A method for preparing amoxicillin dispersible tablets

Abstract

The present application relates to the technical field of pharmaceutical preparation, and in particular to a preparation method of amoxicillin dispersible tablets, comprising the following steps: S1, mixing based on an internal complex cross-linking disintegrant system to form an internal water absorption channel structure, and obtaining first mixed material; S2, granulating after adjusting granulation parameters based on the bulk density and first angle of repose of the first mixed material, and obtaining first mixed granules; S3, mixing based on an external complex cross-linking disintegrant system to form a granule inter-disintegration network structure, and obtaining second mixed material; and S4, tabletting after adjusting the tabletting pressure based on the second angle of repose of the second mixed material and the particle size distribution of the first mixed granules. The present application significantly improves the disintegration performance, dissolution rate and quality stability of the amoxicillin dispersible tablets by constructing intelligent process control logic.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a method for preparing amoxicillin dispersible tablets. Background Technology

[0002] Amoxicillin, a broad-spectrum semi-synthetic penicillin antibiotic, is widely used in clinical anti-infective treatment. Dispersible tablets, which rapidly disintegrate in water to form a homogeneous suspension, are convenient for the elderly, children, and patients with swallowing difficulties, making them one of the ideal dosage forms for amoxicillin.

[0003] Chinese Patent Publication No. CN109394718A discloses an amoxicillin dispersible tablet and its preparation method. In this invention, the amoxicillin dispersible tablet has the active pharmaceutical ingredient amoxicillin distributed in a weight ratio of 4:6 between a sustained-release portion and an immediate-release portion. The sustained-release portion is composed of a pellet core coated with a sustained-release coating solution containing at least microcrystalline cellulose as a filler material. The immediate-release portion is prepared from a filler, a disintegrant, and a lubricant. While this technical solution aims to achieve stable and complete drug release through a composite structure of sustained-release and immediate-release components, ensuring complete dissolution and release within 4 hours and potentially maintaining a long-term effective blood drug concentration in vivo, this design concept and process itself also introduce new technical challenges. Firstly, focusing on long-acting release, its complex coating structure and preparation process may lead to a decrease in the initial disintegration performance of the tablets, which is inherently contradictory to the rapid disintegration characteristics pursued by dispersible tablets. Secondly, the coating process introduces moisture and additional processing steps, which not only increases the complexity of the process but also poses a potential risk to the stability of moisture-sensitive amoxicillin. Third, the process lacks real-time monitoring and adaptive adjustment of key material properties of intermediates (such as flowability and particle size distribution), posing a challenge to batch-to-batch quality consistency control.

[0004] Therefore, there is an urgent need in the field for a new method that can focus on optimizing disintegration performance, precisely controlling the distribution of disintegrants, avoiding the influence of moisture, and adaptively adjusting process parameters according to material characteristics, thereby stably preparing high-quality amoxicillin dispersible tablets. Summary of the Invention

[0005] Therefore, the present invention provides a method for preparing amoxicillin dispersible tablets to overcome the problems of poor disintegration performance, slow dissolution rate, low content uniformity, and batch-to-batch quality instability in the prior art.

[0006] To achieve the above objectives, the present invention provides a method for preparing amoxicillin dispersible tablets, comprising the following steps: Step S1: Based on the internal composite crosslinking disintegrant system, amoxicillin raw material and first crosslinking polyvinyl alcohol are sequentially added to the mixing tank of the mixer, and mixed using the first preset mixer operating parameters. At the end of the mixing, the mixing time of the first preset mixer operating parameters is extended based on the uniformity of amoxicillin content to form an internal water absorption channel structure, thereby obtaining the first mixture. Step S2: The first mixture is fed into the pellet mill. Based on the bulk density of the first mixture and the first rest angle, the feeding speed and / or the roller speed of the preset pellet mill operating parameters are adjusted so as to pelletize using the adjusted preset pellet mill operating parameters to obtain the first mixed particles. Step S3: Based on the external composite crosslinking disintegrant system, the first mixed particles, the second crosslinked povidone, microcrystalline cellulose, and aspartame are sequentially added to the mixer and mixed using the second preset mixer operating parameters to form an interparticle disintegration network structure to obtain the second mixture. Step S4: Based on the second rest angle of the second mixture and the particle size distribution of the first mixed particles, the tableting pressure of the preset tableting machine operating parameters is adjusted, and the second mixture is tableted using the adjusted preset tableting machine operating parameters to complete the preparation of amoxicillin dispersible tablets.

