Preparation method of calcium supplement

Abstract

The invention discloses a preparation method of a calcium supplement. The preparation method comprises the following steps: 1) premixing raw materials and auxiliary materials: mixing calcium carbonate, an adhesive and a flavoring agent according to a prescription amount; 2) granulating: carrying out wet granulation through a fluidized bed technology, and atomizing and spraying a wetting agent; 3) drying: drying the particles obtained in the step 2), and controlling the moisture of the particles; (4) granulating: granulating the granules dried in the step (3) by using a screen to obtain granules A; 5) adding and mixing: taking 1 / 4 of the granules A, rinsing the granules A in a granulator, and then mixing the granules A with the vitamin D3 of the prescription dosage to obtain granules 1; washing the granulator once by using 1 / 4 of the particles A to obtain particles 2; the granules 1, the granules 2, 1 / 4 of the granules A and a prescription amount of preservative are mixed uniformly in a total mixing machine to obtain granules 3, and the granules 3 and the remaining 1 / 4 of the granules A are mixed to obtain granules B. The preparation method is simple, and the prepared granules are uniform in content, good in dissolution effect and high in stability.

Description

[0001] This application is a divisional application of the invention patent with application number "202411345837.X", application date "September 26, 2024", and title "A method for preparing a calcium supplement". Technical Field

[0002] This application belongs to the field of pharmaceutical preparation technology, and specifically relates to a method for preparing a calcium supplement. Background Technology

[0003] In the field of human health and nutrition, calcium is not only a major component of bones and teeth, but also crucial for maintaining essential life activities such as nerve conduction, muscle contraction, bone strength, cell membrane integrity, and capillary permeability. Vitamin D3 plays a central role in calcium and phosphorus metabolism, significantly improving intestinal calcium absorption, thereby promoting bone mineralization and maintaining normal blood calcium levels, and having a decisive impact on bone formation and bone health.

[0004] However, in today's fast-paced lifestyle, unbalanced diets often lead to insufficient calcium intake, putting more and more people at risk of calcium deficiency. Calcium deficiency can not only cause bone health problems, such as osteoporosis, but may also trigger neuromuscular dysfunction.

[0005] Calcium carbonate D3 granules, as a highly effective calcium supplement, can effectively address the aforementioned issues. Its active ingredients are calcium carbonate and vitamin D3. These not only act as antacids, quickly relieving stomach discomfort symptoms such as heartburn, acid reflux, and excessive stomach acid, but also effectively supplement the body's calcium needs. Calcium carbonate neutralizes stomach acid, rapidly alleviating stomach discomfort, while vitamin D3 works synergistically with calcium to promote calcium absorption and utilization, jointly maintaining stable bone and overall health.

[0006] Existing patent CN117379381A discloses calcium carbonate granules, calcium carbonate D3 tablets, and their preparation methods. The method involves mixing calcium carbonate, fillers, disintegrants, and binders, then using a solubilizing aqueous solution as a spray agent for spray granulation and drying to obtain calcium carbonate granules. Finally, vitamin D3 powder is mixed with the calcium carbonate granules, and anti-adhesion agents and lubricants are added and mixed again to obtain a final mixed granule. The products obtained by this method have poor solubility and stability.

[0007] Patent CN118319865A discloses calcium carbonate vitamin D3 granules and their preparation method. Although it achieves an effective combination of calcium carbonate and vitamin D3 to a certain extent, the operation steps of adding an ethanol solution containing vitamin D3 to the calcium carbonate granules in the form of spray are relatively cumbersome, increasing production costs and operational difficulty.

[0008] In the preparation of calcium carbonate vitamin D3 granules, ensuring the content and stability of vitamin D3 in the finished product is a technical challenge due to its relatively low content as a trace component. Vitamin D3 is not only sensitive to light, heat, and humidity, but its activity is also difficult to control precisely due to its trace presence in the formulation. Therefore, effectively protecting vitamin D3 from external environmental factors during production and ensuring its stability and bioavailability in the final product has become a key research focus and technical challenge in this field. Summary of the Invention

[0009] This application provides a method for preparing calcium supplements, particularly a method for preparing calcium carbonate D3 granules. This method is simple, produces granules with uniform content, good dissolution effect, and high stability.

[0010] To achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

[0011] A method for preparing a calcium supplement includes the following steps:

[0012] 1) Premixing of raw materials and auxiliary materials: Mix the prescribed amounts of calcium carbonate, binder and flavoring agent;

[0013] 2) Granulation: Wet granulation is carried out using fluidized bed technology, with the wetting agent sprayed in via atomization;

[0014] 3) Drying: Dry the particles obtained in step 2) and control the moisture content of the particles;

[0015] 4) Granulation: The dried granules from step 3) are granulated using a sieve to obtain granules A;

[0016] 5) Addition and mixing: Take 1 / 4 of the granule A and rinse the granulator, then mix it with the prescribed amount of vitamin D3 to obtain granule 1; rinse the granulator once with the other 1 / 4 of the granule A to obtain granule 2;

[0017] 6) Mixing: Mix the granules 1, granules 2, another 1 / 4 of the granules A and the prescribed amount of preservative in a mixer to obtain granules 3. Mix granules 3 with the remaining 1 / 4 of the granules A to obtain granules B.

