A method of preparing a glucosamine sulfate capsule

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a preparation method of glucosamine sulfate capsules, which comprises the following steps: weighing glucosamine sulfate sodium chloride complex salt, lactose, corn starch, talc and magnesium stearate according to prescription amount; adopting a long premixing and short total mixing strategy to mix materials, first mixing the glucosamine sulfate sodium chloride complex salt, lactose, corn starch and talc to obtain premixed powder through sieving treatment, and the premixing time is t1; then mixing part of the premixed powder with the magnesium stearate to obtain a lubricant premix, and adding the lubricant premix into the remaining premixed powder to perform third mixing, and the total mixing time is t2, and t1>t2; filling the obtained total mixed particles into a hollow capsule shell, and finally performing packaging. The long premixing ensures that the basic materials are uniform, the lubricant pre-dispersion and short total mixing avoid excessive wrapping of the magnesium stearate, the content uniformity is significantly improved, the loading amount difference is effectively controlled, and high dissolution rate and low related substances are ensured.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing glucosamine sulfate capsules. Background Technology

[0002] Glucosamine sulfate is an essential component for the synthesis of proteoglycans in the human articular cartilage matrix. It is necessary for chondrocytes to synthesize proteoglycans, hyaluronic acid, and the articular cartilage matrix. Exogenous supplementation with glucosamine sulfate can stimulate chondrocytes to produce proteoglycans with normal polymeric structures and inhibit the activity of enzymes that damage articular cartilage (such as collagenase and phospholipase A2), thereby delaying the pathological process and progression of osteoarthritis. Glucosamine sulfate also has direct anti-inflammatory effects. Therefore, glucosamine sulfate is widely used for the prevention and treatment of various types of osteoarthritis and is a first-line drug for the clinical treatment of osteoarthritis.

[0003] Glucosamine sulfate is extremely unstable, highly hygroscopic, and prone to degradation under humid and hot conditions, generating inactive byproducts. This characteristic poses a significant challenge to its formulation production. Commercially available glucosamine sulfate products are mostly double salts formed with sodium chloride (glucosamine sulfate sodium chloride double salt). This form is relatively stable and has reduced hygroscopicity, but still requires high temperature and humidity control in the formulation process.

[0004] Currently, the common preparation method for glucosamine sulfate capsules is the direct powder filling process. This process eliminates granulation and drying steps, offering advantages such as simplicity, ease of operation, short production cycle, and low energy consumption. However, this process still faces the following prominent technical challenges in actual production.

[0005] Firstly, since glucosamine sulfate sodium chloride double salt and excipients such as lactose, corn starch, talc and magnesium stearate have significant differences in particle size, shape, density and surface properties, the conventional direct mixing method is prone to uneven mixing of materials, which in turn causes the content uniformity between capsules to not meet the pharmacopoeia requirements, affecting the uniformity of product quality and the reproducibility of clinical efficacy.

[0006] Secondly, to improve powder flowability, magnesium stearate is usually added to the formulation as a lubricant. However, magnesium stearate is a highly hydrophobic substance. When mixed with drug particles for too long, it will uniformly coat the surface of the drug particles, forming a hydrophobic film. This hydrophobic film significantly hinders water penetration, leading to slow disintegration of the capsules in vivo, reduced drug solubility, and thus affecting the bioavailability and clinical efficacy of the drug. Conversely, if the mixing time of magnesium stearate is insufficient, it will result in uneven distribution in the system, failing to effectively exert its lubricating effect, leading to poor powder flowability and large variations in fill weight.

[0007] Third, glucosamine sulfate is sensitive to moisture and heat. Prolonged mechanical mixing can generate frictional heat and mechanical shear force, which may lead to local temperature increases, thereby accelerating the degradation of active ingredients, producing related substances, and affecting the safety and effectiveness of the product. Summary of the Invention

[0008] To overcome the technical defects of existing technologies, this invention provides a method for preparing glucosamine sulfate capsules, comprising the following steps:

[0009] Step 1, Weighing the raw materials: Weigh out the following ingredients according to the prescription: glucosamine sulfate sodium chloride double salt, lactose, corn starch, talc, and magnesium stearate;

