A method for preparing ferrous fumarate granules with uniform particle size

Abstract

The present invention relates to the field of health food processing, and in particular to a method for preparing ferrous fumarate granules with uniform particle size, comprising the following steps: A, stirring and mixing ferrous fumarate, filler A, and flavoring agent in a wet granulator at a low speed, then adding part of a wetting agent, stirring and shearing at a low speed, and obtaining a soft material A; B, adding a filler B to the soft material A, stirring and shearing at a low speed, and obtaining a soft material B; C, adding the remaining wetting agent to the soft material B three times, stirring and shearing granulation at a low speed after each addition, and obtaining wet granules; D, drying the wet granules to obtain a ferrous fumarate granule product; the filler A comprises one or more of sucrose, sorbitol, and starch; and the filler B comprises one or more of dextrin and microcrystalline cellulose. The present invention solves the problems of more fine powder and poor formability of ferrous fumarate granules.

Description

Technical Field

[0001] The invention relates to the field of health food processing, and in particular to a method for preparing ferrous fumarate granules with uniform particle size. Background Art

[0002] Ferrous fumarate is a commonly used iron supplement, which is widely used to treat iron deficiency anemia and other related diseases. Iron deficiency anemia is one of the most common diseases in the world, characterized by low hemoglobin content and abnormal red blood cell morphology. Ferrous fumarate replenishes the body's iron reserves by providing iron, promoting the production and repair of red blood cells, thereby improving anemia symptoms and improving the quality of life of patients.

[0003] Granules are a kind of granular preparations made by combining drugs with appropriate excipients. They can generally be divided into soluble granules, suspension granules and effervescent granules. If the particle size is in the range of 105 to 500 microns, it can be called fine granules. Its main features are easy oral administration, adjustable dosage, rapid absorption, etc. Therefore, granules are widely used in the field of pharmaceutical preparations, especially for situations with special requirements for the release and absorption of drugs in the gastrointestinal tract.

[0004] However, in the process of preparing ferrous fumarate granules, some technical problems are often encountered. One of them is that the particle size does not meet the requirements, and there is usually a problem of more fine powder. This may lead to reduced uniformity and stability of the particles, which in turn affects the solubility and bioavailability of the drug. In addition, there is also the problem of poor formability when preparing ferrous fumarate granules. The formability of particles is very important for preparing high-quality granules. Poor formability may make it difficult for the granules to form a uniform particle structure during the preparation process, increasing the difficulty and inconsistency of the preparation. Summary of the invention

[0005] The object of the present invention is to provide an improved method for preparing ferrous fumarate particles, aiming to solve the problems of more fine powder and poor formability. The present invention can improve the physical properties and molding quality of granules by changing the order of adding fillers and changing the type of wetting agent, and achieve better particle size distribution and stability. This will help to improve the preparation efficiency and quality of ferrous fumarate granules, thereby better meeting the needs of the pharmaceutical industry.

[0006] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0007] A method for preparing ferrous fumarate granules with uniform particle size comprises the following steps:

[0008] A. Mix ferrous fumarate, filler A and flavoring agent in a wet granulator at a low speed, then add part of the wetting agent, stir and shear at a low speed to obtain soft material A;

[0009] B. Add filler B to the soft material A, stir and shear at a low speed to obtain soft material B;

[0010] C. Add the remaining wetting agent to the soft material B three times, stirring and shearing granulation at a low speed after each addition to obtain wet granules;

[0011] D. Drying the wet granules to obtain ferrous fumarate granules product;

[0012] The filler A includes one or more of sucrose, sorbitol, and starch; the filler B includes one or more of dextrin and microcrystalline cellulose.

[0013] Preferably, the wetting agent includes one or more of purified water and ethanol.

[0014] Preferably, the wetting agent includes purified water or 10% to 40% ethanol solution.

[0015] Preferably, the wetting agent includes purified water or 10% ethanol solution.

[0016] Preferably, in step A, the low-speed stirring and mixing includes stirring at 500 rpm for 1 to 3 minutes, and the low-speed stirring and shearing includes stirring and shearing at 1500 rpm for 5 to 10 minutes; in step B, the low-speed stirring and shearing includes stirring and shearing at 1500 rpm for 5 to 10 minutes; in step C, the low-speed stirring and shearing granulation includes stirring and shearing at 1500 rpm for 5 to 10 minutes; in step D, the drying temperature includes 60 to 65°C, and the moisture content of the particles is controlled within 5.0%.