[0018] 7) Packaging: Package the granules obtained in step 6.

[0019] In one embodiment of the present invention, the wetting agent is one or more of water, ethanol, isopropanol, polyethylene glycol solution or glycerin.

[0020] In one embodiment of the present invention, the amount of the wetting agent is 30% to 70% of the total weight of the raw materials and excipients.

[0021] In one embodiment of the present invention, the spraying speed of the atomized wetting agent in step 2) granulation is 5 g / min to 15 g / min.

[0022] In one embodiment of the present invention, the nozzle diameter of the spray gun for atomizing and spraying the wetting agent in step 2) granulation is 1.0~3.0 mm, the spray flow rate is 1 kg / h~3 kg / h, and the atomizing gas pressure is 0.1~0.2 MPa.

[0023] In one embodiment of the present invention, in step 3) drying, the moisture content of the particles is controlled to be below 1.5%.

[0024] In one embodiment of the present invention, the sieve aperture in step 4) granulation is 0.6 mm.

[0025] In one embodiment of the present invention, the calcium supplement comprises, by weight percentage: 80-85% calcium carbonate, 0.1-0.2% vitamin D3, 11-17% binder, 2.3-3.5% flavoring agent and 0.5-1.0% preservative.

[0026] In one embodiment of the present invention, the binder is maltodextrin or povidone K30; the flavoring agent is one or more of anhydrous glucose, aspartame or sucralose; and the preservative is one or more of sodium benzoate, potassium sorbate or sodium citrate.

[0027] On the other hand, the present invention provides a calcium supplement prepared according to the above method, wherein the calcium supplement is preferably calcium carbonate D3 granules.

[0028] Compared with the prior art, the present invention has the following technical effects:

[0029] (1) The calcium carbonate D3 particles prepared by the process of the present invention have excellent calcium dissolution performance and ideal effect, which can significantly improve the absorption efficiency of the product.

[0030] (2) The calcium carbonate D3 granules obtained by the inventors have the required content of both the active ingredient calcium and vitamin D3, and the vitamin D3 content is stable, which ensures the reliability and consistency of the product.

[0031] (3) The present invention uses a specific preparation process to obtain calcium carbonate D3 particles. The whole method is simple and easy to implement, and at the same time, it also shows good stability in terms of related substances, ensuring the quality of the product during production and storage. Attached Figure Description

[0032] Figure 1 It is a simplified diagram illustrating the mixing of raw and auxiliary materials. Detailed Implementation

[0033] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0034] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0035] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0036] The inventors of this application have discovered that by controlling the key processes in the preparation method of calcium carbonate D3 particles, not only is the solubility of calcium improved, but the stability of related substances in the calcium carbonate D3 particles is also maintained at a high level, while the content and stability of vitamin D3 are also good. The entire process includes the following main steps:

[0037] 1) Premixing of raw materials and auxiliary materials: Mix the prescribed amounts of calcium carbonate, binder and flavoring agent;

[0038] In one embodiment of the present invention, the specific operation is as follows: the prescribed amount of calcium carbonate, binder and flavoring agent are added sequentially to a wet mixing granulator for mixing, the stirring parameters are 150rpm±20rpm, the shearing parameters are 1000rpm±300rpm, and the mixing time is 8min.

[0039] 2) Granulation: Wet granulation is carried out using fluidized bed technology, with the wetting agent sprayed in via atomization;

[0040] In one embodiment of the invention, the wetting agent is one or more selected from water, ethanol, isopropanol, polyethylene glycol solution, or glycerin. In a specific embodiment of the invention, the wetting agent is an aqueous solution or an aqueous ethanol solution, with the aqueous ethanol solution being a common concentration, such as 20%, 30%, 40%, 50%, 60%, 70%, or 95% aqueous ethanol solution. However, it is not limited to the listed concentrations, and other commonly used concentrations are also applicable.

[0041] In one embodiment of the present invention, the specific operation is as follows: the inlet air temperature is controlled at 60±10℃, the inlet air volume is 10-30HZ, the wetting agent is atomized and sprayed, the nozzle diameter is 1.0~3.0mm, the spray flow rate is 1kg / h~3kg / h, the atomizing air pressure is 0.1~0.2MPa, the spray speed is 5~15g / min, the material temperature is controlled at 25~35℃, and the peristaltic pump speed is 4~8rpm.

