Preparation method of folic acid pills

Abstract

This invention provides a method for preparing folic acid pellets, wherein the folic acid pellets are made from the following components in parts by weight: 70-98 parts by weight of pellet core, 0.1-10 parts by weight of folic acid, 0.1-6 parts by weight of hydroxypropyl methylcellulose, and 0.1-5 parts by weight of polyvinylpyrrolidone. The method includes the following steps: uniformly mixing the formulated amounts of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and folic acid in water to obtain a mixed solution; feeding the formulated amount of pellet core into a centrifugal granulator; and spraying the mixed solution through a peristaltic pump to adsorb onto the surface of the pellets to obtain the folic acid pellets. The folic acid pellets of this invention avoid the decrease in folic acid content caused by heating during the folic acid pulverization process, have a simple process, short heating time, and the pellets are a combination of small units with a large surface area, allowing for uniform distribution of folic acid.

Description

Technical Field

[0001] This invention relates to the fields of food, pharmaceuticals, and feed, and specifically to a method for preparing folic acid pellets. Background Technology

[0002] Folic acid is a type of B vitamin. It is slightly soluble in water and unstable to heat, light, and acidic solutions.

[0003] Folic acid is composed of pteridine, para-aminobenzoic acid and L-glutamic acid, also known as pteroylglutamic acid, and is a type of B vitamin.

[0004] Molecular formula; C 19 H 19 N7O6

[0005] The structural formula of folic acid;

[0006]

[0007] Since January 1, 1998, the United States has mandated the fortification of folic acid in certain cereal products. The FDA stipulates that 1.4 mg of folic acid should be fortified per kilogram of cereal products. RNI (Recommended Nutrient Intake): This refers to the intake level that can meet the needs of the vast majority (97%–98%) of individuals in a specific sex, age, and physiological condition group. Long-term intake at the RNI level can meet the body's needs for this nutrient, maintain appropriate nutrient reserves in tissues, and maintain health. In my country, folic acid has been fortified in foods for infants, pregnant women, and the elderly. The recommended folic acid supplement is 4-5 mg. Folic acid is abundant in fresh fruits, vegetables, and meats. It is mainly absorbed in the duodenum and proximal jejunum. The human body stores 5–20 mg of folic acid. Folic acid is mainly excreted through urine and feces, with a daily excretion of 2–5 μg. The main functions of folic acid in organisms are: participation in the metabolism of genetic material and proteins; influencing animal reproductive performance; affecting pancreatic secretion; promoting animal growth; and enhancing immunity. Possible causes of folic acid deficiency include insufficient intake; increased requirements; malabsorption; vitamin C deficiency; use of folic acid antagonists; and liver disease. Folic acid is a type of B vitamin. It is slightly soluble in water and unstable to heat, light, and acidic solutions. It is heat-stable in neutral and alkaline solutions, but can be lost in cooking (50-90%).

[0008] Manufacturers of folic acid tablets on the market include those with a 5mg / tablet specification; Tianjin Lisheng Pharmaceutical Co., Ltd. and Jiangsu Yabang Aipusheng Pharmaceutical Co., Ltd. with a 0.4mg / tablet specification; Shenyang Green Bio-Pharmaceutical Group Co., Ltd., Changzhou Pharmaceutical Factory Co., Ltd., Tianjin Yabao Pharmaceutical Technology Co., Ltd., and Jiangxi Pharmaceutical Co., Ltd., among others. The tablet production process involves folic acid → excipients → pulverization → sieving → mixing (fillers, binders, disintegrants) → soft mass preparation → wet granulation → drying → granulation → mixing → sieving → tableting → sorting. This process takes approximately 2 days. The particle size of the folic acid pulverized material affects the uniformity of the mixture, which in turn affects the variation in particle content. Variations in folic acid particle content can lead to substandard folic acid content during tableting, resulting in insufficient folic acid supplementation. These factors present challenges to controlling the tableting process. The disadvantages of this tablet production process include: a long process flow, strict control of temperature and time during production, and operation away from light. The specifications of 5mg / tablet and 0.4mg / tablet are very different, making it difficult to complete them on the same tableting machine mold. Usually, it is necessary to change to another suitable larger mold, which not only increases the purchase of equipment molds, but also lengthens the production cycle and increases management and labor costs.

[0009] There is limited research on folic acid pills in China. While folic acid tablets are available on the market, folic acid pills have not been seen for sale. Summary of the Invention:

[0010] The purpose of this invention is to provide a method for preparing folic acid pellets with small content variations, a production process that is completed in 1-2 hours, a temperature of 40-45 degrees Celsius, a short heating time, and a yield of over 99%, using pellet cores as the parent material.

