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; 6) total mixing: uniformly mixing the particles 1, the particles 2, 1 / 4 of the particles A and a prescription amount of a preservative in a total mixing machine to obtain particles 3, and mixing the particles 3 with the remaining 1 / 4 of the particles A to obtain particles B; and 7) packaging. The preparation method is simple, and the prepared particles are uniform in content, good in dissolution effect and high in stability.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing a calcium supplement. Background Art

[0002] In the field of human health and nutrition, calcium is not only the main component of bones and teeth, but also essential for maintaining basic life activities such as nerve conduction, muscle contraction, bone strength, cell membrane integrity and capillary permeability. Vitamin D3 plays a core role in the metabolism of calcium and phosphorus. It can significantly increase the intestinal absorption rate of calcium, thereby promoting bone mineralization and maintaining normal blood calcium levels, and has a decisive influence on bone formation and bone health.

[0003] However, in the fast-paced modern lifestyle, unbalanced eating habits often lead to insufficient calcium intake, making more and more people face the risk of calcium deficiency. Calcium deficiency can not only lead to bone health problems such as osteoporosis, but also may cause neuromuscular dysfunction.

[0004] Calcium carbonate D3 granules, as a highly effective calcium nutritional supplement, can effectively solve the above problems. Its active ingredients are calcium carbonate and vitamin D3. It can not only act as an antacid to quickly relieve stomach discomfort symptoms such as heartburn, acid indigestion, and hyperacidity, but also effectively supplement the calcium needed by the human body. Calcium carbonate quickly relieves stomach discomfort by neutralizing stomach acid, while vitamin D3 works in synergy with calcium to promote calcium absorption and utilization, and jointly maintain the stable state of bone and systemic health.

[0005] The existing patent CN117379381A discloses calcium carbonate particles, calcium carbonate D3 tablets and their preparation method, which comprises mixing calcium carbonate, a filler, a disintegrant and a binder, then using a solubilizer aqueous solution as a spray, spraying granulation and drying to obtain calcium carbonate particles, and finally mixing vitamin D3 powder with the calcium carbonate particles, adding an anti-adhesive and a lubricant, and mixing to obtain a total mixed particle. The solubility and stability of the product obtained by this method are poor.

[0006] Patent CN118319865A discloses calcium carbonate vitamin D3 granules and a preparation method thereof. Although the effective combination of calcium carbonate and vitamin D3 is achieved to a certain extent, the operation steps of adding an ethanol solution containing vitamin D3 into calcium carbonate particles in the form of a spray are relatively cumbersome, which increases the production cost and the difficulty of operation.

[0007] In the preparation process of calcium carbonate vitamin D3 granules, since vitamin D3 is a trace ingredient with a relatively low content, ensuring its content and stability in the finished product becomes a technical challenge. Vitamin D3 is not only sensitive to light, heat and humidity, but also difficult to accurately control and maintain its activity due to its trace presence in the preparation. Therefore, how to effectively protect vitamin D3 from external environmental factors during the production process and ensure its stability and bioavailability in the final product has become the focus and technical difficulty of research in this field. Summary of the invention

[0008] The present application provides a method for preparing a calcium supplement, in particular a method for preparing calcium carbonate D3 particles. The method is simple, and the particles obtained have uniform content, good dissolution effect, and high stability.

[0009] In order to achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing a calcium supplement comprises the following steps:

[0011] 1) Premixing of raw materials and auxiliary materials: Mixing the prescribed amount of calcium carbonate, binder and flavoring agent;

[0012] 2) Granulation: Wet granulation is carried out by fluidized bed technology, and the wetting agent is sprayed in by atomization;

[0013] 3) Drying: Drying the particles obtained in step 2) to control the moisture content of the particles;

[0014] 4) Granulation: The granules dried in step 3) are sized using a sieve to obtain granules A;

[0015] 5) Addition and mixing: rinse 1 / 4 of the granules A in a granulator, and then mix with the prescribed amount of vitamin D3 to obtain granules 1; rinse the granulator with another 1 / 4 of the granules A to obtain granules 2;

[0016] 6) Total mixing: the granules 1, granules 2, another 1 / 4 of the granules A and the prescribed amount of preservatives are uniformly mixed in a total mixer to obtain granules 3, and the granules 3 are mixed with the remaining 1 / 4 of the granules A to obtain granules B;

[0017] 7) Packaging: Packing the particles obtained in step 6.

