.75. (3) Preparation of colostrum Add the oil phase obtained in step (2) to the aqueous phase obtained in step (1), mix well, and then shear for 30 min at 50~70℃ and 10000~20000 rpm under nitrogen protection to obtain the primary emulsion; (4) Homogenization and emulsification Under nitrogen protection at 50~70℃, the colostrum obtained in step (3) is first homogenized and emulsified at 250~350 bar, and then circulated and emulsified twice; then homogenized and emulsified at 450~550 bar, and circulated and emulsified three times; finally homogenized and emulsified at 600~700 bar, and circulated and emulsified three times to obtain vitamin D3 emulsion. (5) Spray drying The vitamin D3 emulsion obtained in step (4) was spray-dried with silica as a flow aid to obtain vitamin D3 concentrate.

[0029] Secondly, the present invention provides a method for preparing the above-mentioned calcium carbonate D3 effervescent granules, comprising the following steps: S1. Mix adhesive a and adhesive b with water and heat to gelatinize them to prepare adhesive a slurry and adhesive b slurry respectively; S2. Mix anhydrous citric acid, calcium carbonate and filler a, then add the adhesive slurry a obtained in step S1 and prepare a soft material. Granulate the obtained soft material to obtain particles and dry them to obtain particles A. S3. Mix the alkali source, filler b and vitamin D3, then add the adhesive b slurry obtained in step S1 and prepare a soft material. Granulate the obtained soft material to obtain granules and dry them to obtain granules B. S4. Mix the granules A obtained in step S2 with the granules B obtained in step S3, then add an acid source or an acid source and flavoring agent, mix well, and obtain calcium carbonate D3 effervescent granules.

[0030] In a preferred embodiment of the preparation method described in this invention, in step S1, the solid content of the adhesive a slurry or the adhesive b slurry is 8 (w / w).

[0031] In a preferred embodiment of the preparation method of the present invention, in step S2 or step S3, the granulation is carried out using a 24-mesh sieve.

[0032] In a preferred embodiment of the preparation method of the present invention, the drying temperature in step S2 or step S3 is 60~70°C.

[0033] In a preferred embodiment of the preparation method described in this invention, in step S2, the moisture content of particle A is less than 1.5%.

[0034] In a preferred embodiment of the preparation method of the present invention, in step S3, the moisture content of the particles B is less than 10.0%.

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention utilizes calcium carbonate and anhydrous citric acid to prepare granules A, and vitamin D3 and an alkaline source to prepare alkaline granules B. Granules A and B are then mixed with an acid source to obtain calcium carbonate D3 effervescent granules. The calcium carbonate D3 effervescent granules of this invention undergo an acid-base neutralization reaction upon contact with water, rapidly forming a suspension. The calcium carbonate D3 effervescent granules of this invention do not contain organic solvents such as aqueous ethanol, anhydrous ethanol, or isopropanol, resulting in higher product safety and lower production costs. The calcium carbonate D3 effervescent granules remain stable for up to 6 months, without undergoing acid-base reactions or producing carbon dioxide gas, demonstrating excellent stability. This solves the problem of effervescent granules easily undergoing acid-base reactions and producing carbon dioxide during storage, thus affecting product quality. Attached Figure Description

[0036] Figure 1 This is an appearance diagram of the calcium carbonate D3 effervescent granules of Example 1 of the present invention. Detailed Implementation

[0037] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0038] Unless otherwise specified, all other materials and reagents used in the examples are commercially available.