[0011] To achieve the above objectives, the present invention adopts the following technical solution:

[0012] This invention provides a method for preparing folic acid pills, wherein the folic acid pills are made from the following components in parts by weight:

[0013] 70-98 parts by weight of pharmaceutical microcapsule core, 0.1-10 parts by weight of folic acid, 0.1-6 parts by weight of hydroxypropyl methylcellulose, and 0.1-5 parts by weight of polyvinylpyrrolidone;

[0014] The method includes the following steps:

[0015] The formulation amounts of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and folic acid are uniformly mixed in water to obtain a mixed solution. The formulation amounts of pharmaceutical microcapsule cores are fed into a centrifugal granulator. The mixed solution is atomized by a peristaltic pump through a spray gun and adsorbed onto the surface of the sugar capsules to obtain the folic acid pellets.

[0016] Generally speaking, the above-mentioned folic acid pills do not need to be dried. However, if the preparation process is too short and the moisture content exceeds the standard, those skilled in the art will know that they can be dried and then packaged.

[0017] Those skilled in the art will know that the polyvinylpyrrolidone can be common polyvinylpyrrolidone K-30 or polyvinylpyrrolidone K-90.

[0018] Furthermore, the folic acid pills are made from the following components in parts by weight:

[0019] 71-97 parts by weight of pharmaceutical microcapsule core, 0.1-7 parts by weight of folic acid, 0.1-4 parts by weight of hydroxypropyl methylcellulose, and 0.1-3 parts by weight of polyvinylpyrrolidone.

[0020] Preferably, the folic acid pellets are made from the following components in parts by weight:

[0021] 71-97 parts by weight of pharmaceutical microcapsule core, 0.1-7 parts by weight of folic acid, 2 parts by weight of hydroxypropyl methylcellulose, and 1 part by weight of polyvinylpyrrolidone.

[0022] The pharmaceutical microcapsule core, as a carrier for folic acid, can be any human-acceptable core commonly used in the field. According to an embodiment of the present invention, the particle size of the core is 0.3-1.5 mm, preferably one or more of sucrose core, starch core, microcrystalline cellulose core, mannitol core, and silica core.

[0023] Furthermore, the mixed solution is uniformly mixed as follows: the formulation amount of hydroxypropyl methylcellulose is dissolved in purified water A to obtain an aqueous solution of hydroxypropyl methylcellulose; the formulation amount of polyvinylpyrrolidone is dissolved in purified water B to obtain an aqueous solution of polyvinylpyrrolidone; the aqueous solution of hydroxypropyl methylcellulose, the aqueous solution of polyvinylpyrrolidone, and the formulation amount of folic acid are mixed to obtain the mixed solution.

[0024] Preferably, the aqueous solution of hydroxypropyl methylcellulose has a mass concentration of 2%; and the aqueous solution of polyvinylpyrrolidone has a mass concentration of 1%.

[0025] Specifically, the airflow of the centrifugal granulator is controlled at 5-10Hz, and the air pressure is controlled at 0.1-0.6MPa.

[0026] In one embodiment of the present invention, the spraying speed of the atomized slurry from the spray gun is controlled at 60-220 r / min, and the temperature is 40℃-45℃.

[0027] Using a pellet core as the mother core, folic acid is dissolved in an aqueous solution of polyvinylpyrrolidone (PVP), then mixed evenly with an aqueous solution of hydroxypropyl methylcellulose (HPMC). The HPMC binder ensures the folic acid is evenly distributed on the surface of the pellet core, resulting in folic acid pellets that solve the problem of inconsistent single-dose content. This process, using the pellet core as the mother core and spraying the folic acid solution onto it, is characterized by short heating time for folic acid, high yield, controllable quality, and low cost.

[0028] The core of folic acid pills can be sucrose, microcrystalline cellulose, tartaric acid, mannitol, starch, or a combination of various cores.