[0018] In one embodiment of the present invention, the wetting agent is one or more of water, ethanol, isopropanol, polyethylene glycol solution or glycerol.

[0019] In one embodiment of the present invention, the dosage of the wetting agent is 30% to 70% of the total weight of the raw and auxiliary materials.

[0020] In one embodiment of the present invention, the spraying rate of the atomized spraying of the wetting agent in step 2) granulation is 5 g / min to 15 g / min.

[0021] In one embodiment of the present invention, the aperture 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 air pressure is 0.1-0.2 MPa.

[0022] In one embodiment of the present invention, during step 3) drying, the moisture content of the particles is controlled below 1.5%.

[0023] In one embodiment of the present invention, the mesh size in the granulation step (4) is 0.6 mm.

[0024] 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.

[0025] 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.

[0026] In another aspect, the present invention provides a calcium supplement prepared according to the above method, wherein the calcium supplement is preferably calcium carbonate D3 particles.

[0027] Compared with the prior art, the present invention has the following technical effects:

[0028] (1) The calcium carbonate D3 particles prepared by the process of the present invention have excellent performance in calcium dissolution, and the effect is very ideal, which can significantly improve the absorption efficiency of the product;

[0029] (2) The contents of the active ingredients calcium and vitamin D3 in the calcium carbonate D3 particles obtained by the inventors meet the requirements, and the vitamin D3 content is stable, ensuring the reliability and consistency of the product;

[0030] (3) The present invention uses a specific preparation process to obtain calcium carbonate D3 particles. The entire method is simple and easy to implement, and also exhibits good stability in terms of related substances, ensuring the quality of the product during production and storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is a schematic diagram of the mixing of raw and auxiliary materials. DETAILED DESCRIPTION

[0032] The following will be combined with the drawings in the embodiments of the present application to clearly describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of this application.

[0033] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those illustrated or described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated with each other are in an "or" relationship.

[0034] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0035] The inventors of the present application have found that by controlling the key processes in the preparation method of calcium carbonate D3 particles, not only the dissolution of calcium element is improved, but also the stability of related substances in calcium carbonate D3 particles can be maintained at a high level, and the content and stability of vitamin D3 are good. The whole process includes the following main steps:

[0036] 1) Premixing of raw materials and auxiliary materials: Mixing the prescribed amount of calcium carbonate, binder and flavoring agent;

[0037] In one embodiment of the present invention, the specific operation is to add the prescribed amount of calcium carbonate, binder, and flavoring agent into a wet mixing granulator in sequence for mixing, with a stirring parameter of 150 rpm ± 20 rpm, a shear parameter of 1000 rpm ± 300 rpm, and a mixing time of 8 min.

[0038] 2) Granulation: Wet granulation is carried out by fluidized bed technology, and the wetting agent is sprayed in by atomization;

[0039] In one embodiment of the present invention, the wetting agent is one or more of water, ethanol, isopropanol, polyethylene glycol solution or glycerol. In a specific embodiment of the present invention, the wetting agent is an aqueous solution or an ethanol aqueous solution, and the ethanol aqueous solution is a common concentration, for example, 20% ethanol aqueous solution, 30% ethanol aqueous solution, 40% ethanol aqueous solution, 50% ethanol aqueous solution, 60% ethanol aqueous solution, 70% ethanol aqueous solution or 95% ethanol aqueous solution. However, it is not limited to the listed concentrations, and other commonly used concentrations are also applicable.

[0040] In one embodiment of the present invention, the specific operation is to control the inlet air temperature at 60±10°C, the inlet air volume at 10-30HZ, the wetting agent is sprayed in an atomized manner, the spray gun aperture is 1.0-3.0mm, the spray flow rate is 1kg / h-3kg / h, the atomization air pressure is 0.1-0.2MPa, the spray speed is 5-15g / min, the material temperature is controlled at 25-35°C, and the peristaltic pump speed is 4-8rpm.