[0010] Step 2: Use a mixing strategy of long premixing and short total mixing for mixing:

[0011] Step 201: Perform long premixing of the base materials: The weighed glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc are mixed for the first time to obtain premixed powder, wherein the duration of the first mixing is t1;

[0012] Step 202: Add magnesium stearate for distribution mixing: Take a portion of the premixed powder and mix it with magnesium stearate for a second time to obtain a lubricant premix; then add the obtained lubricant premix to the remaining premixed powder for a third mixing to obtain total mixed particles, wherein the duration of the third mixing is t2, and t1>t2;

[0013] Step 3, Capsule filling: The total mixed particles are filled into the hollow capsule shells, and the capsule weight is controlled during the filling process;

[0014] Step 4, Aluminum-Plastic Packaging: Pack the filled capsules in aluminum-plastic blister packaging, add desiccant and composite film bags for packaging, and then box them.

[0015] Preferably, in step 201, before the first mixing, the method further includes a step of pre-treating the glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc by sieving.

[0016] Preferably, the sieving pretreatment involves passing each material through a 40-mesh sieve.

[0017] Preferably, the first and / or third mixing is carried out in a column-type rotating hopper mixer.

[0018] Preferably, the rotation speed of the first mixing is 5-15 rpm, and the duration of the first mixing is 20-40 minutes; the rotation speed of the third mixing is 5-15 rpm, and the duration of the third mixing is 3-8 minutes.

[0019] Preferably, the rotation speed of the first mixing is 8 rpm, and the duration of the first mixing is 25 minutes; the rotation speed of the third mixing is 8 rpm, and the duration of the third mixing is 5 minutes.

[0020] Preferably, in step 202, a portion of the premixed powder has a volume that is 2 to 5 times the volume of magnesium stearate.

[0021] Preferably, in step 2, the mixing strategy of long premixing and short total mixing is performed at a temperature of 18-26℃ and a relative humidity of 35-65%.

[0022] It is carried out in an environment.

[0023] Preferably, during the filling process, the capsule weight is checked every 30 minutes, and the filling parameters are adjusted according to the test results.

[0024] Preferably, the first mixing and / or the third mixing are performed in a three-dimensional motion mixer.

[0025] The beneficial effects of this invention are:

[0026] 1. This invention achieves highly uniform mixing of materials through an innovative long premixing and short total mixing strategy. First, a long premixing step (t1 = 20-40 minutes) ensures thorough mixing of glucosamine sulfate sodium chloride double salt with base materials such as lactose, corn starch, and talc, resulting in a macroscopically uniform premix powder, laying the foundation for the homogeneity of the base materials. Second, a lubricant pre-dispersion step involves manually mixing a portion of the premix powder with the entire prescribed amount of magnesium stearate, pre-dispersing the magnesium stearate in a small amount of premix powder to form a masterbatch. Finally, a short total mixing step (t2 = 3-8 minutes, and t1 > t2) allows the pre-dispersed magnesium stearate to rapidly and uniformly diffuse throughout the system. The synergistic effect of these three steps ensures uniform distribution of magnesium stearate in the system without localized enrichment, effectively avoiding content fluctuations caused by uneven magnesium stearate dispersion.

[0027] 2. This invention effectively avoids the formation of hydrophobic coatings on drug particles due to excessive mixing of magnesium stearate by strictly controlling the total mixing time. Magnesium stearate is a strongly hydrophobic substance; prolonged mixing will cause it to uniformly coat the surface of drug particles, forming a hydrophobic film that hinders water penetration and delays capsule disintegration and drug dissolution. This invention, through a short total mixing strategy, minimizes the contact time between magnesium stearate and drug particles while ensuring uniform dispersion, thus reducing the degree of hydrophobic coating.

[0028] 3. The glucosamine sulfate in this invention is sensitive to heat and humidity, and is prone to degradation under high temperature and high humidity conditions, generating inactive related substances that affect the safety and effectiveness of the product. This invention employs a short-time mixing process, which significantly reduces the heat accumulation and mechanical shear force generated by friction and pressure during the mixing process. Attached Figure Description

[0029] One or more embodiments are illustrated by way of example with reference numerals in the accompanying drawings. These illustrations do not constitute a limitation on the embodiments. Elements with the same reference numerals in the drawings are denoted as similar elements. Unless otherwise stated, the figures in the drawings are not to be limited by scale.