[0039] The vitamin D3 concentrate (vitamin D3 of 100,000 IU / g) of the present invention is prepared according to the preparation method of vitamin D3 formulation in CN101951920A. Specifically, the preparation method of the vitamin D3 concentrate of the present invention includes the following steps: (1) Aqueous phase preparation 1096.5g sodium octenyl succinate starch, 264g sucrose, 60.0g sodium vitamin C and 2475.0g water for injection were mixed and stirred at 50~70℃ to obtain an aqueous phase. (2) Preparation of oil phase 15.0g racemic α-tocopherol, 3.75g vitamin D3 and 45.0g medium-chain triglycerides were mixed and stirred until dissolved to obtain the oil phase; (3) Preparation of colostrum Add the oil phase obtained in step (2) to the aqueous phase obtained in step (1), stir evenly, and then use a high shear dispersion emulsifier to shear for 30 minutes at a speed of 10,000~20,000 rpm and a shearing temperature of 50~70℃, and then purge with nitrogen to obtain the primary emulsion; (4) Homogenization and emulsification The colostrum obtained in step (3) was subjected to nitrogen protection at 50~70℃. First, it was homogenized and emulsified under high pressure of 300±50 bar, and then circulated and emulsified twice. Next, it was homogenized and emulsified under high pressure of 500±50 bar, and then circulated and emulsified three times. Finally, it was homogenized and emulsified under high pressure of 650±50 bar, and then circulated and emulsified three times to obtain vitamin D3 emulsion. (5) Spray drying The vitamin D3 emulsion obtained in step (4) was spray-dried through a nozzle, and silica was added as a flow aid to obtain vitamin D3 concentrate.

[0040] Examples 1-9 A calcium carbonate D3 effervescent granule comprises granule A, granule B, and an acid source. Granule A is obtained by granulation of a mixture A containing calcium carbonate and anhydrous citric acid. Granule B is obtained by granulation of a mixture B containing vitamin D3, an alkali source, filler b, and binder b. The anhydrous citric acid has a particle size of 30-100 mesh. The filler b is rice starch or corn starch, and the binder b is rice starch or corn starch. The acid source is an organic acid in the effervescent granule other than anhydrous citric acid. The mass ratio of calcium carbonate to anhydrous citric acid in particle A is 30~40:40~55; The mass ratio of vitamin D3, alkali source, filler b, and binder b in granule B is 0.1~0.2:3~5:3~6:0.1~0.2; The mixture A also contains filler a and binder a; the mass ratio of calcium carbonate to filler a and binder a in the mixture A is 30~40:3~6:0.3~0.6. The filler a includes one or more of corn starch, rice starch, or maltodextrin; The adhesive a includes one or more of corn starch, rice starch, or pregelatinized starch.

[0041] The vitamin D3 is a vitamin D3 concentrate; the alkaline source includes potassium carbonate, potassium bicarbonate, sodium carbonate, or sodium bicarbonate.

[0042] The calcium carbonate D3 effervescent granules contain calcium carbonate at a mass percentage of 20% to 40%; the mass ratio of calcium carbonate to vitamin D and acid source in the calcium carbonate D3 effervescent granules is 30 to 40: 0.1 to 0.2: 3 to 15.

[0043] The acid source includes malic acid or tartaric acid; the malic acid is DL-malic acid.

[0044] The calcium carbonate D3 effervescent granules also contain a flavoring agent, and the mass percentage of the flavoring agent in the calcium carbonate D3 effervescent granules is 0.05%~0.5%.

[0045] The flavoring agent includes one or more of sodium cyclohexylsulfamate, sodium saccharin, and flavoring.

[0046] The composition and content of calcium carbonate D3 effervescent granules in Examples 1-9 are shown in Table 1. Table 1 The preparation method of calcium carbonate D3 effervescent granules in Examples 1-9 includes the following steps: S1. Mix adhesive a and adhesive b with water and heat to gelatinize, to prepare adhesive a slurry and adhesive b slurry with 8% solid content (w / w); S2. Anhydrous citric acid, calcium carbonate, and filler a are mixed in a wet granulator. The binder a slurry obtained in step S1 is added to prepare a soft material. The soft material is granulated using a 24-mesh sieve to obtain granules, which are then dried in a fluidized bed at a drying temperature of 70°C for 1 hour until the moisture content is below 1.5%, thus obtaining granules A. S3. Mix the alkali source, filler b, and vitamin D3 concentrate in a wet granulator, add the binder b slurry obtained in step S1, prepare a soft material, granulate the obtained soft material using a 24-mesh sieve, obtain granules, and dry them in a fluidized bed at a drying temperature of 60°C for 1 hour until the moisture content is below 10.0%, to obtain granules B. S4. Mix the granules A obtained in step S2 with the granules B obtained in step S3, then add the acid source and flavoring agent, mix well, and obtain calcium carbonate D3 effervescent granules.