[0017] The first stirring step of step A is mainly to mix the materials evenly, and the time can be adjusted according to the actual amount of material added.

[0018] Preferably, in step C, each time granulation is performed until the soft material can be lightly grasped into a ball and falls apart when touched.

[0019] Preferably, in step C, the wet granules are sieved through a 14-mesh sieve; and in step D, the ferrous fumarate granule product is sieved through a 10-mesh sieve.

[0020] In step C, the granulator is stirred at a low speed and a proper amount of wetting agent is added; after each addition, the mixture is stirred and sheared at a low speed and granulated until the soft material can be lightly grasped into a ball and falls apart when touched. The mixture is sieved through a 14-mesh sieve in an oscillating granulator to measure the moisture content of the wet granules.

[0021] In step D, after obtaining the dry granules, the granules are sieved with a 10-mesh sieve, the moisture content and particle size of the dry granules are measured, and the yield and other indicators are calculated.

[0022] Preferably, the mass ratio of the ferrous fumarate, the filler A, the filler B, the wetting agent, and the flavoring agent includes 1::20-23:8-14:3-5:0.1-0.2; the flavoring agent includes one or more of strawberry flavor, sweet orange flavor, and stevioside.

[0023] Preferably, in step A, the mass of the wetting agent added accounts for 45% to 65% of the total amount of the wetting agent.

[0024] In step A, 45% to 65% of the total amount of wetting agent is first added, which is about 9% to 10% of the total weight of the particles. The soft material A obtained by this ratio is relatively moderate, and the soft material A is not too dry and loose or too wet and has a high viscosity. After that, the remaining wetting agent is distributed and added to the granulation to form a uniform and compact particle structure.

[0025] A ferrous fumarate granule product obtained by the preparation method of ferrous fumarate granules with uniform particle size as described above.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. Reduce the generation of fine powder: The method and technology of the present invention improves the problem of more fine powder in the preparation process of ferrous fumarate granules. The present invention can effectively reduce the generation rate of fine powder by changing the order of adding fillers and changing the type of wetting agent, and optimizing the process conditions. This will improve the uniformity and stability of the granules, and increase the solubility and bioavailability of the drug.

[0028] 2. Improve the forming properties of the particles: The present invention also provides a solution to the problem of poor forming properties in the preparation process of granules. By optimizing the formula and ratio of fillers and wetting agents and adopting appropriate process steps, the forming properties of the particles can be improved. This will help to form a uniform and compact particle structure and improve the consistency and controllability of the preparation process.

[0029] 3. Improve the quality and stability of granules: Through the technical improvements of the present invention, the physical properties and chemical stability of granules will be improved. The particle size distribution of the granules will be more uniform, and the drug ingredients will be better encapsulated in the granules, thereby improving the solubility and bioavailability of the drug, and enhancing the efficacy and treatment effect of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a comparison diagram of samples obtained from the embodiment and the comparative example. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the accompanying drawings so that those skilled in the art can better understand the present invention and implement it, but the examples given are not intended to limit the present invention. Without departing from the spirit and essence of the present invention, modifications or replacements made to the method, steps or conditions of the present invention all belong to the scope of the present invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0032] Example 1

[0033] A ferrous fumarate granule is prepared by the following method:

[0034] 1) Mix 45 g of ferrous fumarate, 1000 g of sucrose and 5 g of strawberry essence in a wet granulator at 500 rpm for 3 min, then add 100 g of 10% ethanol solution, stir and shear at 1500 rpm for 5 min, and check the soft material state;

[0035] 2) Add 450 g of dextrin to the soft material, stir and shear at a low speed of 1500 rpm for 5 minutes, then add an appropriate amount of 10% ethanol solution three times, stir and shear at a low speed of 1500 rpm for 5 minutes after each addition, granulate until the soft material can be lightly grasped and falls apart when touched, sieve through a 14-mesh oscillating granulator, and measure the moisture content of the wet granules;