[0029] Compared with existing technologies, the advantages of this invention are as follows: The existing tablet production process involves folic acid → excipients → pulverization → sieving → mixing (binder / disintegrant) → soft mass preparation → wet granulation → drying → granulation → mixing → tableting. The entire production process takes 2 days. In contrast, the production process of the folic acid pellets of this invention involves: adding folic acid solution to the pellet core → pellet preparation → sieving → folic acid pellets. It can be seen that the tablet production process requires 10 steps, is lengthy, and has several process control points: 1. fineness of folic acid pulverization; 2. uniformity of mixing; 3. drying time; 4. uniformity of folic acid particles, as flowability affects the weight of folic acid tablets; 5. the production process requires light-protection measures to prevent excessively long periods of moisture and heat, which can lead to a decrease in folic acid content. In contrast, the folic acid pellets of this invention are produced by dissolving folic acid in a 1% polyvinylpyrrolidone aqueous solution and stirring until completely dissolved, avoiding the decrease in folic acid content caused by heat during the pulverization process. The control point is the amount of pellets added. The process for folic acid pellets involves adding the pellet core to a centrifugal granulator, preheating it to 40 degrees Celsius, and then pumping the folic acid and binder solution through a peristaltic pump to a spray gun, which is then applied to the surface of the pellets. This process takes approximately 1-2 hours. The process is simple, with a short heating time. The pellets are a combination of small units with a large surface area, allowing for uniform distribution of the added folic acid.

[0030] This invention uses a pellet core as a model. Folic acid is used to prepare an aqueous solution of hydroxypropyl methylcellulose and polyvinylpyrrolidone, which are then stirred until completely dissolved. This solution is added to the surface of the pellet core and dried for approximately 1 hour, followed by 0.5 hours of drying. Compared to tablet production, this process has 6 fewer steps, takes 1-2 hours, and operates at 40-50 degrees Celsius. The production process is simpler, quality is more controllable, there are fewer production control points and fewer pieces of equipment, cleaning is simpler, and energy and emissions are reduced. It also reduces labor costs in the production and testing processes and saves on testing reagents.

[0031] Folic acid pellets, as a multi-unit dosage form, typically consist of several pellets per single dose, usually numbering in the dozens or even hundreds. Compared to common tablets, folic acid pellets offer three major advantages. Firstly, the uniform dispersion of folic acid within the small dose unit reduces irritation to the gastric mucosa caused by excessively high local drug concentrations. The active ingredient in folic acid also allows for rapid blood concentration reaching the duodenum for absorption, thus improving absorption and maintaining the drug release rate, thereby enhancing bioavailability. Secondly, the pellets facilitate rapid gastric emptying, minimizing the impact of the patient's dietary status and reducing the influence of gastric emptying rate on the pellet's residence time in the upper gastrointestinal tract. This reduces intra- and inter-individual differences in blood drug concentration, ensuring uniform absorption. Detailed Implementation

[0032] The sources of each raw material in the embodiments of the present invention are as follows:

[0033] Silicon dioxide: Zhejiang Zhongwei Pharmaceutical Co., Ltd., batch number: 110503; Folic acid: Jiangxi Tianxin Pharmaceutical Co., Ltd., batch number: FA21122006; Microcrystalline cellulose: Shandong Liujia Pharmaceutical Excipients Co., Ltd., batch number: 201111601; Microcrystalline cellulose core: Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd., batch number: 20110801; Starch core: Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd., batch number: 20110801; Sucrose core: Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd., batch number: 20110109; Silicon dioxide core: Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd., batch number: 20111001; Mannitol core: Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd. Batch No.: 20110801; Polyvinylpyrrolidone K30: Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; Batch No.: 110201; Hydroxypropyl Methylcellulose: Huzhou Zhanwang Pharmaceutical Co., Ltd.; Batch No.: sp20110101; Silica: Zhejiang Zhongwei Pharmaceutical Co., Ltd.; Batch No.: 110050; Purified Water: Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd.; Batch No.: 20110209; Sucrose: Samyang Co., Ltd. (Korea); Batch No.: 20110129; Starch: Jiaxing Bailang Starch Products Co., Ltd.; Batch No.: 2011031301; Dextrin: Jiaxing Bailang Starch Products Co., Ltd.; Batch No.: 2011031001; Mannitol: Shijiazhuang Huaxu Pharmaceutical Co., Ltd.; Batch No.: 20111009

[0034] The moisture content of the above-mentioned core is less than 5%. During the preparation of folic acid pills, the final folic acid content may be greater than the amount added due to moisture evaporation.

[0035] The method for determining folic acid content in the examples is as follows:

[0036] Chromatographic conditions and system practicality test---Octadecylsilane-bonded silica gel was used as the stationary phase; mobile phase: potassium dihydrogen phosphate buffer: methanol = 95:5; potassium dihydrogen phosphate buffer: 6.8 g of potassium dihydrogen phosphate was weighed, added to water to 1000 ml, stirred and dissolved, and the pH was adjusted to 6.3 with 2 mol / L potassium hydroxide solution. Flow rate: 1.0 ml / min; column temperature: 30℃; detection wavelength: 254 nm. The theoretical plate number, calculated based on the folic acid peak, should not be less than 1000, and the resolution between peaks should meet the requirements.