[0007] Further, in step S1, the process of forming the internal water absorption channel structure to obtain the first mixture includes: Step S111: Add 50% by weight of amoxicillin raw material to the mixer to form the first material layer; Step S112: All of the first cross-linked polyvinyl ketone is put into the mixer to uniformly cover the first material layer, forming a disintegrant intermediate layer. Step S113: The remaining 50% by weight of amoxicillin raw material is fed into the mixer to form a second material layer, thereby forming the first sandwich structure. Step S114: The first sandwich structure is mixed in the first stage using the first mixing time of the first preset mixer operating parameters, so as to realize the spatial network distribution of the first cross-linked polyvinyl ketone in the amoxicillin raw material and form the internal water absorption channel structure. Step S115: Add the first weight component, magnesium stearate, to the mixer and perform a second stage of mixing using the second mixing time of the first preset mixer operating parameters, so that the magnesium stearate is uniformly dispersed to obtain the first mixture.

[0008] Further, in step S1, the process of determining the mixing time for extending the operating parameters of the first preset mixer based on the uniformity of amoxicillin content in the first mixture includes: Step S121: Obtain the near-infrared spectral data of the first mixture to calculate the uniformity of the amoxicillin content. Step S122: Determine the content standard deviation value based on the content uniformity and the preset content uniformity; Step S123: Compare and analyze the content standard deviation value with the preset content standard deviation value; Step S124: Based on the result that the content standard deviation value is greater than the preset content standard deviation value, determine to extend the mixing time.

[0009] Further, in step S2, the process of adjusting the feeding speed and / or roller speed of the preset pellet mill operating parameters based on the bulk density of the first mixture and the first rest angle includes: Step S21: Obtain the stack density and the first rest angle; Step S22: Determine the first comprehensive deviation value based on the bulk density and the first rest angle; Step S23: Determine the first contribution based on the stack density and the preset stack density; Step S24: Determine the second contribution based on the first rest angle and the preset first rest angle; Step S25: Based on the result that the first comprehensive deviation value is greater than the preset first comprehensive deviation value, determine to compare and analyze the first contribution and the second contribution, and based on the comparison and analysis results, determine to adjust the feeding speed and / or the pressure roller speed of the preset pellet mill operating parameters.

[0010] Furthermore, in step S25, the process of determining the adjustment of the feeding speed and / or pressure roller speed of the preset pellet mill operating parameters based on the comparative analysis results includes: Based on the result that the first contribution is greater than the second contribution, it is determined to reduce the feeding speed; Alternatively, based on the result that the first contribution is less than the second contribution, it is determined to increase the rotational speed of the pressure roller; Alternatively, based on the result that the first contribution equals the second contribution, it is determined to reduce the feeding speed while increasing the rotational speed of the pressure roller.

[0011] Further, in step S3, the process of forming an interparticle disintegration network structure to obtain a second mixture includes: Step S31: 50% to 60% by weight of the first mixed particles are fed into the mixer to form the first particle base layer; Step S32: The second cross-linked polyvinylpyrrolidone, microcrystalline cellulose and aspartame are put into a mixer to make the excipients uniformly cover the surface of the first particle base layer to form an excipient coating layer. Step S33: The remaining 40% to 50% by weight of the first mixed particles are fed into the mixer to form a second particle coating layer; Step S34: The second particle covering layer is mixed in the third stage using the first mixing time of the second preset mixer operating parameters, so that the second crosslinked polyvinyl ketone adheres to the particle surface and gaps, forming the interparticle disintegration network structure that connects multiple particles. Step S35: Add the magnesium stearate of the second weight component to the mixer, and perform a fourth stage of mixing using the second mixing time of the second preset mixer operating parameters to uniformly disperse the magnesium stearate and obtain the second mixture.

[0012] Further, in step S4, the process of adjusting the tableting pressure based on the flowability index of the second mixture and the particle size distribution of the first mixed particles includes: Step S41: Obtain the second repose angle and the weight percentage of particles larger than 60 mesh in the first mixed particles; Step S42: Determine the second comprehensive deviation value based on the second rest angle and the weight percentage; Step S43: Determine the third contribution based on the second rest angle and the preset second rest angle; Step S44: Determine the fourth contribution based on the weight percentage and the preset weight percentage; Step S45: Compare the second comprehensive deviation value with the preset second comprehensive deviation value; Step S46: Based on the result that the second comprehensive deviation value is greater than the preset second comprehensive deviation value, it is determined to compare and analyze the third contribution and the fourth contribution to determine the tableting pressure of the preset tablet press operating parameters.

[0013] Further, in step S44, based on the result that the third contribution is greater than the fourth contribution, it is determined to adjust and reduce the tableting pressure; Alternatively, based on the result that the third contribution is less than the fourth contribution, it is determined to adjust and increase the tableting pressure.

[0014] Further, the first preset mixer operating parameters and / or the second preset mixer operating parameters include mixer speed and mixing time, and the pellet mill operating parameters include the distance between pressure rollers and roller hydraulic pressure, wherein, The mixing speed is 900 rpm to 1100 rpm, the first mixing time is 15 minutes to 20 minutes, and the second mixing time is 3 minutes to 8 minutes; The spacing between the pressure rollers is 0.8mm to 1.2mm, and the hydraulic pressure of the rollers is 8MPa to 12MPa.