[0041] In one embodiment of the present invention, the amount of the wetting agent is 30% to 70% of the total weight of the raw material prescription, such as 30%, 35%, 40%, 45%, 55%, 60%, 65% or 70%. However, it is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0042] The amount of wetting agent used is very important because it directly affects the formation and properties of the particles. If the percentage of the wetting agent used is too low (for example, less than 30%), the solution may not provide enough liquid to wet all the powders, resulting in poor particle formation or insufficient adhesion between particles. On the contrary, if the percentage of the wetting agent used is too high (for example, more than 70%), the excess wetting agent may cause the particles to be too wet, affecting the shape and strength of the particles, and even causing the powder to agglomerate, making the subsequent drying process complicated. This will affect the quality of the final product.

[0043] In a specific embodiment of the present invention, the spraying speed is 5 to 15 g / min, such as 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, and other values ​​not listed in the numerical range are also applicable. The spraying speed of the present invention is the amount of wetting agent passing through the nozzle per unit time.

[0044] The spraying speed is very important in the preparation of calcium carbonate D3 particles. A spraying speed in the range of 5 to 15 g / min helps to achieve uniform distribution of the wetting agent on the powder, improve the wetting efficiency, and thus improve the quality of the particles. At the same time, by controlling the spraying speed, uneven distribution of the binder can be avoided, and the generation of large particles and fine powder can be reduced, thereby obtaining particles with a narrower particle size distribution and a smaller average particle size. In addition, uniform wetting and particle formation help to improve the physical stability of the particles and reduce dust and breakage problems during subsequent processing.

[0045] By precisely controlling the spray speed, not only can the production efficiency of calcium carbonate D3 particles be improved, but also the consistency and stability of product quality can be ensured, which is crucial to meeting the high standards of pharmaceutical production and the safety needs of patients.

[0046] In a specific embodiment of the present invention, the aperture of the spray gun is 1.0-3.0 mm, such as 1.0 mm, 2.0 mm or 3.0 mm, but it is not limited to the listed values, and other values ​​not listed within the range are also applicable.

[0047] In a specific embodiment of the present invention, the liquid spraying flow rate is 1kg / h to 3kg / h, for example, 1kg / h, 2kg / h or 3kg / h. However, it is not limited to the listed values, and other values ​​not listed in the numerical range are also applicable. The liquid spraying flow rate of the present invention refers to the flow rate of the wetting agent per unit time.

[0048] In a specific embodiment of the present invention, the atomization gas pressure is 0.1-0.2 MPa, such as 0.1 MPa, 0.15 MPa or 0.2 MPa, but it is not limited to the listed values, and other values ​​not listed in the numerical range are also applicable.

[0049] Atomization pressure is equally important. Appropriate atomization pressure helps to form particles with good structure, moderate density and smooth surface. A range of 0.1-0.2MPa is conducive to improving the fluidity and compressibility of particles. If the atomization pressure is too high, the droplets may be too small and dry too quickly, affecting the formation of particles. If the atomization pressure is too low, the droplets may be too large, resulting in uneven or too large particles, affecting product quality, and adhesion between particles may occur, resulting in the uniformity of the distribution of active ingredients.

[0050] 3) Drying: Dry the granules obtained in step 2) to control the moisture content of the granules.

[0051] In one embodiment of the present invention, the moisture content of the particles is controlled to be below 1.5%, such as 1.5%, 1.2%, 1.0%, 0.8% or 0.5%, but is not limited to the listed values, and other values ​​not listed within the range are also applicable.

[0052] 4) Granulation: The granules dried in step 3) are sized using a sieve;

[0053] In one embodiment of the present invention, the mesh aperture is a conventional aperture used in the art, such as 1.00 mm, 0.85 mm, 0.71 mm, 0.60 mm, 0.50 mm, 0.425 mm, 0.355 mm, 0.300 mm or other conventional apertures.