[0042] In one embodiment of the invention, the amount of wetting agent used is 30% to 70% of the total weight of the raw materials and excipients, for example, 30%, 35%, 40%, 45%, 55%, 60%, 65%, or 70%. However, it is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0043] The amount of wetting agent used is crucial because it directly affects particle formation and properties. If the percentage of wetting agent is too low (e.g., below 30%), the solution may not provide enough liquid to wet all the powder, resulting in poor particle formation or insufficient interparticle adhesion. Conversely, if the percentage of wetting agent is too high (e.g., above 70%), the excess wetting agent may cause the particles to become overly wet, affecting their shape and strength, and even causing powder agglomeration, complicating the subsequent drying process. This, in turn, affects the quality of the final product.

[0044] In one specific embodiment of the present invention, the spraying rate is 5-15 g / min, for example, 5 g / min, 6 g / min, 7 g / min, 8 g / min, 9 g / min, 10 g / min, 11 g / min, 12 g / min, 13 g / min, 14 g / min, or 15 g / min. However, it is not limited to the listed values; other unlisted values ​​within this range are also applicable. The spraying rate described in this invention refers to the amount of wetting agent passing through the nozzle per unit time.

[0045] In the preparation of calcium carbonate D3 particles, the spraying speed is crucial. A speed within the range of 5–15 g / min helps achieve uniform distribution of the wetting agent on the powder, improving wetting efficiency and thus particle quality. Simultaneously, controlling the spraying speed avoids uneven binder distribution, reducing the formation of large particles and fine powder, resulting in particles with a narrower particle size distribution and smaller average particle size. Furthermore, uniform wetting and particle formation contribute to improved particle physical stability, reducing dust and breakage issues during subsequent processing.

[0046] By precisely controlling the spraying speed, not only can the production efficiency of calcium carbonate D3 granules be improved, but the consistency and stability of product quality can also be ensured. This is crucial for meeting the high standards of pharmaceutical production and the safety needs of patients.

[0047] In one specific embodiment of the present invention, the nozzle diameter of the spray gun is 1.0~3.0 mm, for example, 1.0 mm, 2.0 mm or 3.0 mm. However, it is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0048] In one specific embodiment of the present invention, the spray flow rate is 1 kg / h to 3 kg / h, for example, 1 kg / h, 2 kg / h, or 3 kg / h. However, it is not limited to the listed values; other unlisted values ​​within this range also apply. The spray flow rate described in the present invention refers to the flow rate of the wetting agent per unit time.

[0049] In one specific embodiment of the present invention, the atomizing pressure is 0.1~0.2MPa, for example 0.1MPa, 0.15MPa or 0.2MPa. However, it is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0050] Atomization pressure is equally important; appropriate atomization pressure helps form well-structured, moderately dense, and smooth-surfaced particles. A pressure range of 0.1–0.2 MPa is beneficial for improving particle flowability and compressibility. Excessive atomization pressure may result in overly fine droplets and excessively rapid drying, hindering particle formation. Insufficient atomization pressure may lead to overly large droplets, resulting in uneven or excessively large particles, affecting product quality, and potentially causing particle adhesion, thus affecting the uniformity of active ingredient distribution.

[0051] 3) Drying: Dry the particles obtained in step 2) and control the moisture content of the particles.

[0052] In one embodiment of the invention, the moisture content of the particles is controlled below 1.5%, for example, 1.5%, 1.2%, 1.0%, 0.8%, or 0.5%. However, it is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0053] 4) Granulation: The dried granules from step 3) are granulated using a sieve;

[0054] In one embodiment of the present invention, the screen aperture is a conventional aperture commonly used in the art, such as 1.00mm, 0.85mm, 0.71mm, 0.60mm, 0.50mm, 0.425mm, 0.355mm, 0.300mm or other conventional apertures.

[0055] 5) Addition and mixing:

[0056] In one embodiment of the present invention, the specific operation is as follows: a. Pass vitamin D3 through a 0.6mm sieve of a granulator and set aside; b. Take 1 / 4 of the granules A to rinse the granulator, and then mix it with the vitamin D3 prepared in step a) twice to obtain granules 1; rinse the granulator once with another 1 / 4 of the granules A to obtain granules 2.

[0057] 6) Final Mixing: Particles 1, 2, the remaining 1 / 4 of particle A, and sodium citrate are mixed evenly in a final mixer to obtain particle 3. Then, particle 3 is mixed with the remaining 1 / 4 of particle A to obtain particle B. The mixing speed is 15 rpm, and the mixing time is 90 min. (Appendix) Figure 1 This is a schematic diagram of the mixing of raw and auxiliary materials. For details of the specific operation process, please refer to the embodiment. The mixing method of the present invention effectively improves the mixing uniformity, prevents the aggregation of active ingredients, and is easy to operate and control, effectively improving the mixing efficiency. The present invention does not limit the mixing speed and mixing time, as long as the materials can be fully mixed and evenly distributed.