[0015] Furthermore, the first cross-linked polyvinylpyrrolidone is XL-10 type cross-linked polyvinylpyrrolidone, and the second cross-linked polyvinylpyrrolidone is CL type cross-linked polyvinylpyrrolidone.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: The internal composite cross-linking disintegrant system, using XL-10 type cross-linked povidone to form a uniformly distributed internal water-absorbing channel structure in amoxicillin raw material, and the external composite cross-linking disintegrant system, using CL type cross-linked povidone to construct a disintegration network structure between particles, work synergistically to promote rapid water penetration and overall tablet disintegration. This allows the dispersible tablets to rapidly disintegrate into fine particles upon contact with aqueous media, greatly improving the drug dissolution rate, ensuring rapid drug release, and thus enhancing bioavailability.

[0017] Furthermore, during the mixing process, layered feeding and real-time monitoring of content uniformity based on near-infrared spectroscopy, along with dynamic adjustments to the mixing time, ensured the uniform dispersion of amoxicillin raw materials, disintegrants, and other excipients. This optimized mixing strategy effectively reduced localized content differences, resulting in a consistent distribution of the active ingredient in each tablet, meeting high quality standards.

[0018] Furthermore, by linking key indicators such as material bulk density, angle of repose, and particle size distribution with process parameters and making real-time adjustments based on comprehensive deviation values, intelligent and standardized processes were achieved. This data-driven control method reduces the impact of human factors and raw material fluctuations, ensuring consistency and repeatability of product quality across different production batches and reducing scrap rates.

[0019] Furthermore, during the granulation and tableting stages, granulation parameters are adjusted based on bulk density and angle of repose, and tableting pressure is adjusted based on angle of repose and particle size distribution to ensure that the granules have ideal flowability and compressibility. This avoids problems such as sticking and tablet weight differences during the tableting process, further ensuring the stability of tablet hardness and disintegration time.

[0020] Furthermore, by refining and adaptively adjusting process parameters, not only are the problems of poor disintegration performance, slow dissolution rate, low content uniformity, and batch-to-batch quality in the existing technology solved, but production efficiency and product reliability are also improved. This technology is suitable for large-scale industrial production and has significant industrial application value. Attached Figure Description

[0021] Figure 1 This is a flowchart illustrating the steps of preparing amoxicillin dispersible tablets according to an embodiment of the present invention; Figure 2This is a flowchart illustrating the steps of forming an internal water absorption channel structure to obtain the first mixture in an embodiment of the present invention. Figure 3 This is a flowchart illustrating the steps of forming an interparticle disintegration network structure to obtain a second mixture according to an embodiment of the present invention. Figure 4 This is a flowchart illustrating the steps for determining and adjusting the tableting pressure based on preset tableting machine operating parameters, as described in an embodiment of the present invention. Detailed Implementation

[0022] To make the objectives and advantages of the present invention clearer, the present invention will be further described below with reference to embodiments; it should be understood that the specific embodiments described herein are merely for explaining the present invention and are not intended to limit the present invention.

[0023] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings. Those skilled in the art should understand that these embodiments are merely illustrative of the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0024] Please see Figure 1 As shown, Figure 1 This is a flowchart illustrating the steps of preparing amoxicillin dispersible tablets according to an embodiment of the present invention.

[0025] This invention provides a method for preparing amoxicillin dispersible tablets, comprising the following steps: Step S1: Based on the internal composite crosslinking disintegrant system, amoxicillin raw material and first crosslinking polyvinyl alcohol are sequentially added to the mixing tank of the mixer and mixed using the first preset mixer operating parameters. At the end of the mixing, the mixing time of the first preset mixer operating parameters is extended based on the uniformity of amoxicillin content to form an internal water absorption channel structure and obtain the first mixture. Step S2: The first mixture is fed into the pellet mill. Based on the bulk density of the first mixture and the first rest angle, the feeding speed and / or the roller speed of the preset pellet mill operating parameters are adjusted so as to pelletize using the adjusted preset pellet mill operating parameters to obtain the first mixed particles. Step S3: Based on the external composite crosslinking disintegrant system, the first mixed particles, the second crosslinked povidone, microcrystalline cellulose, and aspartame are sequentially added to the mixer and mixed using the second preset mixer operating parameters to form an interparticle disintegration network structure to obtain the second mixture. Step S4: Based on the second rest angle of the second mixture and the particle size distribution of the first mixed particles, the tableting pressure of the preset tableting machine operating parameters is adjusted, and the second mixture is tableted using the adjusted preset tableting machine operating parameters to complete the preparation of amoxicillin dispersible tablets.