[0054] 5) Addition and mixing:

[0055] In one embodiment of the present invention, the specific operation is as follows: a. passing vitamin D3 through a 0.6 mm screen of a pulverizing and granulating machine for standby use; b. taking 1 / 4 of granules A and rinsing the granulating machine, and then mixing it with the vitamin D3 prepared in step a) twice to obtain granules 1; using another 1 / 4 of granules A and rinsing the granulating machine once to obtain granules 2;

[0056] 6) Total mixing: Granule 1, Granule 2, another 1 / 4 of Granule A and sodium citrate are mixed evenly in a total mixer to obtain Granule 3, and then Granule 3 is mixed with the remaining 1 / 4 of Granule A to obtain Granule B. The mixing speed is 15 rpm and the mixing time is 90 min. Figure 1 Detailed description of the invention The mixing method of the invention effectively improves the mixing uniformity, prevents the aggregation of active ingredients and is easy to operate and control, thereby effectively improving the mixing efficiency. The invention does not set a limit on the mixing speed and mixing time, as long as the materials can be fully mixed and evenly distributed.

[0057] 7) Packaging: Packing the particles obtained in step 6. The present invention does not limit the packaging materials and methods, as long as the particles are packaged according to the expected specifications.

[0058] 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.

[0059] 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; 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.

[0060] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0061] Example 1

[0062] 1. The prescription composition is shown in Table 1

[0063] Table 1 Prescription composition

[0064]

[0065] 2. Process description (taking the production of 1000 bags as an example)

[0066] 1) Premixing of raw materials and auxiliary materials

[0067] The prescribed amount of calcium carbonate, maltodextrin and anhydrous glucose were sequentially added into a wet mixing granulator for mixing, with a stirring parameter of 150 rpm±20 rpm, a shear parameter of 1000 rpm±300 rpm and a mixing time of 8 min.

[0068] 2) Fluidized bed granulation (fluidized bed: WBF-5G)

[0069] The inlet air temperature is controlled at 60±10℃, the inlet air volume is 10-30HZ, 675g of aqueous solution is sprayed into the atomized material, water accounts for about 45% of the total amount of raw and auxiliary materials, the spray gun aperture is 1.0-3.0mm, the spray flow rate is 1kg / h-3kg / h, the atomization air pressure is 0.1-0.2MPa, the spray speed is 5g / min, the material temperature is controlled at 25-35℃, and the peristaltic pump speed is 4-8rpm.

[0070] 3) Drying

[0071] After the spraying is completed, the atomizing air pressure is turned off and the material is started to be dried. The material temperature is controlled at 40-45°C and the moisture content is controlled to be no more than 1.5%.

[0072] 4) Whole grain

[0073] The granules obtained after drying in step 3) were sized using a 0.6 mm pore size sieve to obtain granules A.

[0074] 5) Addition and mixing

[0075] a. Pass the vitamin D3 through a 0.6mm sieve of a granulator and set aside.

[0076] b. Take 1 / 4 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; take another 1 / 4 of Granule A and rinse it in the granulator once to obtain Granule 2.

[0077] 6) Total Mixing

[0078] Granule 1, Granule 2, another 1 / 4 of Granule A and sodium citrate were mixed evenly in a total mixer to obtain Granule 3, and then Granule 3 was mixed with the remaining 1 / 4 of Granule A to obtain Granule B. The mixing speed was 15 rpm and the mixing time was 90 min.

[0079] 7) Packaging

[0080] The particles obtained in step 6) are packaged using a polyester / aluminum / polyethylene pharmaceutical composite film.

[0081] Example 2

[0082] The liquid spraying rate in the fluidized bed granulation in step 2) was adjusted to 8 g / min, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0083] Example 3

[0084] The liquid spraying rate in the fluidized bed granulation in step 2) was adjusted to 12 g / min, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0085] Example 4

[0086] The liquid spraying speed in the fluidized bed granulation in step 2) was adjusted to 15 g / min, and the amount of the aqueous solution sprayed by atomization was adjusted to 750 g, which was about 50% of the total amount of the raw and auxiliary materials. The formulation composition and other process steps and conditions were the same as those in Example 1.

[0087] Example 5

[0088] The liquid spraying speed in the fluidized bed granulation in step 2) was adjusted to 10 g / min, and the amount of the aqueous solution sprayed by atomization was adjusted to 900 g, which was about 60% of the total amount of the raw and auxiliary materials. The prescription composition and other process steps and conditions were the same as those in Example 1.