[0037] Diluent: Weigh 7.5g EDTA-2Na, add an appropriate amount of water to dissolve, add 10ml ammonia water, and dilute with water to 500ml.

[0038] Preparation of the reference solution: Accurately weigh 8.0 mg of folic acid reference standard into a 100 ml volumetric flask, add 6 ml of methanol and an appropriate amount of diluent, heat in a 60 °C water bath for 15 min, shaking occasionally, cool, dilute to the mark with diluent, shake well, filter, and collect the filtrate.

[0039] Preparation of the test solution: Weigh 1g of fine powder accurately, place it in a 25ml volumetric flask, add 1.5ml of methanol and an appropriate amount of diluent, heat in a 60℃ water bath for 15min, shaking occasionally, cool, dilute to the mark with diluent, shake well, filter, and collect the filtrate.

[0040] For the assay, inject 20 μl of both the reference solution and the test solution into the liquid chromatograph and record the chromatograms. Calculate the result based on the peak area using the external standard method.

[0041] The folic acid content in the microcapsules is tested. The detected folic acid content divided by the theoretical content yields the labeled content. A labeled content within the range of 90%-110% indicates that the folic acid content in the microcapsules meets the regulations and is evenly distributed. The table below compares the time and cost of this patent with folic acid tablets:

[0042]

[0043] Summarize:

[0044] 1. In terms of process time, this patent significantly reduces the time required for the process, to only 10% of the time required for the tableting process. 2. The folic acid tablet formula adds disintegrants, fillers, binders, and lubricants, and the cost of these additional excipients is 1200 yuan / KG; while the cost of the excipient core of this patent is 100 yuan / KG.

[0045] 3. The tablet manufacturing process typically involves 8-10 steps and requires numerous machines, primarily pulverizers, mixers, granulators, dryers, sizing machines, final mixers, and tablet compressors. This process is energy-intensive, complex to clean, and requires verification and cleaning of each piece of equipment. It also involves 6-7 key control points and high manpower requirements. In contrast, this patent requires only 10% of the manpower needed for the tablet compressing process, and its energy consumption is only 1.5% of that required for the tablet compressing process.

[0046] 4. The testing of each excipient, intermediate, and finished product required for folic acid tablets involves many testing reagents, and the cost is 20 times that of this patent.

[0047] Example 1

[0048] 1. Formula

[0049] Material Name weight percentage Feed amount / g Sugar pellet core (0.3-0.6mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0050] II. Operation

[0051] 1. Weigh out the sucrose core, folic acid, polyvinylpyrrolidone, and hydroxypropyl methylcellulose separately.

[0052] 2. Prepare 2% hydroxypropyl methylcellulose aqueous solution and 1% polyvinylpyrrolidone aqueous solution separately, stirring until completely dissolved. Then add folic acid and stir until completely dissolved and mixed (mixed solution).

[0053] Turn on the centrifugal granulator main unit and the blower, controlling the airflow at 5-10 Hz and the air pressure at 0.1-0.6 MPa. Add the sucrose pellet cores. The peristaltic pump atomizes the mixed solution onto the surface of the pellets via a spray gun, controlling the spraying speed at 60-220 r / min and maintaining a temperature of 40-45℃. After adding the mixed solution, turn off the spraying system. Maintain the centrifugal granulator blower airflow at 20-60 Hz and ensure the moisture content is within acceptable limits.

[0054] The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0055] Example 2

[0056] 1. Formula

[0057] Material Name weight percentage Feed amount / g Sugar pellet core (0.7-0.9mm) 96.79 967.9. folic acid 0.21 2.1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0058] The operation was the same as in Example 1, except for the feeding ratio and the particle size of the sucrose core. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0059] Example 3

[0060] 1. Formula

[0061]

[0062]

[0063] The operation was the same as in Example 1, except for the feeding ratio and the particle size of the sucrose core. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0064] Example 4

[0065] 1. Formula

[0066] Material Name weight percentage Feed amount / g Starch pellet core (1.0-1.5mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0067] The procedure was the same as in Example 1, except that the starch core was replaced with a sucrose core. Folic acid pellets were then produced. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0068] Example 5