[0026] Specifically, the internal composite cross-linking disintegrant system refers to a disintegrant system with the first cross-linked polyvinylpyrrolidone as the core, which forms an internal water absorption channel through a sandwich structure. Externally cross-linked disintegrant system refers to a disintegrant system that uses second cross-linked polyvinyl ketone as the core and forms a disintegrant network structure on the particle surface and in the gaps.

[0027] Please see Figure 2 As shown, Figure 2 This is a flowchart illustrating the steps of forming an internal water absorption channel structure to obtain the first mixture in an embodiment of the present invention.

[0028] Specifically, in step S1, the process of forming the internal water absorption channel structure to obtain the first mixture includes: Step S111: Add 50% by weight of amoxicillin raw material to the mixer to form the first material layer; Step S112: All of the first cross-linked polyvinyl ketone is put into the mixer to uniformly cover the first material layer, forming a disintegrant intermediate layer. Step S113: The remaining 50% by weight of amoxicillin raw material is fed into the mixer to form a second material layer, thereby forming the first sandwich structure. Step S114: The first sandwich structure is mixed in the first stage using the first mixing time of the first preset mixer operating parameters, so as to realize the spatial network distribution of the first cross-linked polyvinyl ketone in the amoxicillin raw material and form an internal water absorption channel structure. Step S115: Add magnesium stearate, the first weight component, to the mixer and perform a second stage of mixing using the second mixing time of the first preset mixer operating parameters to uniformly disperse the magnesium stearate and obtain the first mixture.

[0029] In this embodiment of the invention, step S114 involves mixing the first sandwich structure using the first preset mixer operating parameters. The mixer is a three-dimensional motion mixer, which, through the translation, rotation, and tumbling motion of the container in three-dimensional space, subjects the material within the container to intense turbulence and diffusion. During this process, the first cross-linked polyvinyl acetate particles located in the middle layer of the sandwich structure are effectively deagglomerated from their aggregated state under the combined forces of shearing, convection, and diffusion generated by the three-dimensional motion. They are then forcibly and uniformly dispersed and intercalated between the amoxicillin raw material particles, partially embedding into the surface of the soft drug particles and partially forming bridges between the particles. This specific hybrid dynamics forces the first cross-linked polyvinyl acetate to form a continuous, porous, and highly absorbent three-dimensional spatial network framework within the amoxicillin particle phase—that is, an internal water absorption channel structure. The first mixing time in this stage is 15 to 20 minutes to ensure the full formation of the aforementioned spatial network structure.

[0030] Specifically, in step S1, the process of determining the mixing time for extending the operating parameters of the first preset mixer based on the uniformity of amoxicillin content in the first mixture includes: Step S121: Obtain near-infrared spectral data of the first mixture to calculate the uniformity of amoxicillin content. Step S122: Determine the content standard deviation value based on the content uniformity and the preset content uniformity; Step S123: Compare and analyze the content standard deviation value with the preset content standard deviation value; Step S124: Based on the result that the content standard deviation value is greater than the preset content standard deviation value, determine to extend the mixing time.

[0031] In step S124 of this embodiment of the invention, based on the result that the content standard deviation value σ is greater than the preset content standard deviation value σ0, it is determined to extend the mixing time; The specific method for extending the mixing time is as follows: calculate the extension coefficient K based on the degree to which the content standard deviation exceeds the preset value. m And based on K m Determine the final extension duration; 1. Elongation coefficient K m Calculated using the following formula:

[0032] The duration extension ΔT is calculated using the following formula: ΔT = T0×K m Wherein, T0 is the baseline extension duration, which is set to 5 minutes in this embodiment; 2. The final blending time is the adjusted blending time T. final It can be calculated using the following formula: T final = T initial +ΔT σ is the standard deviation of the content (dimensionless), σ0 is the preset standard deviation of the content (dimensionless), T0 is the baseline extension time in minutes, and T initial The first preset mixing duration is in minutes. In this embodiment, T initial Set to 15 minutes Specifically, in step S2, the process of adjusting the feeding speed and / or roller speed of the preset pellet mill operating parameters based on the bulk density of the first mixture and the first rest angle includes: Step S21: Obtain the bulk density and the first rest angle; Step S22: Determine the first comprehensive deviation value based on the bulk density and the first rest angle; Step S23: Determine the first contribution based on the stack density and the preset stack density; Step S24: Determine the second contribution based on the first rest angle and the preset first rest angle; Step S25: Based on the result that the first comprehensive deviation value is greater than the preset first comprehensive deviation value, determine to compare and analyze the first contribution and the second contribution, and based on the comparison and analysis results, determine to adjust the feeding speed and / or the speed of the pressure roller of the preset pellet mill operating parameters.