[0047] The calcium carbonate D3 effervescent granules obtained in Examples 1-9 were white to off-white granules. The appearance of the calcium carbonate D3 effervescent granules in Example 1 is shown in the image below. Figure 1 As shown.

[0048] Comparative Examples 1-4 The four comparative examples of calcium carbonate D3 effervescent granules of the present invention differ from Example 1 only in the binder b and filler b in granule B. Specifically, Comparative Example 1: Compared with Example 1, the corn starch of binder b and filler b in particle B of Example 1 was changed to pregelatinized starch, resulting in yellow-green particles, indicating that the materials are incompatible; Comparative Example 2: Compared with Example 1, the corn starch of binder b and filler b in particle B of Example 1 was changed to potato starch, resulting in slightly yellow particles, indicating that the materials are incompatible; Comparative Example 3: Compared with Example 1, the corn starch of binder b and filler b in granules B of Example 1 was replaced with wheat starch, resulting in yellow granules, indicating that the materials are incompatible; Comparative Example 4: Compared with Example 1, the binder b and filler b corn starch in particle B of Example 1 were changed to maltodextrin, resulting in yellow-green particles, indicating that the materials are incompatible.

[0049] Comparative Example 5 This invention provides a comparative example of calcium carbonate D3 effervescent granules. The only difference between this comparative example and Example 1 is the particle size of anhydrous citric acid in granules A. In this comparative example, the anhydrous citric acid with a particle size of 50-100 mesh in Example 1 is adjusted to anhydrous citric acid with a particle size of less than 120 mesh. During the preparation of granules A, after adding the binder a slurry, the material undergoes a strong acid-base reaction and cannot form the expected granules.

[0050] Comparative Example 6 This invention provides a comparative example of calcium carbonate D3 effervescent granules. The only difference between this comparative example and Example 1 is the granule composition. Specifically, the calcium carbonate D3 effervescent granules in this comparative example are obtained by mixing acidic granules, alkaline granules, and sodium saccharin (flavoring agent). The acidic granules consist of the following components in parts by weight: 430 parts anhydrous citric acid, 29 parts DL-malic acid (acid source), 3.5 parts corn starch (binder a), and 28.18 parts maltodextrin (filler a). The alkaline granules consist of the following components in parts by weight: 250 parts calcium carbonate, 28.84 parts potassium carbonate (alkaline source), 35.8 parts corn starch (1 part as binder b and 34.8 parts as filler b), and 0.88 parts vitamin D3 concentrate. The sodium saccharin (flavoring agent) in the calcium carbonate D3 effervescent granules is 0.8 parts by weight.

[0051] The preparation method of this comparative example of calcium carbonate D3 effervescent granules includes the following steps: S1. Mix adhesive a and adhesive b with water and heat to gelatinize, to prepare adhesive a slurry and adhesive b slurry with 8% solid content (w / w); S2. Anhydrous citric acid, DL-malic acid, and maltodextrin (filler a) are mixed in a wet granulator, and the binder a slurry obtained in step S1 is added to prepare a soft material. The soft material is granulated using a 24-mesh sieve to obtain granules, which are then dried in a fluidized bed at a drying temperature of 70°C for 1 hour until the moisture content is below 1.5%, thus obtaining acidic granules. S3. Calcium carbonate, potassium carbonate (alkali source), filler b, and vitamin D3 concentrate are mixed in a wet granulator, and the binder b slurry obtained in step S1 is added to prepare a soft material. The soft material is granulated using a 24-mesh sieve to obtain granules, which are then dried in a fluidized bed at a drying temperature of 60°C for 1 hour until the moisture content is below 10.0%, thus obtaining alkaline granules. S4. Mix the acidic granules obtained in step S2 with the alkaline granules obtained in step S3, then add sodium saccharin (flavoring agent), mix well, and obtain white to off-white calcium carbonate D3 effervescent granules.