[0089] Example 6

[0090] The liquid spraying speed in the fluidized bed granulation in step 2) was adjusted to 15 g / min, and the amount of the aqueous solution sprayed by atomization was adjusted to 450 g, which was about 30% of the total amount of the raw and auxiliary materials. The formulation composition and other process steps and conditions were the same as those in Example 1.

[0091] Example 7

[0092] The liquid spraying speed in the fluidized bed granulation in step 2) was adjusted to 10 g / min, and the amount of the aqueous solution sprayed by atomization was adjusted to 1050 g, which was about 70% of the total amount of the raw and auxiliary materials. The formulation composition and other process steps and conditions were the same as those in Example 1.

[0093] Example 8

[0094] The liquid spraying speed in the fluidized bed granulation of step 2) was adjusted to 10 g / min, and the atomized aqueous solution was adjusted to a 50% ethanol solution, with an amount of 750 g, which was about 50% of the total amount of the raw and auxiliary materials. The formulation composition and other process steps and conditions were the same as those in Example 1.

[0095] Comparative Example 1

[0096] The liquid spraying rate in the fluidized bed granulation in step 2) was adjusted to 3 g / min, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0097] Comparative Example 2

[0098] The liquid spraying rate in the fluidized bed granulation in step 2) was adjusted to 17 g / min, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0099] Comparative Example 3

[0100] The liquid spraying speed in the fluidized bed granulation in step 2) was adjusted to 12 g / min, and the amount of the aqueous solution sprayed by atomization was adjusted to 375 g, which was about 25% of the total amount of the raw and auxiliary materials. The formulation composition and other process steps and conditions were the same as those in Example 1.

[0101] Comparative Example 4

[0102] The liquid spraying speed in the fluidized bed granulation in step 2) was adjusted to 12 g / min, and the amount of the aqueous solution sprayed by atomization was adjusted to 1125 g, which was about 75% of the total amount of the raw and auxiliary materials. The formulation composition and other process steps and conditions were the same as those in Example 1.

[0103] Comparative Example 5

[0104] The process of adding and mixing in step 5) and total mixing and processing in step 6) is as follows. The formulation composition and other process steps and conditions are the same as those in Example 1.

[0105] a. Pass the vitamin D3 through a 0.6mm sieve of a granulating machine and set aside

[0106] b. Add the vitamin D3 prepared in step a) and the prescribed amount of sodium citrate to the particles A and mix them together for 3 times at a mixing speed of 15 rpm for 90 min.

[0107] Comparative Example 6

[0108] The addition and mixing of step 5) and the total mixing of step 6) are adjusted as follows. The formulation composition and other process steps and conditions are the same as those in Example 1.

[0109] 5) Addition and mixing

[0110] a. Pass the vitamin D3 through a 0.6mm sieve of a granulator and set aside.

[0111] 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 another 1 / 2 of Granule A and rinse it in the granulator once to obtain Granule 2-1.

[0112] 6) Total Mixing

[0113] 1 / 2 of granule 2-1, granule 1-1 and sodium citrate were mixed evenly in a total mixer to obtain granule B1, and then another 1 / 2 of granule 2-1 was added and mixed to obtain granule C. The mixing speed was 15 rpm and the mixing time was 90 min.

[0114] Comparative Example 7

[0115] The addition and mixing of step 5) and the total mixing of step 6) are adjusted as follows. The formulation composition and other process steps and conditions are the same as those in Example 1.

[0116] 5) Addition and mixing

[0117] a. Pass the vitamin D3 through a 0.6mm sieve of a granulator and set aside.

[0118] b. Take 1 / 2 of granules A and rinse it through a granulator, then mix it twice with the vitamin D3 prepared in step a) to obtain granules 1-1; rinse 1 / 2 of granules A through a granulator once to obtain granules 2-1.

[0119] 6) Total Mixing

[0120] Granules 2-1, granules 1-1 and sodium citrate were mixed uniformly in a total mixer to obtain granules B2. The mixing speed was 15 rpm and the mixing time was 90 min.