[0033] In this embodiment of the invention, the first comprehensive deviation value D1 is calculated using the following formula: D1 = w1×Eρ + w2×Eθ Where w1 is the influence coefficient of the first contribution on D1, w2 is the influence coefficient of the second contribution on D1, weighting coefficients, Eρ is the first contribution, Eθ is the second contribution, and in this embodiment, w1=0.5, w2=0.5; The first contribution Eρ is calculated using the following formula:

[0034] Wherein, ρ is the bulk density, and ρ0 is the preset bulk density. In this embodiment, the preset bulk density is set to 0.45 g / mL. The second contribution Eθ1 is calculated using the following formula:

[0035] Wherein, θ1 is the first rest angle, and θ10 is the preset first rest angle. In this embodiment, the preset first rest angle is set to 35°.

[0036] Specifically, in step S25, the process of adjusting the feeding speed and / or pressure roller speed of the preset pellet mill operating parameters based on the comparative analysis results includes: Based on the fact that the first contribution is greater than the second contribution, it is determined to reduce the feeding speed; Alternatively, based on the result that the first contribution is less than the second contribution, it is determined to increase the speed of the pressure roller; Alternatively, based on the result that the first contribution equals the second contribution, it is determined to reduce the feeding speed while increasing the pressure roller speed.

[0037] In step S25 of this embodiment of the invention, the feeding speed and / or the rotational speed of the pressure roller of the preset pellet mill operating parameters are adjusted. The adjustment amount is determined based on the first comprehensive deviation value D1, specifically as follows: Introduce an adjustment coefficient K = D1 / D10, where D10 is a preset first comprehensive deviation value, and set the basic adjustment amount of the feeding speed to 5 rpm and the basic adjustment amount of the pressure roller speed to 2 rpm. The final adjustment amount is executed according to the comparison result of the first contribution degree Eρ and the second contribution degree Eθ according to the following rules: When Eρ > Eθ×(1 + α), the new feeding speed = the original feeding speed - (5×K), and the new pressure roller speed = the original pressure roller speed + (1×K); When Eρ < Eθ×(1 - α), the new feeding speed = the original feeding speed - (2.5×K), and the new pressure roller speed = the original pressure roller speed + (2×K); When the contribution degrees of the two are equal, the new feeding speed = the original feeding speed - (5×K), and the new pressure roller speed = the original pressure roller speed + (2×K).

[0038] Please refer to Figure 3 as shown Figure 3 It is the process flow chart of forming the second mixed material with an intergranular disintegration network structure in the embodiment of the present invention.

[0039] Specifically, in step S3, the process of forming an intergranular disintegration network structure to obtain the second mixed material includes: Step S31, put 50% - 60% by weight of the first mixed particles into the mixer to form a first particle base layer; Step S32, put the second cross-linked povidone, microcrystalline cellulose and aspartame into the mixer to uniformly cover the surface of the first particle base layer to form an auxiliary material coating layer; Step S33, put the remaining 40% - 50% by weight of the first mixed particles into the mixer to form a second particle covering layer; Step S34, perform the third-stage mixing on the second particle covering layer with the first mixing duration of the second preset mixer operating parameters, so that the second cross-linked povidone adheres to the surface and gaps of the particles to form an intergranular disintegration network structure connecting multiple particles; Step S35, add the second weight component of magnesium stearate to the mixer, and perform the fourth-stage mixing with the second mixing duration of the second preset mixer operating parameters to make the magnesium stearate uniformly dispersed to obtain the second mixed material.

[0040] Please refer to Figure 4 as shown Figure 4 It is the process flow chart of determining the adjustment of the tableting pressure of the preset tableting machine operating parameters in the embodiment of the present invention.

[0041] Specifically, in step S4, the process of determining the adjustment of the tableting pressure of the preset tableting machine operating parameters based on the fluidity index of the second mixed material and the particle size distribution of the first mixed particles includes: Step S41: Obtain the second repose angle and the weight percentage of particles larger than 60 mesh in the first mixed particles; Step S42: Determine the second comprehensive deviation value based on the second rest angle and the weight percentage; Step S43: Determine the third contribution based on the second rest angle and the preset second rest angle; Step S44: Determine the fourth contribution based on the weight percentage and the preset weight percentage; Step S45: Compare the second comprehensive deviation value with the preset second comprehensive deviation value; Step S46: Based on the result that the second comprehensive deviation value is greater than the preset second comprehensive deviation value, the third contribution and the fourth contribution are compared and analyzed to determine the tableting pressure of the preset tablet press operating parameters.

[0042] In this embodiment of the invention, the second comprehensive deviation value D2 is calculated using the following formula: D2 = w3×Eθ2+ w4×Eρ Where w3 is the influence coefficient of the third contribution on D2, and w4 is the influence coefficient of the fourth contribution on D2. In this embodiment, w3=0.5 and w4=0.5 are set. The third contribution Eθ2 is calculated using the following formula:

[0043] Wherein, θ2 is the second rest angle, and θ20 is the preset second rest angle. In this embodiment, the preset second rest angle is set to 35°.