[0058] 7) Packaging: The granules obtained in step 6 are packaged. This invention does not limit the packaging materials and methods, as long as they are packaged according to the expected specifications.

[0059] In one embodiment of the present invention, the calcium supplement comprises, by weight percentage: 80-85% calcium carbonate, 0.1-0.2% vitamin D3, 11-17% binder, 2.3-3.5% flavoring agent, and 0.5-1.0% preservative. In a specific embodiment, the calcium supplement comprises, by weight percentage: 83.33% calcium carbonate, 0.13% vitamin D3, 13% binder, 2.87% flavoring agent, and 0.67% preservative.

[0060] In one embodiment of the present invention, the binder is maltodextrin or polyvinylpyrrolidone K30; the flavoring agent is one or more of anhydrous glucose, aspartame, or sucralose; and the preservative is one or more of sodium benzoate, potassium sorbate, or sodium citrate. In a specific embodiment, the binder is maltodextrin, the flavoring agent is anhydrous glucose, and the preservative is sodium citrate.

[0061] The specific embodiments and comparative examples of the present invention are listed below, but the present invention is not limited to the following examples.

[0062] Example 1

[0063] 1. The prescription composition is shown in Table 1.

[0064] Table 1 Prescription Composition

[0065]

[0066] 2. Process description (taking the production of 1000 bags as an example)

[0067] 1) Premixing of raw and auxiliary materials

[0068] The prescribed amounts of calcium carbonate, maltodextrin, and anhydrous glucose were sequentially added to a wet granulation mixer for mixing. The stirring parameters were 150 rpm ± 20 rpm, the shearing parameters were 1000 rpm ± 300 rpm, and the mixing time was 8 min.

[0069] 2) Fluidized bed granulation (fluidized bed: WBF-5G)

[0070] Control the inlet air temperature to 60±10℃, the inlet air volume to 10-30HZ, atomize and spray 675g of aqueous solution, with water accounting for approximately 45% of the total raw and auxiliary material formula, the spray gun orifice diameter to 1.0~3.0mm, the spray flow rate to 1kg / h~3kg / h, the atomizing air pressure to 0.1~0.2MPa, the spray speed to 5g / min, control the material temperature to 25~35℃, and the peristaltic pump speed to 4~8rpm.

[0071] 3) Drying

[0072] After the spraying is finished, turn off the atomizing air pressure and start drying the material. Control the material temperature at 40~45℃ and the moisture content at no more than 1.5%.

[0073] 4) Whole grains

[0074] The dried particles from step 3) are granulated using a 0.6 mm mesh sieve to obtain particle A.

[0075] 5) Additives and mixtures

[0076] a. Pass the vitamin D3 through a 0.6mm sieve of a granulator and set aside.

[0077] b. Take 1 / 4 of granule A and rinse the granulator, then mix it twice with the vitamin D3 prepared in step a) to obtain granule 1; take another 1 / 4 of granule A and rinse the granulator once to obtain granule 2.

[0078] 6) Total Mix

[0079] Particle 1, particle 2, another 1 / 4 of particle A, and sodium citrate were mixed evenly in a mixer to obtain particle 3. Then, particle 3 was mixed with the remaining 1 / 4 of particle A to obtain particle B. The mixing speed was 15 rpm and the mixing time was 90 min.

[0080] 7) Packaging

[0081] The granules obtained in step 6) are packaged using a pharmaceutical-grade polyester / aluminum / polyethylene composite film.

[0082] Example 2

[0083] In step 2), the spraying speed in fluidized bed granulation is adjusted to 8 g / min, and the formulation and other process steps and conditions are the same as in Example 1.

[0084] Example 3

[0085] In step 2), the spraying speed in fluidized bed granulation was adjusted to 12 g / min, and the formulation and other process steps and conditions were the same as in Example 1.

[0086] Example 4

[0087] In step 2), the spraying speed in fluidized bed granulation is adjusted to 15 g / min, and the amount of atomized sprayed aqueous solution is adjusted to 750 g, which is about 50% of the total amount of raw and auxiliary materials in the formulation. The formulation composition and other process steps and conditions are the same as in Example 1.

[0088] Example 5

[0089] In step 2), the spraying speed in fluidized bed granulation is adjusted to 10 g / min, and the amount of atomized sprayed aqueous solution is adjusted to 900 g, which is about 60% of the total amount of raw and auxiliary materials in the prescription. The prescription composition and other process steps and conditions are the same as in Example 1.