[0121] Determination of the calcium carbonate D3 particles obtained in Examples 1 to 8 and Comparative Examples 1 to 7 and the commercially available calcium carbonate particles for children (sustained The certificate is A&Z Pharmaceutical, Inc., and the batch number is 3B239005) for calcium content and vitamin D3 content, dissolution and Related substances

[0122] Calcium and vitamin D3 content determination method

[0123] Vitamin D3 was determined by high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition) in a light-protected environment.

[0124] The chromatographic conditions were as follows: silica gel was used as filler (Welch Ultimate SiO2; 4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent performance); 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.

[0125] Calcium Take 20 tablets of this product, weigh accurately, grind finely, weigh an appropriate amount of fine powder (equivalent to about 30 mg of calcium), add 15 ml of 1 mol / L hydrochloric acid solution, heat on a steam bath for 5 to 10 minutes until the reaction stops completely, 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 ethylenediaminetetraacetic acid titrant (0.05 mol / L) until the solution changes from pink to blue. Each 1 ml of disodium ethylenediaminetetraacetic acid titrant (0.05 mol / L) is equivalent to 2.004 mg of Ca.

[0126] Table 2 Calcium content and vitamin D3 content in calcium carbonate D3 particles (%)

[0127]

[0128]

[0129] As can be seen from Table 2, the calcium content in the calcium carbonate D3 particles obtained in Examples 1 to 8 is within the range specified by the labeled amount (95.0% to 105.0%), and the vitamin D3 content is within the range specified by the labeled amount (90.0% to 120.0%), which all meet the existing most stringent standard British Pharmacopoeia 2018 edition quality standard for this product. The vitamin D3 content in the calcium carbonate D3 particles obtained by Comparative Example 1 (slower spray speed), Comparative Example 3 (less wetting agent) and Comparative Example 5 (direct mixing) is not within the specified range. Because the amount of vitamin D3 in the calcium carbonate D3 particles is small and unstable, the inventors further determined the changes in the content of vitamin D3 under different conditions (the placement conditions are high temperature 40°C, high temperature 60°C, high humidity 75%, high humidity 90%, and light. The observation time is 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] According to the data analysis of the degradation of vitamin D3 in calcium carbonate vitamin D3 particles under high temperature (40°C, 60°C), high humidity (75%, 90%) and light conditions within 30 days in Table 3, it can be seen that in Examples 1 to 8, the degradation of vitamin D3 in the prepared calcium carbonate vitamin D3 particles under the above environmental conditions is relatively small, showing good stability. In contrast, the degradation of vitamin D3 in the calcium carbonate vitamin D3 particles prepared in Comparative Examples 1 to 7 is significantly increased under the same conditions, indicating that its stability is poor.

[0134] It can be inferred from this that the preparation method of calcium carbonate vitamin D3 particles proposed in the present invention can significantly improve the stability of vitamin D3 in the product, so that it can still maintain a high activity under various adverse environmental conditions.

[0135] Dissolution test method

[0136] The dissolution and release rate was determined according to the dissolution and release rate determination method (Method 2, Part 4, General Rules 0931, Chinese Pharmacopoeia 2020 Edition).

[0137] The dissolution conditions were 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, a rotation speed of 75 revolutions per minute, and sampling was performed 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 of the test sample, filter it, and take the filtrate.

[0139] Determination method: 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 ethylenediaminetetraacetic acid titrant (0.05 mol / L) until the solution changes from pink to blue. Each 1 ml of disodium ethylenediaminetetraacetic acid titrant (0.05 mol / L) is equivalent to 2.004 mg of Ca. Calculate the dissolution amount of each tablet.

[0140] The dissolution results are shown in Table 4

[0141] Table 4 Dissolution results of the embodiments and comparative examples in 0.1M hydrochloric acid medium

[0142]

[0143]

[0144] From the data in Table 4, it can be seen that the dissolution amount of calcium element in both the embodiments and the comparative examples can reach more than 85% in 15 minutes. It is believed that the dissolution of calcium carbonate D3 particles obtained in embodiments 1 to 8 and comparative examples 1 to 7 is similar to that of commercially available products.