[0052] Comparative Example 7 This invention provides a comparative example of calcium carbonate D3 effervescent granules. The only difference between this comparative example and Example 1 is the granule composition. Specifically, the calcium carbonate D3 effervescent granules in this comparative example are obtained by mixing alkaline granules, anhydrous citric acid, DL-malic acid (acid source), binder a, filler a, vitamin D3 concentrate, and sodium saccharin (flavoring agent). The calcium carbonate D3 effervescent granules are composed of the following components in parts by weight: 314.64 parts alkaline granules, 430 parts anhydrous citric acid, 29 parts DL-malic acid (acid source), 3.5 parts corn starch (binder a), 28.18 parts maltodextrin (filler a), 0.88 parts vitamin D3 concentrate, and 0.8 parts sodium saccharin (flavoring agent). The alkaline granules are composed of the following components in parts by weight: 250 parts calcium carbonate, 28.84 parts potassium carbonate (alkaline source), and 35.8 parts corn starch (1 part as binder b and 34.8 parts as filler b).

[0053] The preparation method of this comparative example of calcium carbonate D3 effervescent granules includes the following steps: S1. Mix adhesive b with water and heat to gelatinize, to prepare an adhesive b slurry with 8% solid content (w / w); S2. Calcium carbonate, potassium carbonate (alkali source), and filler b are mixed in a wet granulator, and the binder b slurry obtained in step S1 is added to prepare a soft material. The soft material is granulated using a 24-mesh sieve to obtain granules, which are then dried in a fluidized bed at a drying temperature of 60°C for 1 hour until the moisture content is below 10.0%, thus obtaining alkaline granules. S3. The alkaline granules obtained in step S2 are mixed with anhydrous citric acid, DL-malic acid, corn starch (binder a), maltodextrin (filler a), vitamin D3 concentrate and sodium saccharin (flavoring agent) to obtain white to off-white calcium carbonate D3 effervescent granules.

[0054] Comparative Example 8 This invention provides a comparative example of calcium carbonate D3 effervescent granules. The only difference between this comparative example and Example 2 is the type of acid source. In this comparative example, the acid source 119 parts DL-malic acid in Example 2 is adjusted to 90 parts anhydrous citric acid and 29 parts DL-malic acid. The preparation method of the calcium carbonate D3 effervescent granules in this comparative example is the same as in Example 2.

[0055] Test Example 1 The stability of the calcium carbonate D3 effervescent granules from Examples 1-2 and Comparative Examples 6-8 was tested. The calcium carbonate D3 effervescent granules were packaged in bags and placed at 60±2℃ for 10 days and 30 days, and the color change, clumping, and gas production of the effervescent granules were detected. The materials in Comparative Examples 1-4 were incompatible, and granules A could not be prepared in Comparative Example 5; therefore, no stability test was performed.

[0056] The stability test results of calcium carbonate D3 effervescent granules in Examples 1-2 and Comparative Examples 6-8 are shown in Table 2. Table 2 Based on the results of Example 1 and Comparative Examples 6 and 7, it can be seen that the stability of the samples prepared by combining calcium carbonate with anhydrous citric acid of a specific particle size, filler, and binder to prepare granules A, combining vitamin D3 concentrate with alkali source, filler, and binder to prepare granules B, and then mixing granules A and B with acid source and flavoring agent to prepare calcium carbonate D3 effervescent granules can be guaranteed.

[0057] Based on the results of Example 1 and Comparative Example 8, it is evident that the combination of anhydrous citric acid as an acid source with particles A and B leads to a decrease in the stability of calcium carbonate D3 effervescent particles. Therefore, the acid source of this invention must be an organic acid in the effervescent particles other than anhydrous citric acid.

[0058] Based on the results of Example 2 and Comparative Example 8, it can be seen that when DL-malic acid is selected as the acid source for mixing with particles A and B, the resulting calcium carbonate D3 effervescent particles have better stability.

[0059] Test Example 2 The solubility, color change, clumping, and gas production of the calcium carbonate D3 effervescent granules in Examples 1-9 were measured.

[0060] Calcium carbonate D3 effervescent granules were dissolved in water, and their complete dispersion time was measured to evaluate their solubility.

[0061] Calcium carbonate D3 effervescent granules were packaged in bags and placed at a temperature of 60±2℃ for 30 days and under accelerated conditions of 40±2℃ and relative humidity RH75±5% for 6 months to test whether color change, clumping, gas production, and other properties occurred.