[0090] Example 6

[0091] In step 2), the spraying speed in fluidized bed granulation is adjusted to 15 g / min, and the amount of atomized sprayed aqueous solution is adjusted to 450 g, which is about 30% of the total amount of raw and auxiliary materials in the formulation. The formulation composition and other process steps and conditions are the same as in Example 1.

[0092] Example 7

[0093] In step 2), the spraying speed in fluidized bed granulation is adjusted to 10 g / min, and the amount of atomized sprayed aqueous solution is adjusted to 1050 g, which is about 70% of the total amount of raw and auxiliary materials in the formulation. The formulation composition and other process steps and conditions are the same as in Example 1.

[0094] Example 8

[0095] In step 2), the spraying speed in fluidized bed granulation was adjusted to 10 g / min, and the atomized spraying of aqueous solution was adjusted to atomized spraying of 50% ethanol solution with a concentration of 750 g, which is about 50% of the total amount of raw materials and excipients. The composition of the formulation and other process steps and conditions are the same as in Example 1.

[0096] Comparative Example 1

[0097] In step 2), the spraying speed in fluidized bed granulation is adjusted to 3 g / min, and the formulation and other process steps and conditions are the same as in Example 1.

[0098] Comparative Example 2

[0099] In step 2), the spraying speed in fluidized bed granulation was adjusted to 17 g / min, and the formulation and other process steps and conditions were the same as in Example 1.

[0100] Comparative Example 3

[0101] In step 2), the spraying speed in fluidized bed granulation is adjusted to 12 g / min, and the amount of atomized sprayed aqueous solution is adjusted to 375 g, which is about 25% of the total amount of raw materials and excipients. The composition of the formula and other process steps and conditions are the same as in Example 1.

[0102] Comparative Example 4

[0103] In step 2), the spraying speed in fluidized bed granulation is adjusted to 12 g / min, and the amount of atomized sprayed aqueous solution is adjusted to 1125 g, which is about 75% of the total amount of raw materials and excipients. The composition of the formula and other process steps and conditions are the same as in Example 1.

[0104] Comparative Example 5

[0105] The process of adding, mixing, and mixing in step 5) and the total mixing in step 6) is as follows, with the same formulation and other process steps and conditions as in Example 1.

[0106] a. Pass the vitamin D3 through a 0.6mm sieve of a granulator and set aside.

[0107] b. Add the vitamin D3 prepared in step a) and the prescribed amount of sodium citrate to granules A and mix three times at a speed of 15 rpm for 90 minutes.

[0108] Comparative Example 6

[0109] The addition, mixing, and total mixing in step 5) and step 6) are adjusted as follows, with the formulation and other process steps and conditions being the same as in Example 1.

[0110] 5) Additives and mixtures

[0111] a. Pass the vitamin D3 through a 0.6mm sieve of a granulator and set aside.

[0112] b. Take 1 / 2 of granule A and rinse it in the granulator, then mix it twice with the vitamin D3 prepared in step a) to obtain granule 1-1; take the other 1 / 2 of granule A and rinse it in the granulator once to obtain granule 2-1.

[0113] 6) Total Mix

[0114] Half of particle 2-1, particle 1-1 and sodium citrate were mixed evenly in a general mixer to obtain particle B1. Then, the other half of particle 2-1 was added and mixed to obtain particle C. The mixing speed was 15 rpm and the mixing time was 90 min.

[0115] Comparative Example 7

[0116] The addition, mixing, and total mixing in step 5) and step 6) are adjusted as follows, with the formulation and other process steps and conditions being the same as in Example 1.

[0117] 5) Additives and mixtures

[0118] a. Pass the vitamin D3 through a 0.6mm sieve of a granulator and set aside.

[0119] b. Take 1 / 2 granule A and rinse it in the granulator, then mix it twice with the vitamin D3 prepared in step a) to obtain granule 1-1; rinse 1 / 2 granule A in the granulator once to obtain granule 2-1.

[0120] 6) Total Mix

[0121] Particles 2-1, 1-1, and sodium citrate were mixed evenly in a mixer to obtain particle B2. The mixing speed was 15 rpm and the mixing time was 90 min.

[0122] The calcium carbonate D3 granules obtained from Examples 1-8 and Comparative Examples 1-7 were tested, as well as commercially available pediatric calcium carbonate granules (certified). The product (manufactured by A&Z Pharmaceutical, Inc., batch number 3B239005) was tested for calcium content, vitamin D3 content, dissolution rate, and other properties. Related substances

[0123] Methods for determining calcium and vitamin D3 content

[0124] Vitamin D3 was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512) under light-protected conditions.

[0125] Chromatographic conditions: Silica gel was used as the packing material (Welch Ultimate SiO2; 4.6 mm × 250 mm, 5 μm or equivalent column); n-hexane-n-pentanol (997:3) was used as the mobile phase; the flow rate was 2.0 mL per minute; the column temperature was 30 °C; the detection wavelength was 265 nm; and the injection volume was 100 μl.