[0030] Figure 1 This is a schematic diagram of the steps of the present invention. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the various embodiments of this invention will be described in detail below with reference to the accompanying drawings. However, those skilled in the art will understand that many technical details have been provided in the various embodiments of this invention to facilitate a better understanding of this application. However, the technical solutions claimed in the claims of this application can be implemented even without these technical details and with various variations and modifications based on the following embodiments.

[0032] Example 1: This example provides a method for preparing glucosamine sulfate capsules. This example provides the most preferred embodiment of the present invention, such as... Figure 1 The specific steps shown are as follows:

[0033] Step 1: Raw Material Pretreatment and Weighing: Accurately weigh 31400g of glucosamine sulfate sodium chloride double salt, 2850g of lactose, 6000g of corn starch, 250g of talc, and 500g of magnesium stearate according to the prescription for preparing 100,000 capsules. Sift the glucosamine sulfate sodium chloride double salt, lactose, corn starch, and talc through a 40-mesh sieve (0.425mm aperture) to remove lumps caused by moisture absorption or compression, and to ensure uniform particle size, laying the foundation for subsequent homogeneous mixing. Seal and store the sieved materials in clean polyethylene bags for later use.

[0034] Step 2: Adopt a mixing strategy of long premixing and short total mixing for mixing (core step):

[0035] Step 201: Premixing the base materials (first mixing): Add the sieved glucosamine sulfate sodium chloride double salt, lactose, corn starch, and talc to the mixing hopper of the column-type rotary hopper mixer in sequence. The feeding order is to add the largest amount of glucosamine sulfate sodium chloride double salt first, followed by talc, lactose, and corn starch, to facilitate initial stratification of the materials within the mixer. Close the mixer inlet and set the mixing speed to 8 rpm. Premix under ambient temperature of 18-26℃ and relative humidity of 35-65%. The premixing time is 25 minutes. The column-type rotary hopper mixer generates strong turbulence and shearing during mixing, thereby achieving macroscopically uniform mixing in a relatively short time. Next step.

[0036] Step 202: Adding magnesium stearate for distribution and mixing: This step is the core operation that distinguishes this invention from existing technologies, and it is specifically divided into two sub-steps: Preparation of the lubricant premix (second mixing): Take a portion of the premixed powder (approximately 4 times the total volume of magnesium stearate) from the evenly mixed premixed powder and place it in a clean, sufficiently large polyethylene bag. Add the entire prescribed amount of magnesium stearate to the polyethylene bag, leaving space for mixing; fold and tie the bag opening tightly to ensure a seal. The operator holds the sealed polyethylene bag and mixes it manually using kneading, pinching, rubbing, and patting methods for approximately 2 minutes; this avoids material loss due to multiple transfers. During this process, magnesium stearate and the premixed powder achieve full contact and dispersion in a relatively static, enclosed space through external force. Short total mixing (third mixing): Open the polyethylene bag containing the lubricant premix and transfer all its contents to the remaining premixed powder in the three-dimensional motion mixer. Scrape off any powder adhering to the inner wall of the bag to ensure that all magnesium stearate is added. Close the mixer inlet and set the mixing speed to 8 rpm for final mixing. The final mixing time should be strictly controlled to 5 minutes. The purpose of this step is to allow the magnesium stearate, already dispersed in a small amount of premixed powder, to rapidly diffuse throughout the entire system through extremely short mixing times, achieving a uniform lubrication effect. Simultaneously, the extremely short mixing time effectively prevents excessive coating of the drug particles by the magnesium stearate.

[0037] Step 3, Capsule Filling: Transfer the total mixed granules obtained in Step 2 to the hopper of the fully automatic capsule filling machine via a feeding machine. Select No. 1 gelatin hollow capsule shells. Start the capsule filling machine and set the filling speed to 1600 capsules / minute. During the filling process, strictly follow the operating procedures for process control:

[0038] Weigh the capsules every 15 minutes using an electronic balance, and randomly select 20 capsules each time to calculate the average capsule weight and the difference in content.