[0044] The fourth contribution Ep is calculated using the following formula:

[0045] Where p is the weight percentage and p0 is the preset weight percentage. In this embodiment, the preset weight percentage is set to 50% and the preset second rest angle is 35°.

[0046] Specifically, in step S44, based on the result that the third contribution is greater than the fourth contribution, it is determined to adjust and reduce the tableting pressure; Alternatively, based on the result that the third contribution is less than the fourth contribution, it is determined to adjust and increase the tableting pressure; Otherwise, based on the fact that the third contribution is equivalent to the fourth contribution, i.e., Ep×(1-α)≤Eθ2≤Ep×(1+α), no adjustments are made, where, α is a precision control coefficient, which is set to 0.1 in this embodiment.

[0047] In step S44 of the embodiment of the present invention, in step S25, the third contribution degree is greater than the fourth contribution degree, that is, Eθ2>Ep×(1 + α); The third contribution degree is less than the fourth contribution degree, that is, Eθ2>Ep×(1 + α); Otherwise, it is the case where the contribution degrees of the two are equivalent, which is defined in this embodiment as , and no adjustment is made at this time; α is a precision control coefficient, which is set to 0.1 in this embodiment, that is, it represents a control precision with a difference not exceeding 10%.

[0048] In the embodiment of the present invention, the tableting pressure of the preset tableting machine operating parameters is adjusted, and the adjustment amount is calculated and determined based on the second comprehensive deviation value D2. Specifically: An adjustment coefficient K' = D2 / D20 is introduced, where D20 is a preset second comprehensive deviation value, and the basic adjustment amount of the tableting pressure is set as ΔP0 = 0.5 kN; The final adjustment amount is executed according to the comparison result between the third contribution degree Eθ2 and the fourth contribution degree Ep according to the following rules: When Eθ2>Ep×(1 + α), the new tableting pressure = the original tableting pressure - (ΔP0×K'); When Eθ2<Ep×(1 - α), the new tableting pressure = the original tableting pressure + (ΔP0×K'). Specifically, the first preset mixer operating parameters and / or the second preset mixer operating parameters include the mixer rotation speed and the mixing duration, and the granulator operating parameters include the distance between the pressing wheels and the roller hydraulic pressure. Among them, The mixing rotation speed is 900 rpm to 1100 rpm, the first mixing duration is 15 minutes to 20 minutes, and the second mixing duration is 3 minutes to 8 minutes; The distance between the pressing wheels is 0.8 mm to 1.2 mm, and the roller hydraulic pressure is 8 Mpa to 12 Mpa.

[0049] In the embodiment of the present invention, the disintegration time limit of the dispersible tablets is within 30 seconds, and the hardness is greater than 100 N.

[0050] Specifically, the first cross-linked povidone is a cross-linked povidone with a particle size range of 10 - 50 μm and a water absorption rate ≥ 5 mL / g; The second cross-linked povidone is a cross-linked povidone with a particle size range of 50 - 100 μm and a water absorption rate ≥ 10 mL / g.

[0051] Example 1 Weigh 250 g of amoxicillin raw material, 4 g of XL - 10 type cross-linked povidone, 12 g of CL type cross-linked povidone, 95 g of microcrystalline cellulose PH102, 5 g of aspartame, 3 g of the first weight component of magnesium stearate, and 2 g of the second total component according to C16H19N3O5S.

[0052] Step S1: The method for forming the internal water absorption channel structure according to the present invention is carried out, specifically including steps S111 to S115. The first preset mixer operating parameters are: a three-dimensional motion mixer speed of 1000 rpm. The first stage mixing time is 15 minutes; after adding magnesium stearate, the second stage mixing time is 5 minutes.

[0053] Step S2: Use an LG200 dry pellet mill. Preset parameters are: feeding speed 120 rpm, pressure roller speed 20 rpm, pressure roller spacing 1.0 mm, and roller hydraulic pressure 10 MPa. The bulk density of the first mixture was measured to be 0.43 g / mL, and the first angle of repose was 36°. After adjustments according to the preset rules, the actual feeding speed was adjusted to 115 rpm, and the pressure roller speed was adjusted to 21 rpm. The resulting first mixed pellets contained 55% particles larger than 60 mesh.

[0054] Step S3: Operate according to the method of forming an interparticle disintegration network structure according to the present invention, specifically including steps S31 to S35. The second preset mixer operating parameters are: three-dimensional motion mixer speed 1000 rpm. The third stage mixing time is 20 minutes; after adding magnesium stearate, the fourth stage mixing time is 5 minutes.

[0055] Step S4: Use an S250PLUS tablet press. The second angle of repose of the second mixture was measured to be 32°. Based on this and the aforementioned particle size distribution, the tableting pressure was adjusted to 8.5 kN according to the preset rules. The final tablet dispersion obtained by compression had a hardness of 105 N and a disintegration time of 26 seconds.