[0126] Accurately weigh 20 tablets of this product, grind them into a fine powder, and accurately weigh an appropriate amount of the powder (approximately equivalent to 30 mg of calcium). Add 15 ml of 1 mol / L hydrochloric acid solution, heat in a steam bath for 5-10 minutes until the reaction is completely stopped, cool, add 100 ml of water and 20 ml of 1 mol / L sodium hydroxide solution, add 0.3 ml of hydroxynaphthol blue indicator solution, shake well, and titrate with disodium ethylenediaminetetraacetate titrant (0.05 mol / L) until the solution changes from pink to blue. Each 1 ml of disodium ethylenediaminetetraacetate titrant (0.05 mol / L) is equivalent to 2.004 mg of calcium.

[0127] Table 2. Calcium and Vitamin D3 Content (%) in Calcium Carbonate D3 Granules

[0128]

[0129] As shown in Table 2, the calcium content and vitamin D3 content in the calcium carbonate D3 granules obtained in Examples 1-8 were all within the specified range (95.0%~105.0%), and were also within the specified range (90.0%~120.0%), thus meeting the most stringent existing standard, the British Pharmacopoeia 2018 edition's quality standard for this product. The vitamin D3 content in the calcium carbonate D3 granules obtained in Comparative Example 1 (slower spraying speed), Comparative Example 3 (lower wetting agent dosage), and Comparative Example 5 (direct mixing) was outside the specified range. Because the amount of vitamin D3 in the calcium carbonate D3 granules was small and unstable, the inventors further determined the changes in vitamin D3 content under different conditions (high temperature 40°C, high temperature 60°C, high humidity 75%, high humidity 90%, and light exposure; observation time was 10 days and 30 days), and the results are as follows:

[0130] Table 3. Stability of Vitamin D3 Content in Calcium Carbonate D3 Granules

[0131]

[0132]

[0133] Based on the data analysis in Table 3 regarding the vitamin D3 degradation of calcium carbonate vitamin D3 granules under high temperature (40℃, 60℃), high humidity (75%, 90%), and light conditions over 30 days, it can be seen that the calcium carbonate vitamin D3 granules prepared in Examples 1-8 exhibited relatively low vitamin D3 degradation under the aforementioned environmental conditions, demonstrating good stability. In contrast, the calcium carbonate vitamin D3 granules prepared in Comparative Examples 1-7 showed significantly increased vitamin D3 degradation under the same conditions, indicating poor stability.

[0134] Therefore, it can be inferred that the preparation method of calcium carbonate vitamin D3 granules proposed in this invention can significantly improve the stability of vitamin D3 in the product, enabling it to maintain high activity under various adverse environmental conditions.

[0135] Dissolution test method

[0136] Dissolution and release were determined according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0137] The dissolution conditions were as follows: 900 ml of 0.1 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 75 rpm. Samples were taken after 5 min, 15 min, 30 min, 45 min and 120 min according to the procedure.

[0138] Take an appropriate amount of the dissolution solution from the test sample solution, filter it, and collect the filtrate.

[0139] For the assay, accurately measure 50 ml of the filtrate, add 100 ml of water and 10 ml of sodium hydroxide test solution, add 0.3 ml of hydroxynaphthol blue indicator solution, shake well, and titrate with disodium ethylenediaminetetraacetate titrant (0.05 mol / L) until the solution changes from pink to blue. Each 1 ml of disodium ethylenediaminetetraacetate titrant (0.05 mol / L) is equivalent to 2.004 mg of Ca. Calculate the dissolution amount per tablet.

[0140] Dissolution results are shown in Table 4

[0141] Table 4. Dissolution results of the Examples and Comparative Examples in 0.1M hydrochloric acid medium.

[0142]

[0143] As can be seen from the data in Table 4, the calcium dissolution rate of the examples and comparative examples was greater than 85% within 15 minutes. It is believed that the dissolution of calcium carbonate D3 particles obtained in Examples 1-8 and Comparative Examples 1-7 is similar to that of commercially available products.

[0144] Related substances determination methods

[0145] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512) under light-protected conditions.

[0146] The extract contains 0.02% 2,6-di-tert-butyl-p-cresol (BHT) in a 75% dimethyl sulfoxide aqueous solution.

[0147] The solvent is a 75% dimethyl sulfoxide aqueous solution containing 0.02% 2,6-di-tert-butyl-p-cresol (BHT) in hexane (1:20). After standing, the hexane layer is collected.