[0062] Test results showed that the calcium carbonate D3 effervescent granules in Examples 1-9 could be completely dispersed within 5 minutes. After being placed at 60°C for 30 days and then accelerated at 40°C with a relative humidity of 75% for 6 months, the granules showed no color change, no clumping / agglomeration, and no gas production, indicating that the calcium carbonate D3 effervescent granules did not undergo an acid-base reaction and did not produce carbon dioxide gas. The solubility and properties test results of Examples 1-4 are shown in Table 3. Table 3 Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A calcium carbonate D3 effervescent granule, characterized in that, Includes particle A, particle B, and acid source. Particle A is obtained by granulation of a mixture A containing calcium carbonate and anhydrous citric acid, and particle B is obtained by granulation of a mixture B containing vitamin D3, an alkali source, filler b and binder b. The anhydrous citric acid has a particle size of 30-100 mesh; The filler b is rice starch or corn starch, and the adhesive b is rice starch or corn starch; The acid source is an organic acid in the effervescent granules, excluding anhydrous citric acid.

2. The calcium carbonate D3 effervescent granules as described in claim 1, characterized in that, The mass ratio of calcium carbonate to anhydrous citric acid in particle A is 30~40:40~55; And / or, the mass ratio of vitamin D3, alkali source, filler b and binder b in the particle B is 0.1~0.2:3~5:3~6:0.1~0.

2.

3. The calcium carbonate D3 effervescent granules as described in claim 1, characterized in that, The calcium carbonate D3 effervescent granules contain 20% to 40% calcium carbonate by mass. And / or, in the calcium carbonate D3 effervescent granules, the mass ratio of calcium carbonate to vitamin D and acid source is 30~40:0.1~0.2:3~15.

4. The calcium carbonate D3 effervescent granules as described in claim 1, characterized in that, The mixture A also contains filler a and binder a; And / or, the calcium carbonate D3 effervescent granules also contain a flavoring agent.

5. The calcium carbonate D3 effervescent granules as described in claim 4, characterized in that, The mass ratio of calcium carbonate to filler a and binder a in particle A is 30~40:3~6:0.3~0.6; The flavoring agent in the calcium carbonate D3 effervescent granules is 0.05%~0.5% by mass.

6. The calcium carbonate D3 effervescent granules as described in claim 4 or 5, characterized in that, The filler a includes one or more of corn starch, rice starch, or maltodextrin; And / or, the adhesive a comprises one or more of corn starch, rice starch, or pregelatinized starch; And / or, the flavoring agent includes one or more of sodium cyclohexylsulfamate, sodium saccharin, and flavoring.

7. The calcium carbonate D3 effervescent granules as described in claim 1, characterized in that, The vitamin D3 mentioned is a vitamin D3 concentrate; And / or, the alkali source includes potassium carbonate, potassium bicarbonate, sodium carbonate, or sodium bicarbonate; And / or, the acid source includes malic acid or tartaric acid.

8. The method for preparing calcium carbonate D3 effervescent granules according to any one of claims 1 to 7, characterized in that, Includes the following steps: S1. Mix adhesive a and adhesive b with water and heat to gelatinize them to prepare adhesive a slurry and adhesive b slurry respectively; S2. Mix anhydrous citric acid, calcium carbonate and filler a, then add the adhesive slurry a obtained in step S1 and prepare a soft material. Granulate the obtained soft material to obtain particles and dry them to obtain particles A. S3. Mix the alkali source, filler b and vitamin D3, then add the adhesive b slurry obtained in step S1 and prepare a soft material. Granulate the obtained soft material to obtain granules and dry them to obtain granules B. S4. Mix the granules A obtained in step S2 with the granules B obtained in step S3, then add an acid source or an acid source and flavoring agent, mix well, and obtain calcium carbonate D3 effervescent granules.

9. The preparation method according to claim 8, characterized in that, In step S2 or step S3, the drying temperature is 60~70℃.

10. The preparation method according to claim 8, characterized in that, In step S2, the moisture content of particle A is less than 1.5%; And / or, in step S3, the moisture content of particle B is less than 10.0%.

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