[0145] Determination method of related substances

[0146] The determination was carried out in a light-protected manner according to the high performance liquid chromatography method (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0147] The extract contained 0.02% 2,6-di-tert-butyl-p-cresol (BHT) in a 75% dimethyl sulfoxide aqueous solution.

[0148] The solvent is 75% dimethyl sulfoxide aqueous solution-n-hexane (1:20) containing 0.02% 2,6-di-tert-butyl-p-cresol (BHT). The solution is allowed to stand and the n-hexane layer is taken.

[0149] Test solution Take 25 bags of this product, weigh accurately, and grind finely. Weigh an appropriate amount of fine powder (equivalent to about 100 μg of vitamin D3) accurately, place it in a 200 ml brown volumetric bottle, add about 50 ml of extract, vortex for 3 minutes, shake for 30 minutes, accurately add 5 ml of solvent, seal, shake for 30 minutes, vortex for 3 minutes, centrifuge at 3000 rpm for 10 minutes, take the upper solution, and centrifuge at 13000 rpm for 5 minutes to take the clear solution.

[0150] Reference solution Take about 20 mg of vitamin D3 reference (each 1 mg is equivalent to 40000 IU), weigh accurately, place in a 100 ml volumetric bottle, add solvent to dissolve and dilute to scale, shake well. Accurately measure 5 ml, place in a 50 ml volumetric bottle, add solvent to dilute to scale, shake well.

[0151] For the system suitability solution, take appropriate amounts of impurity A, impurity B, impurity C, and vitamin D3 reference substance, add solvent to dilute them to make a mixed solution containing 0.3 μg of impurity A, 0.2 μg of impurity B and impurity C each, and 20 μg of vitamin D3 per 1 ml.

[0152] The chromatographic conditions were as follows: silica gel was used as filler (Welch Ultimate SiO2; 4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent performance); 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.

[0153] System suitability requirements In the system suitability solution chromatogram, the order of chromatographic peaks should be impurity A, vitamin D3, impurity B, impurity C, and the separation between each impurity should meet the requirements;

[0154] Determination method: Take the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0155] If there are impurity peaks (except the excipient peak and provitamin D3 peak) in the chromatogram of the limit test solution, the impurity A shall not exceed 1.5%, the impurity B and other individual impurities shall not exceed 1.0%, and the total impurities shall not exceed 2.5% when calculated by peak area using the external standard method.

[0156] Impurity information is shown in Table 5:

[0157] Table 5 Impurity information in calcium carbonate D3 particles

[0158]

[0159] The results of relevant substances are shown in Table 6

[0160] Table 6 Test results of related substances in Examples and Comparative Examples

[0161]

[0162]

[0163]

[0164]

[0165] From the related substance detection results of the embodiments and comparative examples in Table 6, it can be seen that although on the 0th day, the related substance contents in the calcium carbonate D3 particles obtained in Examples 1 to 8 and Comparative Examples 1 to 7 were all lower than the limit requirements, the calcium carbonate D3 particles obtained in the embodiments had slightly lower related substance contents than those in the comparative examples.

[0166] The changes in impurity content after being placed under high temperature 40°C, high temperature 60°C, high humidity 90%, and light 5000Lx for 10 days and 30 days were further investigated.

[0167] When other conditions are the same, when the spraying rate is low (such as Comparative Example 1, 3 g / min), the obtained calcium carbonate D3 particles are left naked at 60°C for 30 days, and the total impurity content is 1.98%, which is significantly higher than 1.28% in Example 1 (spraying rate is 5 g / min), 1.22% in Example 2 (spraying rate is 8 g / min) and 1.66% in Example 3 (spraying rate is 12 g / min).

[0168] When other conditions are the same, when the spraying speed is high (such as Comparative Example 2, 17 g / min), the total impurity content of the obtained calcium carbonate D3 particles is 2.34% when left naked at 60°C for 30 days, which is close to the limit value of 2.5%, and is significantly higher than 1.28% in Example 1 (spraying speed of 5 g / min), 1.22% in Example 2 (spraying speed of 8 g / min) and 1.66% in Example 3 (spraying speed of 12 g / min).