[0148] For the test solution, accurately weigh 25 sachets of this product and grind them into a fine powder. Accurately weigh an appropriate amount of the fine powder (approximately equivalent to 100 μg of vitamin D3), place it in a 200 ml brown volumetric flask, add approximately 50 ml of extraction solution, vortex for 3 minutes, shake for 30 minutes, accurately add 5 ml of solvent, seal tightly, shake for 30 minutes, vortex for 3 minutes, centrifuge at 3000 rpm for 10 minutes, collect the supernatant solution, and then centrifuge at 13000 rpm for 5 minutes to collect the clear solution.

[0149] For the reference solution, accurately weigh approximately 20 mg of vitamin D3 reference standard (each mg is equivalent to 40,000 IU), place it in a 100 ml volumetric flask, dissolve and dilute to the mark with solvent, and mix well. Accurately measure 5 ml of the solution, place it in a 50 ml volumetric flask, dilute to the mark with solvent, and mix well.

[0150] For system suitability solution, take appropriate amounts of impurity A, impurity B, impurity C, and vitamin D3 reference standard, dilute with solvent to prepare a mixed solution containing 0.3 μg of impurity A, 0.2 μg each of impurity B and impurity C, and 20 μg of vitamin D3 per 1 ml.

[0151] Chromatographic conditions: Silica gel was used as the packing material (Welch Ultimate SiO2; 4.6 mm × 250 mm, 5 μm or equivalent column); n-hexane-n-pentanol (997:3) was used as the mobile phase; the flow rate was 2.0 mL per minute; the column temperature was 30 °C; the detection wavelength was 265 nm; and the injection volume was 100 μl.

[0152] System suitability requirements: In the chromatogram of the solution, the elution order of each chromatographic peak should be impurity A, vitamin D3, impurity B, and impurity C, and the resolution between each impurity should meet the requirements.

[0153] For the assay, take the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatograms.

[0154] If impurity peaks are present in the chromatogram of the test solution (excluding excipient peaks and pre-vitamin D3 peaks), the impurity A shall not exceed 1.5% by peak area, calculated using the external standard method; impurity B and other individual impurities shall not exceed 1.0%; and the total impurity shall not exceed 2.5%.

[0155] Impurity information is shown in Table 5:

[0156] Table 5. Impurity information in calcium carbonate D3 particles

[0157]

[0158] The results for relevant substances are shown in Table 6.

[0159] Table 6. Results of related substance detection in the examples and comparative examples.

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] As can be seen from the related substance test results of the Examples and Comparative Examples in Table 6, although the related substance content of the calcium carbonate D3 particles obtained in Examples 1-8 and Comparative Examples 1-7 was lower than the limit requirement on day 0, the related substance content of the calcium carbonate D3 particles obtained in the Examples was slightly lower than that in the Comparative Examples.

[0168] Further investigation was conducted into the changes in impurity content after 10 and 30 days of storage under conditions of high temperature (40°C), high temperature (60°C), high humidity (90%), and light exposure (5000 Lx).

[0169] Under otherwise identical conditions, when the spraying rate is low (e.g., Comparative Example 1, 3 g / min), the total impurity content of the obtained calcium carbonate D3 particles after being exposed at 60°C for 30 days is 1.98%, which is significantly higher than 1.28% in Example 1 (spraying rate of 5 g / min), 1.22% in Example 2 (spraying rate of 8 g / min), and 1.66% in Example 3 (spraying rate of 12 g / min).

[0170] Under otherwise identical conditions, when the spraying rate was high (e.g., Comparative Example 2, 17 g / min), the total impurity content of the obtained calcium carbonate D3 particles after being exposed at 60°C for 30 days was 2.34%, close to the limit value of 2.5%, and significantly higher than 1.28% in Example 1 (spraying rate of 5 g / min), 1.22% in Example 2 (spraying rate of 8 g / min), and 1.66% in Example 3 (spraying rate of 12 g / min).

[0171] Under otherwise identical conditions, when the amount of wetting agent was low (e.g., Comparative Example 3, 25%), the total impurity content of the obtained calcium carbonate D3 particles after being placed at a high temperature of 60°C and under a light irradiation of 5000 Lx for 30 days was 2.31% and 2.65% respectively (exceeding the limit value), which was significantly higher than that of Example 3 (wetting agent amount of 45%), which was 1.66% and 1.41%.

[0172] Under otherwise identical conditions, when the amount of wetting agent was high (e.g., Comparative Example 4, 75%), the total impurity content of the obtained calcium carbonate D3 particles after being exposed at a high temperature of 60°C for 30 days was 2.54%, which exceeded the limit value of 2.5%.

[0173] Through comparative analysis of different mixing methods, it can be seen that Example 3 (according to Appendix) Figure 1 The diagram showing the mixing of raw materials and excipients (involving four mixing processes) demonstrates excellent performance in ensuring a uniform distribution of vitamin D3 within the calcium carbonate granules. Specifically:

[0174] Initial impurity content: Example 3 had the lowest total impurity content on day 0, at 1.66%, indicating that it could effectively control product quality in the early stages of production.