[0039] Adjust the height of the filling metering plate or the filling pressure to ensure that the average capsule weight is controlled within ±6.5% of the labeled fill weight (0.25g (calculated as glucosamine sulfate) or 0.314g (calculated as glucosamine sulfate sodium chloride), and the fill weight difference meets the requirements of the Chinese Pharmacopoeia (±7.5%).

[0040] Regularly check the capsule locking condition and remove capsules that are not up to standard in appearance, such as those that are flat, not properly locked, or have cracks.

[0041] Step 4, Aluminum-Plastic Packaging: Place the qualified filled capsules into the vibrating hopper of the aluminum-plastic blister packaging machine. Use 0.300mm thick solid pharmaceutical sheet as the base material and 0.024mm thick pharmaceutical aluminum foil as the cover material. Set the heat sealing temperature between 150 and 170℃, and perform blister forming, aluminum-plastic packaging, aluminum foil heat sealing, and die-cutting to form aluminum-plastic blister boards with 10 capsules per board. Then, seal the aluminum-plastic boards with composite film using a pillow packaging machine, and finally pack them into boxes and label them to obtain the finished product.

[0042] This invention achieves highly uniform mixing of materials through an innovative long premixing and short total mixing strategy. First, a long premixing step (t1 = 20-40 minutes) ensures thorough mixing of glucosamine sulfate sodium chloride double salt with base materials such as lactose, corn starch, and talc, resulting in a macroscopically uniform premix powder, laying the foundation for the homogeneity of the base materials. Second, a lubricant pre-dispersion step involves manually mixing a portion of the premix powder with the entire prescribed amount of magnesium stearate, pre-dispersing the magnesium stearate in a small amount of premix powder to form a masterbatch. Finally, a short total mixing step (t2 = 3-8 minutes, and t1 > t2) allows the pre-dispersed magnesium stearate to rapidly and uniformly diffuse throughout the system. The synergistic effect of these three steps ensures uniform distribution of magnesium stearate in the system without localized enrichment, effectively avoiding content fluctuations caused by uneven magnesium stearate dispersion. Experimental data show that the content uniformity (A+2.2S value) of glucosamine sulfate capsules prepared by the method of this invention can be as low as 5.6, which is far superior to the traditional one-pot method of total mixing (12.3) and the process without pre-dispersion (10.8), and significantly lower than the limit requirement of 15.0 specified in the pharmacopoeia, ensuring the accuracy of the content of active ingredients in each capsule and the consistency of quality between batches.

[0043] The uniform material composition endows the total mixed particles with excellent powder flowability (angle of repose 42°~46°). During high-speed capsule filling, the material can be uniformly and stably filled into each hollow capsule shell, allowing for precise control of the weight of each capsule. Experimental data show that the fill weight variation of glucosamine sulfate capsules prepared using the method of this invention can be controlled within ±5%, far exceeding the pharmacopoeia's limit of ±7.5%. This smaller fill weight variation ensures accurate and stable dosage of the active ingredient ingested by patients with each dose, thereby ensuring the reproducibility of clinical efficacy and medication safety. Effective control of fill weight variation is of significant clinical importance, especially for drugs like glucosamine sulfate that require long-term use.

[0044] This invention effectively avoids the formation of hydrophobic coatings on drug particles due to excessive mixing of magnesium stearate by strictly controlling the total mixing time (t2 = 3~8 minutes, preferably 5 minutes). Magnesium stearate is a strongly hydrophobic substance; prolonged mixing will cause it to uniformly coat the surface of drug particles, forming a hydrophobic film that hinders water penetration and delays capsule disintegration and drug dissolution. This invention, through a short total mixing strategy, minimizes the contact time between magnesium stearate and drug particles while ensuring uniform dispersion, thus reducing the degree of hydrophobic coating. The method of this invention ensures rapid disintegration and drug release of the capsules after administration, resulting in higher dissolution rates and facilitating rapid drug absorption in the gastrointestinal tract, thereby improving drug bioavailability and clinical efficacy.