[0069] 1. Formula

[0070] Material Name weight percentage Feed amount / g Starch pellet core (0.7-1.0mm) 96.79 967.9. folic acid 0.21 2.1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0071] The procedure was the same as in Example 1, except that the starch core was replaced with a sucrose core. Folic acid pellets were then produced. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0072] Example 6

[0073] 1. Folic acid formula

[0074] Material Name weight percentage Feed amount (g) Starch pellet core (0.4-0.6mm) 96.7 967 folic acid 0.3 3 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0075] The procedure was the same as in Example 1, except that the starch core was replaced with a sucrose core. Folic acid pellets were then produced. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0076] Example 7

[0077] 1. Formula

[0078] Material Name weight percentage Feed amount (g) Microcrystalline cellulose pellet core (0.4-0.6mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0079] The procedure was the same as in Example 1, except that the sucrose core was replaced with a microcrystalline cellulose core. Folic acid pellets were then produced. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0080] Example 8

[0081] 1. Formula

[0082] Material Name weight percentage Feed amount (g) Microcrystalline cellulose pellets (0.7-1.0mm) 96.79 967.9. folic acid 0.21 2.1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0083] The procedure was the same as in Example 1, except that the sucrose core was replaced with a microcrystalline cellulose core. Folic acid pellets were then produced. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0084] Example 9

[0085] 1. Formula

[0086] Material Name weight percentage Feed amount (g) Microcrystalline cellulose pellets (1.0-1.2mm) 96.7 967 folic acid 0.3 3 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0087] The procedure was the same as in Example 1, except that the sucrose core was replaced with a microcrystalline cellulose core. Folic acid pellets were then produced. The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0088] Example 10

[0089] 1. Formula

[0090] Material Name weight percentage Feed amount (g) Mannitol pellet core (0.4-0.7mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0091] The procedure was the same as in Example 1, except that the mannitol core was replaced with a sucrose core. Folic acid pellets were then produced. The folic acid pellet content and uniformity were tested, and the moisture content is shown in Table 1.

[0092] Example 11

[0093] 1. Formula

[0094] Material Name weight percentage Feed amount (g) Mannitol pellet core (0.8-1.0mm) 91.79 917.9. folic acid 0.21 2.1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0095] The procedure was the same as in Example 1, except that the mannitol core was replaced with a sucrose core. Folic acid pellets were then produced. The folic acid pellet content and uniformity were tested, and the moisture content is shown in Table 1.

[0096] Example 12

[0097] 1. Formula

[0098] Material Name weight percentage Feed amount (g) Mannitol pellet core (1.1-1.4mm) 96.7 967 folic acid 0.3 3 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0099] The procedure was the same as in Example 1, except that the mannitol core was replaced with the sucrose core. The folic acid content and uniformity of the pellets were measured, and the moisture content is shown in Table 1.

[0100] Example 13

[0101] 1. Formula

[0102] Material Name weight percentage Feed amount (g) Silica pellets (0.4-0.7mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0103] The procedure was the same as in Example 1, except that the silica core was replaced with a sucrose core. The folic acid content and uniformity of the pellets were measured; moisture content is shown in Table 1.

[0104] Example 14

[0105] 1. Formula

[0106] Material Name weight percentage Feed amount (g) Silica core pellets (0.8-1.2mm) 91.79 917.9. folic acid 0.21 2.1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0107] The procedure was the same as in Example 1, except that the silica core was replaced with a sucrose core. The folic acid content and uniformity of the pellets were measured; moisture content is shown in Table 1.

[0108] Example 15

[0109] 1. Formula

[0110] Material Name weight percentage Feed amount (g) Silica core pellets (1.2-1.5mm) 96.7 967 folic acid 0.3 3 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0111] The procedure was the same as in Example 1, except that the silica core was replaced with a sucrose core. The folic acid content and uniformity of the pellets were measured; moisture content is shown in Table 1.

[0112] Example 16

[0113] 1. Formula

[0114] Material Name weight percentage Feed amount (g) Sugar pulverized to 80 mesh 59 590 Folic acid powder (80 mesh) 1 10 Pregelatinized starch 35 350 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0115] II. Operation

[0116] 1. Weigh out equal amounts of sucrose and folic acid (finely ground), mix them three times in stages, then add the remaining sucrose and pregelatinized starch and mix (mixed powder).

[0117] 2. Add purified water to the aqueous solutions of polyvinylpyrrolidone and hydroxypropyl methylcellulose separately and stir until completely dissolved, then mix them together (mix the binder).