[0056] Comparative Example 1 Amoxicillin dispersible tablets were prepared using a ball milling process. The proportions of raw materials and excipients were the same as in Example 1. Amoxicillin, crospovidone (single type), microcrystalline cellulose, and aspartame were added to a ball mill and mixed at a fixed speed of 1000 rpm for 30 minutes. Then, 5 g of magnesium stearate was added, and the mixture was mixed for 5 minutes before being directly compressed into tablets. The resulting dispersible tablets had a disintegration time of 65 seconds, a hardness of 85 N, and a content uniformity of 8.5%.

[0057] Comparative Example 2 The ratio of raw materials and excipients was the same as in Example 1. Amoxicillin raw material was mixed with some excipients, including 4g of XL-10 type crospovidone and 95g of microcrystalline cellulose (PH102). Purified water (20% of the total weight of the materials) was added for granulation. After drying, the granules were sized and then mixed with the remaining excipients for tableting. The resulting dispersible tablets had a disintegration time of 50 seconds, a hardness of 90N, and a decrease in amoxicillin content (due to degradation caused by moisture introduction), with a content uniformity of 7.2%.

[0058] Effect Comparison The key performance indicators of Example 1 were compared with those of Comparative Examples 1 and 2, and the results are shown in Table 1. Table 1 shows the performance indicator comparison data of amoxicillin prepared in Example 1, Comparative Examples 1, and Comparative Examples 2: Table 1

[0059] As can be seen from Table 1, the amoxicillin dispersible tablets prepared in Example 1 of the present invention are significantly better than those in Comparative Example 1 and Comparative Example 2 in terms of disintegration time, hardness, content uniformity and dissolution rate, which fully demonstrates the excellent effect of the method of the present invention in improving product quality and stability.

[0060] The technical solution of the present invention has been described above with reference to the preferred embodiments shown in the accompanying drawings. However, it will be readily understood by those skilled in the art that the scope of protection of the present invention is obviously not limited to these specific embodiments. Without departing from the principles of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will all fall within the scope of protection of the present invention.

[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing amoxicillin dispersible tablets, characterized in that the steps include... include: Step S1: Based on the internal composite crosslinking disintegrant system, amoxicillin raw material and first crosslinking polyvinyl alcohol are sequentially added to the mixing tank of the mixer, and mixed using the first preset mixer operating parameters. At the end of the mixing, the mixing time of the first preset mixer operating parameters is extended based on the uniformity of amoxicillin content to form an internal water absorption channel structure, thereby obtaining the first mixture. Step S2: The first mixture is fed into the pellet mill. Based on the bulk density of the first mixture and the first rest angle, the feeding speed and / or the roller speed of the preset pellet mill operating parameters are adjusted so as to pelletize using the adjusted preset pellet mill operating parameters to obtain the first mixed particles. Step S3: Based on the external composite crosslinking disintegrant system, the first mixed particles, the second crosslinked povidone, microcrystalline cellulose, and aspartame are sequentially added to the mixer and mixed using the second preset mixer operating parameters to form an interparticle disintegration network structure to obtain the second mixture. Step S4: Based on the second rest angle of the second mixture and the particle size distribution of the first mixed particles, the tableting pressure of the preset tableting machine operating parameters is adjusted, and the second mixture is tableted using the adjusted preset tableting machine operating parameters to complete the preparation of amoxicillin dispersible tablets.

2. The method for preparing amoxicillin dispersible tablets according to claim 1, characterized in that, In step S1, the process of forming the internal water absorption channel structure to obtain the first mixture includes: Step S111: Add 50% by weight of amoxicillin raw material to the mixer to form the first material layer; Step S112: All of the first cross-linked polyvinyl ketone is put into the mixer to uniformly cover the first material layer, forming a disintegrant intermediate layer. Step S113: The remaining 50% by weight of amoxicillin raw material is added to the mixer to form a second material layer, thereby forming the first sandwich structure. Step S114: The first sandwich structure is mixed in the first stage using the first mixing time of the first preset mixer operating parameters, so as to realize the spatial network distribution of the first cross-linked polyvinyl ketone in the amoxicillin raw material and form the internal water absorption channel structure. Step S115: Add the first weight component, magnesium stearate, to the mixer and perform a second stage of mixing using the second mixing time of the first preset mixer operating parameters, so that the magnesium stearate is uniformly dispersed to obtain the first mixture.

3. The method for preparing amoxicillin dispersible tablets according to claim 2, characterized in that, In step S1, the process of determining the mixing time for extending the operating parameters of the first preset mixer based on the uniformity of amoxicillin content in the first mixture includes: Step S121: Obtain the near-infrared spectral data of the first mixture to calculate the uniformity of the amoxicillin content. Step S122: Determine the content standard deviation value based on the content uniformity and the preset content uniformity; Step S123: Compare and analyze the content standard deviation value with the preset content standard deviation value; Step S124: Based on the result that the content standard deviation value is greater than the preset content standard deviation value, determine to extend the mixing time.