[0045] Example 2 (Long Premixing Time Gradient Example): This example has the same formulation and basic steps as Example 1, except that the premixing time t1 in step 201 is adjusted to 20 minutes and 35 minutes, respectively, as Example 2a and Example 2b, to verify the impact of premixing time on the quality of the final product.

[0046] Example 3 (Gradual Mixing Time Example): This example has the same formulation and basic steps as Example 1, except that the total mixing time t2 in step 202 is adjusted to 3 minutes and 8 minutes, respectively, as Example 3a and Example 3b, to verify the key influence of total mixing time on dissolution.

[0047] Example 4 (Premixed Powder Sampling Ratio Example): This example has the same formulation and basic steps as Example 1, except that the volume of premixed powder taken out in step 202 is 2 times (about 50g) and 5 times (about 125g) the volume of magnesium stearate, respectively, as Example 4a and Example 4b, to verify the rationality of the premixed powder ratio in the lubricant premix.

[0048] Example 5 (Manual Mixing Time Example): This example has the same formulation and basic steps as Example 1, except that the manual mixing time in step 202 is adjusted to 1 minute and 3 minutes, respectively, as Example 5a and Example 5b, to verify the effect of manual mixing time on the dispersion effect of lubricant.

[0049] Example 6 (Examples with different mixing speeds): The formulation and basic steps of this example are exactly the same as those of Example 1. The difference is that the speed of the three-dimensional motion mixer is adjusted to 5 rpm and 15 rpm, respectively, as Example 6a and Example 6b, to verify the effect of mixing speed on mixing efficiency and material properties.

[0050] III. Comparative Example 1 (Traditional One-Pot Long-Term Mixing): The formulation was exactly the same as in Example 1. All weighed materials (glucosamine sulfate sodium chloride double salt, lactose, corn starch, talc, and magnesium stearate) were added to a three-dimensional motion mixer and continuously mixed at 8 rpm for 30 minutes. Subsequent capsule filling and packaging steps were exactly the same as in Example 1.

[0051] Comparative Example 2 (long premix + long total mix, no predispersion) had the same formulation as Example 1. First, long premixing (8 rpm, 25 minutes) was performed as in Example 1. Then, magnesium stearate was directly added to the premixed powder in the mixer (without predispersion), and then total mixed at 8 rpm for 25 minutes. Subsequent steps were exactly the same as in Example 1.

[0052] Comparative Example 3 (long premix + short total mix, no predispersion) had the same formulation as Example 1. First, long premixing (8 rpm, 25 minutes) was performed as in Example 1. Then, magnesium stearate was directly added to the premixed powder in the mixer (without predispersion), and total mixing was performed at 8 rpm for 5 minutes. Subsequent steps were identical to those in Example 1.

[0053] Comparative Example 4 (no long premixing, only short total mixing) had the same formulation as Example 1. No premixing step was performed; all weighed materials (including magnesium stearate) were added to a three-dimensional motion mixer and directly mixed at 8 rpm for 5 minutes. Subsequent steps were exactly the same as in Example 1.

[0054] For efficacy verification and data comparison, samples of glucosamine sulfate capsules prepared in Examples 1-6 and Comparative Examples 1-4 were tested according to the following methods in the General Chapters of Part IV of the Chinese Pharmacopoeia (2020 Edition): content uniformity test (General Chapter 0941), fill weight difference test (General Chapter 0103), dissolution test (General Chapter 0931, Method II), and related substances test (General Chapter 0512, High Performance Liquid Chromatography). Simultaneously, the angle of repose of each sample was measured to evaluate powder flowability. The following table shows the quality test results of each example and comparative example.