[0118] 3. Start the centrifugal granulator main unit, turn on the blower, and control the air volume at 5-10 Hz and the air pressure at 0.1-0.6 MPa. Add 1 / 4 of the mixture, and the peristaltic pump will atomize the mixed binder aqueous solution onto the surface of the mixed powder through a spray gun. Control the spraying speed at 60-220 r / min. After the powder is moistened and granules are formed, add another 1 / 4 of the mixed powder and turn off the spraying system. Discharge the material and sieve to obtain 0.2-0.4 mm masterbatch. Feed the masterbatch into the centrifugal granulator, and the peristaltic pump will atomize the mixed binder aqueous solution onto the surface of the masterbatch through a spray gun. Add the remaining mixed powder. The temperature is 40-45℃. After adding the mixed powder, turn off the spraying system. Control the air volume of the centrifugal granulator blower at 20-60 Hz and discharge the material.

[0119] 4. Drying: The folic acid pellets are dried for 2 hours at a fluidized bed temperature of 40-45℃ until the moisture content is qualified, and then sieved.

[0120] The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0121] Folic acid is micronized, passed through an 80-mesh sieve, mixed with sucrose and pregelatinized starch, and then made into folic acid pellets using a polyvinylpyrrolidone K-30 aqueous solution. The process results in significant losses, as the centrifugal granulator blows away the folic acid from the mixed powder during the preparation process, leading to poor uniformity of folic acid content in the pellets and substandard content.

[0122] Example 17

[0123] 1. Formula

[0124] Material Name weight percentage Feed amount (g) Sugar pulverized to 80 mesh 49 490 Folic acid powder (80 mesh) 1 10 starch 40 400 Polyvinylpyrrolidone 5 50 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0125] 1. Weigh out sucrose and folic acid (finely ground), mix them in equal batches three times, then add the remaining sucrose, starch, and polyvinylpyrrolidone and mix (mixed powder).

[0126] 2. Add purified water to the aqueous solutions of polyvinylpyrrolidone and hydroxypropyl methylcellulose separately and stir until completely dissolved, then mix them together (mix the binder).

[0127] 3. Start the centrifugal granulator main unit, turn on the blower, and control the air volume at 5-10 Hz and the air pressure at 0.1-0.6 MPa. Add 1 / 4 of the mixture, and use the peristaltic pump to atomize the mixed binder aqueous solution onto the surface of the mixed powder through a spray gun. Control the spraying speed at 60-220 r / min. Once the powder is wetted and granules form, add another 1 / 4 of the mixed powder and turn off the spraying system. Discharge and sieve to obtain 0.2-0.4 mm masterbatch. Feed the masterbatch into the centrifugal granulator, and use the peristaltic pump to atomize the 5% hydroxypropyl methylcellulose aqueous solution onto the surface of the masterbatch through a spray gun. Add the remaining mixed powder. The temperature is 40-45℃. After adding the mixed powder, turn off the spraying system. Control the centrifugal granulator blower air volume at 20-60 Hz and discharge.

[0128] 4. Fluidized bed temperature 40-45℃, dry for 1 hour until the moisture content is qualified, then sieve.

[0129] Folic acid was micronized and passed through an 80-mesh sieve. Sucrose, starch, and polyvinylpyrrolidone were used as fillers, and 5% hydroxypropyl methylcellulose aqueous solution was used as a binder to make folic acid pellets. However, the uniformity of the content was not up to standard, and the folic acid content was too low.

[0130] The folic acid content and uniformity were tested, and the moisture content is shown in Table 1.

[0131] Example 18

[0132] 1. Formula

[0133] Material Name weight percentage Feed amount (g) Sugar pulverized to 80 mesh 35 350 Folic acid powder 100 mesh 1 10 microcrystalline cellulose 59 590 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0134] The operation was the same as in Example 16. The folic acid content, uniformity, and moisture content are shown in Table 1.

[0135] Folic acid is crushed, passed through a 100-mesh sieve, and mixed with sucrose, microcrystalline cellulose filler, and binder to make folic acid pellets. However, the uniformity of the folic acid content is not up to standard, and the folic acid content is too low.

[0136] The folic acid content and uniformity were tested, and the moisture content is shown in Table 1.

[0137] Example 19

[0138] 1. Formula

[0139] Material Name weight percentage Feed amount (g) Sugar pellet core (0.3-0.6mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% sucrose aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0140] The procedure was the same as in Example 1, with the binder being a 2% hydroxypropyl methylcellulose aqueous solution and a 1% sucrose aqueous solution. Due to the poor solubility of folic acid, the resulting folic acid pellets had substandard content uniformity and low folic acid content.