4. The method for preparing amoxicillin dispersible tablets according to claim 3, characterized in that, In step S2, the process of adjusting the feeding speed and / or roller speed of the preset pellet mill operating parameters based on the bulk density of the first mixture and the first rest angle includes: Step S21: Obtain the stack density and the first rest angle; Step S22: Determine the first comprehensive deviation value based on the bulk density and the first rest angle; Step S23: Determine the first contribution based on the stack density and the preset stack density; Step S24: Determine the second contribution based on the first rest angle and the preset first rest angle; Step S25: Based on the result that the first comprehensive deviation value is greater than the preset first comprehensive deviation value, determine to compare and analyze the first contribution and the second contribution, and based on the comparison and analysis results, determine to adjust the feeding speed and / or the pressure roller speed of the preset pellet mill operating parameters.

5. The method for preparing amoxicillin dispersible tablets according to claim 4, characterized in that, In step S25, the process of determining the adjustment of the feeding speed and / or pressure roller speed of the preset pellet mill operating parameters based on the comparative analysis results includes: Based on the result that the first contribution is greater than the second contribution, it is determined to reduce the feeding speed; Alternatively, based on the result that the first contribution is less than the second contribution, it is determined to increase the rotational speed of the pressure roller; Alternatively, based on the result that the first contribution equals the second contribution, it is determined to reduce the feeding speed while increasing the rotational speed of the pressure roller.

6. The method for preparing amoxicillin dispersible tablets according to claim 5, characterized in that, In step S3, the process of forming an interparticle disintegration network structure to obtain a second mixture includes: Step S31: 50% to 60% by weight of the first mixed particles are fed into the mixer to form the first particle base layer; Step S32: The second cross-linked polyvinylpyrrolidone, microcrystalline cellulose and aspartame are put into a mixer to make the excipients uniformly cover the surface of the first particle base layer to form an excipient coating layer. Step S33: The remaining 40% to 50% by weight of the first mixed particles are fed into the mixer to form a second particle coating layer; Step S34: The second particle covering layer is mixed in the third stage using the first mixing time of the second preset mixer operating parameters, so that the second crosslinked polyvinyl ketone adheres to the particle surface and gaps, forming the interparticle disintegration network structure that connects multiple particles. Step S35: Add the magnesium stearate of the second weight component to the mixer, and perform a fourth stage of mixing using the second mixing time of the second preset mixer operating parameters to uniformly disperse the magnesium stearate and obtain the second mixture.

7. The method for preparing amoxicillin dispersible tablets according to claim 6, characterized in that, In step S4, the process of adjusting the tableting pressure based on the flowability index of the second mixture and the particle size distribution of the first mixture includes: Step S41: Obtain the second repose angle and the weight percentage of particles larger than 60 mesh in the first mixed particles; Step S42: Determine the second comprehensive deviation value based on the second rest angle and the weight percentage; Step S43: Determine the third contribution based on the second rest angle and the preset second rest angle; Step S44: Determine the fourth contribution based on the weight percentage and the preset weight percentage; Step S45: Compare the second comprehensive deviation value with the preset second comprehensive deviation value; Step S46: Based on the result that the second comprehensive deviation value is greater than the preset second comprehensive deviation value, it is determined to compare and analyze the third contribution and the fourth contribution to determine the tableting pressure of the preset tablet press operating parameters.

8. The method for preparing amoxicillin dispersible tablets according to claim 7, characterized in that, In step S44, based on the result that the third contribution is greater than the fourth contribution, it is determined to adjust and reduce the tableting pressure; Alternatively, based on the result that the third contribution is less than the fourth contribution, it is determined to adjust and increase the tableting pressure.

9. The method for preparing amoxicillin dispersible tablets according to claim 2 or 6, characterized in that, The first preset mixer operating parameters and / or the second preset mixer operating parameters include mixer speed and mixing time, and the pellet mill operating parameters include the distance between pressure rollers and roller hydraulic pressure, wherein, The mixing speed is 900 rpm to 1100 rpm, the first mixing time is 15 minutes to 20 minutes, and the second mixing time is 3 minutes to 8 minutes; The spacing between the pressure rollers is 0.8mm to 1.2mm, and the hydraulic pressure of the rollers is 8MPa to 12MPa.

10. The method for preparing amoxicillin dispersible tablets according to claim 9, characterized in that, The first cross-linked polyvinylpyrrolidone is XL-10 type cross-linked polyvinylpyrrolidone, and the second cross-linked polyvinylpyrrolidone is CL type cross-linked polyvinylpyrrolidone.

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