[0055] Example 1 Long premixing + predispersion + short total mixing (optimal) 25 5 4 times the volume of premixed powder + 2 minutes of hand mixing 5.6 ±4.2 98.6 0.02 Example 2a Premix time: 20 minutes 20 5 Same as above 7.2 ±5.1 97.1 0.03 Example 2b Premix time: 35 minutes 35 5 Same as above 5.1 ±3.9 97.8 0.03 Example 3a Total mixing time: 3 minutes 25 3 Same as above 6.8 ±5.3 99.2 0.04 Example 3b Total mixing time: 8 minutes 25 8 Same as above 5.9 ±4.5 94.3 0.03 Example 4a Premixed powder, twice the volume (1000g) 25 5 2 times the volume of premixed powder + 2 minutes of hand mixing 7.5 ±5.6 96.5 0.04 Example 4b Premixed powder, 5 times its volume (2500g) 25 5 5 times the volume of premixed powder + 2 minutes of hand mixing 5.8 ±4.0 98.1 0.02 Example 5a Mix by hand for 1 minute 25 5 4 times the volume of premixed powder + 1 minute of hand mixing 8.1 ±5.8 95.8 0.04 Example 5b Mix by hand for 3 minutes 25 5 4 times the volume of premixed powder + 3 minutes of hand mixing 5.3 ±4.1 97.5 0.03 Example 6a Mixed speed 5 rpm 25 5 Same as above 6.5 ±4.8 96.9 0.04 Example 6b Mixed speed 15 rpm 25 5 Same as above 5.8 ±4.3 95.2 0.05 Comparative Example 1 Traditional one-pot method (all materials are mixed together for 30 minutes) — 30 none 12.3 ±6.2 85.5 0.09 Comparative Example 2 Long-term premixing + long-term total mixing (without predispersion) 25 25 none 11.5 ±6.7 95.1 0.07 Comparative Example 3 Long premixing + short total mixing (no predispersion) 25 5 none 10.8 ±5.9 95.2 0.07 Comparative Example 4 No premixing, only short total mixing — 5 none 14.6 ±7.3 95.5 0.08 Pharmacopoeia Limits — — — — ≤15.0 ≤±7.5% ≥80% (Q) ≤0.5%

[0056] The content uniformity (A+2.2S value) of all embodiments was below the pharmacopoeia limit of 15.0, and the content variation was controlled within ±6.5%, which is significantly better than the comparative examples (some of which exceeded ±8%, exceeding the pharmacopoeia limit of ±7.5%). This fully demonstrates the superiority of the "long premixing + predispersion + short total mixing" process design of this invention in improving the macroscopic and microscopic uniformity of materials.

[0057] The effect of premixing time: The A+2.2S value of Example 2a (t1=20min) is 7.2, which is higher than that of Example 1 (t1=25min, A+2.2S=5.6), indicating that too short a premixing time may lead to insufficient mixing of the base materials, affecting the final content uniformity. Although the uniformity of Example 2b (t1=35min, A+2.2S=5.1) is slightly better than that of Example 1, the improvement is limited, but it significantly increases production time and energy consumption. Considering both quality and efficiency, 25min is the optimal premixing time.

[0058] The Importance of the Pre-dispersion Step: The A+2.2S value of Comparative Example 3 (with premixing, without pre-dispersion, t2=5min) was 10.8, significantly higher than that of Example 1 (5.6). This indicates that directly adding magnesium stearate to the premixed powder, even with the same total mixing time (5min), makes it difficult to achieve a uniform distribution of magnesium stearate, easily causing local over- or under-lubrication, thus affecting the uniformity of content and the difference in fill weight. The A+2.2S value of Comparative Example 4 (without premixing, only short total mixing) was as high as 14.6, approaching the pharmacopoeia limit, further illustrating the necessity of the premixing step for homogenizing the base materials.

[0059] Effect of premixed powder sampling amount: The uniformity of Example 4a (using 2 times the volume of premixed powder for pre-dispersion) was slightly worse (A+2.2S=7.5), while the uniformity of Example 4b (using 5 times the volume of premixed powder) was better (A+2.2S=5.8), indicating that an appropriate amount of premixed powder helps in the pre-dispersion of magnesium stearate. However, too much premixed powder (e.g., more than 5 times the volume) will increase the difficulty and time cost of manual mixing; therefore, 2 to 5 times the volume is a reasonable and preferred range.