[0036] 3) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0037] 4) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0038] Example 2

[0039] A ferrous fumarate granule is prepared by the following method:

[0040] 1) Mix 45 g of ferrous fumarate, 1000 g of sucrose and 5 g of strawberry essence in a wet granulator at 500 rpm for 3 min, then add 100 g of purified water, stir and shear at 1500 rpm for 5 min, and check the soft material state;

[0041] 2) Add 450 g of dextrin to the soft material, stir and shear at a low speed of 1500 rpm for 5 minutes, then add an appropriate amount of purified water three times, stir and shear at a low speed of 1500 rpm for 5 minutes after each addition, granulate until the soft material can be lightly grasped and falls apart when touched, sieve through a 14-mesh oscillating granulator, and measure the moisture content of the wet granules;

[0042] 3) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0043] 4) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0044] Example 3

[0045] A ferrous fumarate granule is prepared by the following method:

[0046] 1) Mix 45 g of ferrous fumarate, 950 g of sorbitol, and 5 g of strawberry flavor in a wet granulator at 500 rpm for 3 min, then add 100 g of purified water, stir and shear at 1500 rpm for 5 min, and check the soft material state;

[0047] 2) Add 500 g of microcrystalline cellulose to the soft material, stir and shear at a low speed of 1500 rpm for 5 minutes, then add an appropriate amount of purified water three times, stir and shear at a low speed of 1500 rpm for 5 minutes after each addition, granulate until the soft material can be lightly grasped and falls apart when touched, sieve through a 14-mesh oscillating granulator, and measure the moisture content of the wet granules;

[0048] 3) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0049] 4) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0050] Comparative Example 1

[0051] A ferrous fumarate granule is prepared by the following method:

[0052] 1) Mix 45 g of ferrous fumarate, 450 g of dextrin, and 5 g of strawberry essence in a wet granulator at 500 rpm for 3 min, then add 90 g of 10% ethanol solution, stir and shear at 1500 rpm for 5 min, and check the soft material state;

[0053] 2) Add 1000 g of sucrose to the soft material, stir and shear at a low speed of 1500 rpm for 5 minutes, then add an appropriate amount of 10% ethanol solution three times, stir and shear at a low speed of 1500 rpm for 5 minutes after each addition, granulate until the soft material can be lightly grasped and falls apart when touched, sieve through a 14-mesh oscillating granulator, and measure the moisture content of the wet granules;

[0054] 3) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0055] 4) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0056] Comparative Example 2

[0057] A ferrous fumarate granule is prepared by the following method:

[0058] 1) Mix 45 g of ferrous fumarate, 1000 g of sucrose and 5 g of strawberry essence in a wet granulator at 500 rpm for 3 min, then add 100 g of 20% ethanol solution, stir and shear at 1500 rpm for 5 min, and check the soft material state;

[0059] 2) Add 450 g of dextrin to the soft material, stir and shear at a low speed of 1500 rpm for 5 minutes, then add an appropriate amount of 20% ethanol solution three times, stir and shear at a low speed of 1500 rpm for 5 minutes after each addition, granulate until the soft material can be lightly grasped and falls apart when touched, sieve through a 14-mesh oscillating granulator, and measure the moisture content of the wet granules;

[0060] 3) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0061] 4) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0062] Comparative Example 3

[0063] A ferrous fumarate granule is prepared by the following method:

[0064] 1) Mix 45 g of ferrous fumarate, 1000 g of sucrose and 5 g of strawberry essence in a wet granulator at 500 rpm for 3 min, then add 100 g of 30% ethanol solution, stir and shear at 1500 rpm for 5 min, and check the soft material state;

[0065] 2) Add 450 g of dextrin to the soft material, stir and shear at a low speed of 1500 rpm for 5 minutes, then add an appropriate amount of 30% ethanol solution three times, stir and shear at a low speed of 1500 rpm for 5 minutes after each addition, granulate until the soft material can be lightly grasped and falls apart when touched, sieve through a 14-mesh oscillating granulator, and measure the moisture content of the wet granules;

[0066] 3) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0067] 4) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0068] Comparative Example 4

[0069] A ferrous fumarate granule is prepared by the following method:

[0070] 1) 45 g of ferrous fumarate, 1000 g of sucrose, and 5 g of strawberry essence were mixed in a wet granulator at 500 rpm for 3 min, and then 100 g of 40% ethanol solution was added, and the mixture was stirred and sheared at 1500 rpm for 5 min, and the soft material state was checked;

[0071] 2) Add 450 g of dextrin to the soft material, stir and shear at a low speed of 1500 rpm for 5 minutes, then add an appropriate amount of 40% ethanol solution three times, stir and shear at a low speed of 1500 rpm for 5 minutes after each addition, granulate until the soft material can be lightly grasped and falls apart when touched, sieve through a 14-mesh oscillating granulator, and measure the moisture content of the wet granules;

[0072] 3) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0073] 4) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0074] Comparative Example 5

[0075] A ferrous fumarate granule is prepared by the following method:

[0076] 1) 45 g of ferrous fumarate, 1000 g of sucrose, 450 g of dextrin, and 5 g of strawberry essence were mixed in a wet granulator at a low speed of 500 rpm for 5 min, 172.50 g of a wetting agent (10% ethanol solution) equal to that in Example 1 was added, and the mixture was stirred and sheared at a low speed of 1500 rpm for 5 min, then the machine was stopped and the soft material was manually stirred. The same operation was repeated 4 times, and finally the soft material was sieved through a 14-mesh sieve of a swing granulator, and the moisture content of the wet granules was measured;

[0077] 2) Drying the wet granules at a drying temperature of 65° C. to control the granule moisture content to less than 5.0%;

[0078] 3) First, take 100g of dry granules to check the particle size of the granules (Pharmacopoeia General Chapter 0982 Method 2 Double Sieving Method). Then, sieve the granules with a 10-mesh sieve, check the particle size distribution of 100g of granules (Pharmacopoeia General Chapter 0982 Method 2 Mechanical Sieving Method), determine the moisture content of the dry granules, and calculate the yield and other indicators.

[0079] Effect Example 1

[0080] Summary of experimental results:

[0081] Table 1

[0082]

[0083] *According to the 2020 edition of the Chinese Pharmacopoeia, granules must be inspected according to the particle size and particle size distribution determination method (General Rule 0982 Method 2 Double Screening Method), and the sum of particles that cannot pass through the No. 1 sieve (2mm) and can pass through the No. 5 sieve (180μm) shall not exceed 15%.

[0084] Table 2

[0085] Batch number retention rate No. 2 sieve (24 mesh) No. 4 sieve (65 mesh) No. 5 sieve (80 mesh) No. 6 sieve (100 mesh) Example 1 9.68 87.78 1.89 0.65 Example 2 10.25 85.83 2.25 1.67 Example 3 10.57 85.11 2.28 2.04 Comparative Example 1 11.05 76.40 7.31 5.24 Comparative Example 2 13.58 77.33 5.85 3.24 Comparative Example 3 14.05 75.96 5.52 4.47 Comparative Example 4 14.27 75.74 5.38 5.09 Comparative Example 5 21.48 68.05 4.97 4.28

[0086] *Powder grades are as follows:

[0087] Powder Grade Screen number that can pass all Supplementary Provisions Coarsest powder Sieve No. 1 Mixed with powder that can pass through the No. 3 sieve not more than 20% meal Sieve No.2 Mixed with powder that can pass through the No. 4 sieve not more than 40% Medium powder No. 4 sieve Mixed with powder that can pass through the No. 5 sieve not more than 60% powder No. 5 sieve Containing not less than 95% of the powder passing through No. 6 sieve The finest powder No. 6 sieve and containing not less than 95% of powder passing through No. 7 sieve; Ultrafine powder No. 8 sieve Containing not less than 95% of the powder passing through No. 9 sieve

[0088] As shown in Table 1, Table 2 and Figure 1 As shown, by comparing the particle size and particle size distribution of the granules of Example 1 and Comparative Example 1, it is found that the powder rate of the granules of Example 1 is high and the fine powder rate and the finest powder rate are low. It can be seen that the order of adding fillers can affect the particle size of the granules. Combined with the particle size and particle size distribution of the granules of Examples 1 to 3, it is not difficult to find that the method used in the preparation of granules of the present invention is to pre-granulate the material with sugars or sugar alcohols that are easily induced to be sticky by the wetting agent, and then add other fillers to granulate again. This method can effectively reduce the generation of fine powder in the granules and improve the uniformity of the granules.