[0141] The folic acid content and uniformity of the pellets were tested, and the moisture content is shown in Table 1.

[0142] Example 20

[0143] 1. Formula

[0144] Material Name weight percentage Feed amount (g) Sugar pellet core (0.3-0.6mm) 96.9 969.0 folic acid 0.1 1 2% sucrose aqueous solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0145] The procedure was the same as in Example 1, using a 1% polyvinylpyrrolidone aqueous solution and a 2% sucrose aqueous solution as the binder. Due to the poor solubility of folic acid, the resulting folic acid pellets had substandard content uniformity and low folic acid content. The content and uniformity of the folic acid pellets were tested, and the moisture content is shown in Table 1.

[0146] Example 21

[0147] 1. Formula

[0148] Material Name weight percentage Feed amount (g) Sugar pellet core (0.3-0.6mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% gelatin aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0149] The procedure was the same as in Example 1, using a 1% gelatin aqueous solution and a 2% hydroxypropyl methylcellulose aqueous solution as the binder. Due to the poor solubility of folic acid, the resulting folic acid pellets had substandard content uniformity and low folic acid content. The content and uniformity of the folic acid pellets were tested, and the moisture content is shown in Table 1.

[0150] Example 22

[0151] 1. Formula

[0152] Material Name weight percentage Feed amount (g) Sugar pellet core (0.3-0.6mm) 96.9 969.0 folic acid 0.1 1 2% sucrose aqueous solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0153] The procedure was the same as in Example 1, using a 1% polyvinylpyrrolidone aqueous solution and a 2% sucrose aqueous solution as the binder. Due to the poor solubility of folic acid, the resulting folic acid pellets had substandard content uniformity and low folic acid content. The content and uniformity of the folic acid pellets were tested, and the moisture content is shown in Table 1.

[0154] Example 23

[0155] 1. Formula

[0156] Material Name weight percentage Feed amount (g) Sugar pellet core (0.3-0.6mm) 96.9 969.0 folic acid 0.1 1 2% polyethylene glycol aqueous solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyvinylpyrrolidone K-30 aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0157] The procedure was the same as in Example 1, using a 1% polyvinylpyrrolidone aqueous solution and a 2% polyethylene glycol aqueous solution as the binder. Due to the poor solubility of folic acid, the resulting folic acid pellets had substandard content uniformity and low folic acid content. The content and uniformity of the folic acid pellets were tested, and the moisture content is shown in Table 1.

[0158] Example 24

[0159] 1. Formula

[0160] Material Name weight percentage Feed amount (g) Sugar pellet core (0.3-0.6mm) 96.9 969.0 folic acid 0.1 1 2% Hydroxypropyl Methylcellulose Aqueous Solution Add 2 grams to purified water to make 100 grams 20 Excluding solvents 1% polyethylene glycol aqueous solution Add 1 gram to purified water to make 100 grams 10 Excluding solvents

[0161] The procedure was the same as in Example 1, but the binder was a 1% polyethylene glycol aqueous solution and a 2% hydroxypropyl methylcellulose aqueous solution. Due to the poor solubility of folic acid, the resulting folic acid pellets had substandard content uniformity and low folic acid content. The content and uniformity of the folic acid pellets were tested, and the moisture content is shown in Table 1.

[0162] Table 1. Results of folic acid pellet uniformity and content detection;

[0163] Serial Number Average content RSD Moisture <3.5% determination Example 1 0.11 0.81％ 2.88 qualified Example 2 0.21 0.44％ 2.16 qualified Example 3 0.30 0.06％ 3.15 qualified Example 4 0.10 0.05％ 2.56 qualified Example 5 0.20 0.12％ 2.15 qualified Example 6 0.30 0.11％ 2.35 qualified Example 7 0.11 0.56％ 2.10 qualified Example 8 0.21 0.89％ 2.56 qualified Example 9 0.30 0.87％ 2.05 qualified Example 10 0.10 0.67％ 2.36 qualified Example 11 0.20 0.21％ 2.55 qualified Example 12 0.30 0.35％ 2.52 qualified Example 13 0.10 0.39％ 2.16 qualified Example 14 0.20 0.77％ 2.98 qualified Example 15 0.30 0.92％ 2.74 qualified Example 16 0.08 62.51％ 2.98 Unqualified Example 17 0.06 58.72％ 2.56 Unqualified Example 18 0.06 25.70％ 2.15 Unqualified Example 19 0.08 25.70％ 2.35 Unqualified Example 20 0.06 33.48％ 2.10 Unqualified Example 21 0.06 60.57％ 2.56 Unqualified Example 22 0.08 55.36％ 2.05 Unqualified Example 23 0.06 42.18％ 2.36 Unqualified Example 24 0.06 33.42％ 2.55 Unqualified

[0164] Examples 1-15 show that sucrose pellets, starch pellets, microcrystalline cellulose pellets, mannitol pellets, and silica pellets were processed in a centrifugal granulator. A peristaltic pump then transported the binder to a spray gun for atomization to produce folic acid pellets. Tests showed that the content was uniform and met the standards.