[0060] The effect of manual mixing time: The A+2.2S value of Example 5a (manual mixing for 1 min) is 8.1, which is significantly higher than that of Example 1 (manual mixing for 2 min, 5.6). This indicates that if the manual mixing time is too short, magnesium stearate will not be sufficiently dispersed in the premix, thus affecting the uniformity of the final system. The uniformity of Example 5b (manual mixing for 3 min, A+2.2S=5.3) is basically the same as that of Example 1, indicating that the dispersion effect tends to saturate after manual mixing for 2 min. Continuing to extend the time will not significantly improve the uniformity, but will instead increase the operation time. Therefore, 2 min is the optimal choice.

[0061] The effect of mixing speed: The uniformity of Example 6a (5 rpm, A+2.2S=6.5) and Example 6b (15 rpm, A+2.2S=5.8) is slightly worse than that of Example 1 (8 rpm, 5.6), indicating that the material movement intensity is insufficient when the speed is too low, which is not conducive to uniform mixing; short mixing time may result in uneven mixing, and long mixing time will lead to a longer construction period.

[0062] Environmental Control: Due to the hygroscopic nature of glucosamine sulfate, all embodiments are recommended to be performed in an environment with a relative humidity below 60%. In summary, the preparation method of glucosamine sulfate capsules provided by this invention ensures the homogeneity of the base materials through long premixing, achieves effective predisposition of magnesium stearate through lubricant premix, and precisely controls the degree of mixing through short total mixing. These three factors work synergistically to perfectly resolve the contradiction between uniformity, flowability, and dissolution in traditional processes. This method offers controllable quality, good reproducibility, and is suitable for large-scale industrial production, possessing extremely high technical value and market application prospects.

[0063] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. A method for preparing glucosamine sulfate capsules, characterized in that, Includes the following steps: 、 Step 1, Weighing the raw materials: Weigh out the following ingredients according to the prescription: glucosamine sulfate sodium chloride double salt, lactose, corn starch, talc, and magnesium stearate; Step 2: Use a mixing strategy of long premixing and short total mixing for mixing: Step 201: Perform long premixing of the base materials: The weighed glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc are mixed for the first time to obtain premixed powder, wherein the duration of the first mixing is t1; Step 202: Add magnesium stearate for distribution mixing: Take a portion of the premixed powder and mix it with magnesium stearate for a second time to obtain a lubricant premix; then add the obtained lubricant premix to the remaining premixed powder for a third mixing to obtain total mixed particles, wherein the duration of the third mixing is t2, and t1>t2; Step 3, Capsule filling: The total mixed particles are filled into the hollow capsule shells, and the capsule weight is controlled during the filling process; Step 4, Aluminum-Plastic Packaging: Pack the filled capsules in aluminum-plastic blister packaging, add desiccant and composite film bags for packaging, and then box them.

2. The method for preparing a glucosamine sulfate capsule according to claim 1, characterized in that: In step 201, before the first mixing, the method further includes a step of pre-treating the glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc by sieving.

3. The method for preparing a glucosamine sulfate capsule according to claim 2, characterized in that: The pretreatment by sieving involves passing each material through a 40-mesh sieve.

4. The method for preparing a glucosamine sulfate capsule according to claim 1, characterized in that: The first and / or third mixing is carried out in a column-type rotating hopper mixer.

5. The method for preparing a glucosamine sulfate capsule according to claim 1, characterized in that: The first mixing speed is 5-15 rpm, and the first mixing time t1 is 20-40 minutes; the third mixing speed is 5-15 rpm, and the third mixing time t2 is 3-8 minutes.

6. The method for preparing a glucosamine sulfate capsule according to claim 5, characterized in that: The first mixing speed is 8 rpm, and the first mixing time t1 is 25 minutes; the third mixing speed is 8 rpm, and the third mixing time t2 is 5 minutes.

7. The method for preparing a glucosamine sulfate capsule according to claim 1, characterized in that: In step 202, a portion of the premixed powder has a volume that is 2 to 5 times the volume of magnesium stearate.

8. The method for preparing a glucosamine sulfate capsule according to claim 1, characterized in that: In step 2, the mixing strategy of long premixing and short total mixing is carried out in an environment with a temperature of 18-26℃ and a relative humidity of 35-65%.

9. The method for preparing a glucosamine sulfate capsule according to claim 1, characterized in that: During the filling process, the weight of the capsule is checked every 30 minutes, and the filling parameters are adjusted according to the test results.

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