[0169] When other conditions are the same, when the amount of wetting agent is low (such as Comparative Example 3, 25%), the total impurity content of the obtained calcium carbonate D3 particles after being placed at high temperature of 60°C and light of 5000Lx for 30 days is 2.31% and 2.65% (exceeding the limit value), which is significantly higher than 1.66% and 1.41% in Example 3 (the amount of wetting agent is 45%).

[0170] When other conditions are the same, when the amount of wetting agent is higher (such as 75% in Comparative Example 4), the obtained calcium carbonate D3 particles are left at a high temperature of 60°C for 30 days, and the total impurity content is 2.54%, which exceeds the limit value of 2.5%.

[0171] Through comparative analysis of different mixing methods, it can be seen that Example 3 (according to the attached Figure 1 The schematic diagram of mixing raw materials and auxiliary materials shown in the figure performs well in ensuring the uniform distribution of vitamin D3 in calcium carbonate particles. Specifically:

[0172] Initial impurity content: Example 3 had the lowest total impurity content on day 0, which was 1.66%, indicating that the product quality could be effectively controlled in the early stage of production.

[0173] Long-term stability: After being placed at high temperature (60°C) for 30 days, the total impurity content of Example 3 remained at a relatively low level (1.66%), much lower than that of Comparative Example 5 (2.65%), Comparative Example 6 (2.82%) and Comparative Example 7 (2.98%), and all of them did not exceed the prescribed limit value. This shows that Example 3 has better stability in a high temperature environment.

[0174] It is worth noting that although increasing the number of mixing times can improve uniformity to a certain extent, this does not mean that the more times the mixing is performed, the better the quality and stability of the product. In fact, excessive mixing may cause changes in the physical properties of the material, increase mechanical stress, and even cause unnecessary side reactions, thereby affecting the performance of the final product. For example, although Comparative Example 5 adopts a direct mixing method, its impurity content (2.65%) is still higher than that of Example 3. In contrast, the impurity contents of Comparative Example 6 (added in three times) and Comparative Example 7 (added in two times) are higher, at 2.82% and 2.98%, respectively.

[0175] Therefore, Example 3 is not only superior to other comparative examples in practical effect, but also reaches an optimal balance point in the number of mixing times, ensuring the quality and stability of the product. This method not only ensures the uniform distribution of vitamin D3 in the calcium carbonate particles, but also avoids the negative effects caused by excessive mixing through reasonable mixing steps.

[0176] In summary, the embodiment adopts a specific spray speed (5-15 g / min), a wetting agent dosage (30%-70%) and a calcium carbonate particle addition method so that the obtained calcium carbonate D3 particles have better effects on related substances and their stability, while ensuring the calcium content and dissolution and the vitamin D3 content and stability.

[0177] Table 7 Comparison of process conditions between the embodiment and the comparative example

[0178]

[0179]

[0180] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for preparing a calcium supplement, characterized in that: The steps include: 1) Premixing of raw materials and auxiliary materials: Mixing the prescribed amount of calcium carbonate, binder and flavoring agent; 2) Granulation: Wet granulation is carried out by fluidized bed technology, and the wetting agent is sprayed in by atomization; 3) Drying: Drying the particles obtained in step 2) to control the moisture content of the particles; 4) Granulation: The granules dried in step 3) are sized using a sieve to obtain granules A; 5) Addition and mixing: rinse 1 / 4 of the granules A in a granulator, and then mix with the prescribed amount of vitamin D3 to obtain granules 1; rinse the granulator with another 1 / 4 of the granules A to obtain granules 2; 6) Total mixing: the granules 1, granules 2, another 1 / 4 of the granules A and the prescribed amount of preservatives are uniformly mixed in a total mixer to obtain granules 3, and the granules 3 are mixed with the remaining 1 / 4 of the granules A to obtain granules B; 7) Packaging: Packing the particles obtained in step 6.

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

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

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

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

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

7. The method for preparing a calcium supplement according to claim 6, characterized in that: The aperture of the sieve in the 4) granulation is 0.6 mm.

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

9. The method for preparing a calcium supplement according to claim 8, characterized in that: The adhesive 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.

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

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