[0165] Examples 19-24: Different types of adhesives; 2% hydroxypropyl methylcellulose aqueous solution, 1% sucrose aqueous solution, 1% hydroxypropyl methylcellulose aqueous solution, 2% sucrose aqueous solution; 1% gelatin aqueous solution, 2% hydroxypropyl methylcellulose aqueous solution, 2% gelatin aqueous solution, 1% hydroxypropyl methylcellulose aqueous solution; 1% polyvinylpyrrolidone aqueous solution, 2% polyethylene glycol aqueous solution, 2% polyvinylpyrrolidone aqueous solution, 1% polyethylene glycol aqueous solution; When made into folic acid pellets, the content is uneven, resulting in low folic acid content and failure to meet standards.

Claims

1. A method for preparing folic acid pills, characterized in that... The folic acid pills are made from the following components in parts by weight: 70-98 parts by weight of pharmaceutical microcapsule core, 0.1-10 parts by weight of folic acid, 0.1-6 parts by weight of hydroxypropyl methylcellulose, and 0.1-5 parts by weight of polyvinylpyrrolidone; The method includes the following steps: The formulation amounts of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and folic acid are uniformly mixed in water to obtain a mixed solution. The formulation amounts of pharmaceutical microcapsule cores are fed into a centrifugal granulator. The mixed solution is atomized by a peristaltic pump through a spray gun and adsorbed onto the surface of the sugar capsules to obtain the folic acid pellets.

2. The method for preparing folic acid pellets as described in claim 1, characterized in that: The polyvinylpyrrolidone is polyvinylpyrrolidone K-30 or polyvinylpyrrolidone K-90.

3. The method for preparing folic acid pellets as described in claim 1, characterized in that: The folic acid pills are made from the following components in parts by weight: 71-97 parts by weight of pharmaceutical microcapsule core, 0.1-7 parts by weight of folic acid, 0.1-4 parts by weight of hydroxypropyl methylcellulose, and 0.1-3 parts by weight of polyvinylpyrrolidone.

4. The method for preparing folic acid pellets as described in claim 3, characterized in that: The folic acid pills are made from the following components in parts by weight: 71-97 parts by weight of pharmaceutical microcapsule core, 0.1-7 parts by weight of folic acid, 2 parts by weight of hydroxypropyl methylcellulose, and 1 part by weight of polyvinylpyrrolidone.

5. The method for preparing folic acid pellets as described in claim 1, characterized in that: The particle size of the pharmaceutical micro-pellets is 0.3-1.5 mm.

6. The method for preparing folic acid pellets as described in claim 1, characterized in that: The pharmaceutical microcapsule core is one or more of the following: sucrose core, starch core, microcrystalline cellulose core, mannitol core, and silica core.

7. The method for preparing folic acid pellets as described in claim 1, characterized in that: The mixed solution is uniformly mixed as follows: the formulation amount of hydroxypropyl methylcellulose is dissolved in purified water A to obtain an aqueous solution of hydroxypropyl methylcellulose; the formulation amount of polyvinylpyrrolidone is dissolved in purified water B to obtain an aqueous solution of polyvinylpyrrolidone; the aqueous solution of hydroxypropyl methylcellulose, the aqueous solution of polyvinylpyrrolidone, and the formulation amount of folic acid are mixed to obtain the mixed solution.

8. The method for preparing folic acid pellets as described in claim 7, characterized in that: The aqueous solution of hydroxypropyl methylcellulose has a mass concentration of 2%; the aqueous solution of polyvinylpyrrolidone has a mass concentration of 1%.

9. The method for preparing folic acid pellets as described in claim 1, characterized in that: The airflow of the centrifugal granulator is controlled at 5-10Hz, and the air pressure is controlled at 0.1-0.6MPa.

10. The method for preparing folic acid pellets as described in claim 1, characterized in that: The spraying speed of the spray gun is controlled at 60-220 r / min, and the temperature is 40℃-45℃.

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