[0175] Long-term stability: After being exposed to high temperature (60°C) for 30 days, the total impurity content of Example 3 remained at a low level (1.66%), far lower than that of Comparative Example 5 (2.65%), Comparative Example 6 (2.82%) and Comparative Example 7 (2.98%), and none exceeded the specified limit value. This indicates that Example 3 has better stability under high temperature conditions.

[0176] It is worth noting that while increasing the number of mixing cycles can improve homogeneity to some extent, this does not necessarily mean that more mixing cycles will improve product quality and stability. In fact, over-mixing may lead to changes in the physical properties of the materials, increase mechanical stress, and even cause unnecessary side reactions, thereby affecting the performance of the final product. For example, although Comparative Example 5 used a direct mixing method, its impurity content (2.65%) was still higher than that of Example 3. In contrast, Comparative Example 6 (added in three parts) and Comparative Example 7 (added in two parts) had even higher impurity contents, at 2.82% and 2.98%, respectively.

[0177] Therefore, Example 3 not only outperforms other comparative examples in practical results, but also achieves an optimal balance in the number of mixing steps, ensuring product quality and stability. This method not only guarantees the uniform distribution of vitamin D3 in calcium carbonate granules, but also avoids the negative effects of over-mixing through reasonable mixing steps.

[0178] In summary, the specific spraying speed (5~15g / min), wetting agent dosage (30%~70%), and calcium carbonate particle addition method used in the embodiments resulted in better effects on the related substances and their stability of the obtained calcium carbonate D3 particles, while ensuring the calcium content and dissolution, as well as the content and stability of vitamin D3.

[0179] Table 7 Comparison of process conditions between the examples and the comparative examples

[0180]

[0181]

[0182] The embodiments of this application have been described above with reference to the accompanying drawings. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for preparing a calcium supplement, characterized in that, Includes the following steps: 1) Premixing of raw materials and auxiliary materials: Mix the prescribed amounts of calcium carbonate, binder and flavoring agent; 2) Granulation: Wet granulation is carried out using fluidized bed technology, with the wetting agent being sprayed in via atomization; 3) Drying: Dry the particles obtained in step 2) and control the moisture content of the particles; 4) Granulation: The dried granules from step 3) are granulated using a sieve to obtain granules A; 5) Addition and mixing: Take 1 / 4 of the granules A described above and rinse the granulator, then mix it with the prescribed amount of vitamin D3 to obtain granules 1; rinse the granulator once with the other 1 / 4 of the granules A described above to obtain granules 2; 6) Mixing: Mix the granules 1, granules 2, another 1 / 4 of the granules A and the prescribed amount of preservative in a mixer to obtain granules 3. Mix granules 3 with the remaining 1 / 4 of the granules A to obtain granules B. 7) Packaging: Package the granules obtained in step 6; The calcium supplement contains 95.0% to 105.0% calcium and 90.0% to 120.0% vitamin D3.

2. The method for preparing the calcium supplement according to claim 1, characterized in that, The wetting agent is one or more of water, ethanol, isopropanol, polyethylene glycol solution, or glycerin.

3. The method for preparing the calcium supplement according to claim 2, characterized in that, The amount of the wetting agent is 30% to 70% of the total weight of the raw materials and excipients.

4. The method for preparing the calcium supplement according to claim 3, characterized in that, Step 2) The spraying speed of the wetting agent in the granulation process is 5 g / min to 15 g / min.

5. The method for preparing the calcium supplement according to claim 4, characterized in that, In step 2), the nozzle diameter of the spray gun for atomizing and spraying the wetting agent in granulation is 1.0~3.0mm, the spray flow rate is 1kg / h~3kg / h, and the atomizing air pressure is 0.1~0.2MPa.

6. The method for preparing the calcium supplement according to claim 5, characterized in that, In step 3) of drying, the moisture content of the particles is controlled to be below 1.5%.

7. The method for preparing the calcium supplement according to claim 6, characterized in that, The mesh size of the sieve in the granulation process described in 4) is 0.6 mm.

8. The method for preparing the calcium supplement according to any one of claims 1 to 7, characterized in that: The calcium supplement comprises, by weight percentage: 80-85% calcium carbonate, 0.1-0.2% vitamin D3, 11-17% binder, 2.3-3.5% flavoring agent, and 0.5-1.0% preservative.

9. The method for preparing the calcium supplement according to claim 8, characterized in that, The binder is maltodextrin or polyvinylpyrrolidone K30; the flavoring agent is one or more of anhydrous glucose, aspartame, or sucralose; and the preservative is one or more of sodium benzoate, potassium sorbate, or sodium citrate.

10. A calcium supplement prepared by the method according to any one of claims 1 to 9, wherein the calcium supplement is preferably calcium carbonate D3 granules.

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