[0089] As shown in Table 1, Table 2 and Figure 1 As shown, by comparing the particle size and particle size distribution of the granules of Example 1 and Comparative Example 2, Comparative Example 3, and Comparative Example 4, when the order of adding the fillers is the same, the higher the concentration of the added ethanol, the more fine powder the prepared granules produce, which may be related to the decrease in viscosity after wetting as the concentration of ethanol increases. Combined with the particle size and particle size distribution of the granules of Example 1 and Example 2, it is found that the granulation effect of 10% ethanol solution is better than that of purified water, so the optimal wetting agent of the present invention is 10% ethanol solution.

[0090] As shown in Table 1, Table 2 and Figure 1 As shown, by comparing the particle size and particle size distribution of the particles of Example 1 and Comparative Example 5, the particles of Comparative Example 5 have a low medium powder rate and a high fine powder rate and the finest powder rate. Similarly, the yield of the particles is much lower than that of Example 1, indicating that the filler is added all at once, and then the wetting agent is slowly added all at once. During the granulation process, the filler and the wetting agent cannot be mixed evenly, and the soft material is partially dry (producing more fine powder) or wet (the soft material is bonded to cause more coarse particles, and the loss is large during the granulation and granulation process), and it is impossible to obtain granules with uniform particle size. The appearance of each group of samples is as follows Figure 1 As shown, the particles of the samples in the embodiment group are obviously coarser than those in the control group, and there are more small particles visible to the naked eye in the samples in the control group, indicating that the method provided by the present invention of pre-granulating the material with sugars or sugar alcohols that are easily induced to be sticky by a wetting agent and then adding other fillers for secondary granulation is feasible, which can significantly increase the particle size of the granules and reduce the generation of fine powder.

[0091] The above disclosure is only the preferred embodiment of the present invention, which cannot be used to limit the scope of the present invention. Therefore, equivalent changes made according to the claims of the present invention are still within the scope of the present invention.

Claims

1. A method for preparing ferrous fumarate granules with uniform particle size, characterized in that: The steps include: A. Mix ferrous fumarate, filler A and flavoring agent in a wet granulator at a low speed, then add part of the wetting agent, stir and shear at a low speed to obtain soft material A; B. Add filler B to the soft material A, stir and shear at a low speed to obtain soft material B; C. Add the remaining wetting agent to the soft material B three times, stirring and shearing granulation at a low speed after each addition to obtain wet granules; D. Drying the wet granules to obtain ferrous fumarate granules product; The filler A is one or both of sucrose and sorbitol; the filler B is one or both of dextrin and microcrystalline cellulose; and the wetting agent is purified water or 10% ethanol solution.

2. The method for preparing ferrous fumarate granules with uniform particle size as claimed in claim 1, characterized in that: In step A, the low-speed stirring and mixing is stirring at 500 rpm for 1 to 3 minutes, and the low-speed stirring and shearing is stirring and shearing at 1500 rpm for 5 to 10 minutes; in step B, the low-speed stirring and shearing is stirring and shearing at 1500 rpm for 5 to 10 minutes; in step C, the low-speed stirring and shearing granulation is stirring and shearing at 1500 rpm for 5 to 10 minutes; in step D, the drying temperature is 60 to 65° C., and the moisture content of the particles is controlled within 5.0%.

3. The method for preparing the ferrous fumarate granules with uniform particle size as claimed in claim 1, characterized in that: The mass ratio of the ferrous fumarate, the filler A, the filler B, the wetting agent, and the flavoring agent is 1:20-23:8-14:3-5:0.1-0.2; the flavoring agent includes one or more of strawberry flavor, sweet orange flavor, and stevioside.

4. The method for preparing the ferrous fumarate granules with uniform particle size as claimed in claim 1, characterized in that: In step A, the mass of the partial wetting agent added accounts for 45% to 65% of the total amount of the wetting agent.

5. A ferrous fumarate granule product obtained by the method for preparing ferrous fumarate granules with uniform particle size as claimed in claim 1.

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