Structured granulation method of xylitol granules with high compressibility and low hygroscopicity

Abstract

The invention relates to the technical field of pharmaceutical preparations and food processing, and discloses a high-compressibility low-hygroscopicity xylitol particle structured granulation method which comprises the following steps: preheating a xylitol raw material in a fluidized bed; performing kernel granulation, and spraying a first adhesive solution with the concentration being equal to the atomization air pressure being equal to the atomization air pressure, so that the powder is gathered into particle kernels; carrying out surface modification, and switching to spray a second adhesive solution with the concentration of 0 and the atomized air pressure of 0, so as to form a modification layer on the surface of the inner core; and finally drying and granulating. And the like. By coupling control of concentration gradient and pressure gradient, a high-strength framework is constructed in the particles to improve compressibility and prevent top cracking, and a compact layer with spread fine fog drops is formed on the surfaces of the particles to reduce hygroscopicity. The obtained particles realize the unification of high hardness, low moisture absorption and excellent flowability under the condition of low adhesive dosage, and are suitable for high-speed tabletting production.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical formulation and food processing technology, specifically to a structured granulation method for highly compressible and low-hygroscopic xylitol particles. Background Technology

[0002] Xylitol, as a functional sugar alcohol, is widely used in chewable tablets, lozenges, and health foods due to its unique refreshing taste, low calorie content, and anti-caries properties. However, commercially available xylitol raw materials are usually in the form of crystalline powder, which has a smooth surface, poor plasticity, and strong hygroscopicity. Directly using the raw material powder in tablet production often results in problems such as poor flowability leading to large variations in tablet weight, insufficient material binding resulting in low tablet hardness, and easy moisture absorption and sticking.

[0003] To improve the tableting performance of xylitol, fluidized bed wet granulation technology is commonly used in industry, which agglomerates powder into granules by spraying a binder solution. In conventional fluidized bed granulation processes, a constant binder concentration and atomization pressure are usually set. This single-parameter control method faces a technical contradiction when processing xylitol granules, as it is difficult to balance compressibility and hygroscopicity.

[0004] To improve the compressibility of granules and obtain tablets with acceptable hardness, it is usually necessary to increase the concentration of the binder solution or the amount of binder to build strong solid bridges within the granules. However, high-concentration binder solutions have higher viscosity, resulting in larger droplet sizes under conventional atomization pressures, leading to rough granule surfaces and higher porosity. This loose and porous surface structure not only increases the specific surface area but also exposes the hydrophilic binder to more ambient moisture, causing the granules to absorb moisture and gain weight significantly in high-humidity environments, and making the tablet surface prone to stickiness or liquefaction.

[0005] Conversely, reducing the binder concentration or increasing the atomization pressure to decrease droplet size in order to reduce hygroscopicity may help form a denser particle surface, but it often leads to insufficient internal binding force within the particles. This lack of internal skeleton strength prevents the particles from effectively transmitting pressure and forming a stable interlocking structure when subjected to mechanical compression during tableting, making them highly susceptible to cracking. Furthermore, the resulting tablets have low hardness and cannot meet packaging and transportation requirements.

[0006] While existing technologies employ methods to improve performance by adding antihypertensive agents or using compound excipients, these methods increase production costs and process complexity, and negatively impact product purity and taste. Therefore, achieving both high compressibility and low hygroscopicity in xylitol granules by optimizing granulation process parameters without significantly increasing excipient usage is a pressing technical problem in this field. This invention provides a structured granulation method for highly compressible, low-hygroscopic xylitol granules to address the shortcomings of existing technologies. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a structured granulation method for highly compressible and low-hygroscopic xylitol particles, solving the problems mentioned in the background section.

[0008] In a first aspect, the present invention provides a structured granulation method for highly compressible and low-hygroscopic xylitol particles, employing the following technical solution: A structured granulation method for high compressibility and low hygroscopicity xylitol particles includes the following steps: S1: Xylitol raw material is fed into a fluidized bed, the fluidization process is initiated, and the bed is preheated; S2: Core granulation step: While maintaining the material in a fluidized state, a first binder solution is sprayed into the xylitol raw material, the concentration of which is... The atomizing air pressure is This causes the xylitol powder to aggregate into particle cores; S3: Surface modification step: After the first adhesive solution spraying is completed, the second adhesive solution is sprayed in, and the concentration of the second adhesive solution is... The atomizing air pressure is A modification layer is formed on the surface of the particle core; S4: Drying and granulation: After spraying, the particles are dried until the moisture content meets the requirements, and then granulated; wherein, the concentration And the atomizing air pressure .

[0009] By employing the above technical solution and utilizing the dual coupling control of concentration and pressure gradients, the stepwise construction of the internal structure and surface properties of the particles is achieved. Specifically, in the core granulation stage, a higher concentration of binder with higher viscosity, combined with a lower atomization pressure, results in larger droplet sizes generated by the nozzle. These droplets effectively wet the xylitol powder and establish strong liquid bridge connections, thereby constructing a strongly bonded skeletal structure within the particles. This skeletal structure ensures the mechanical transmission performance of the particles under compression, solves the problem of top cracking, and provides good compressibility. In the surface modification stage, a lower concentration of binder with reduced viscosity, combined with a higher atomization pressure, promotes the dispersion of the solution into fine droplets. These fine droplets rapidly spread into a film upon contact with the particle surface, reducing penetration into the particle interior, thus forming a dense modification layer on the particle core surface. This modification layer effectively seals the micropores on the particle surface, preventing environmental moisture from entering the particle interior and significantly reducing the moisture absorption and weight gain rate of the finished product. This method solves the technical contradiction between poor compressibility and high hygroscopicity in direct compression of xylitol at the single particle scale by first constructing a high-strength core and then coating it with a dense outer layer.

[0010] Preferably, in step S2, the concentration of the first adhesive solution is... The concentration is 1.5% to 2.5% (w / w); in step S3, the concentration of the second adhesive solution... The concentration is 0.5% to 1.5% (w / w). By adopting the above technical solution, it is ensured that the first adhesive solution has sufficient solid content to form effective adhesion, while avoiding the second adhesive solution from affecting the atomization effect due to excessive viscosity, thus ensuring the density and smoothness of the surface film. Preferably, in step S2, the atomizing air pressure... The pressure is 0.1 MPa to 0.3 MPa; in step S3, the atomizing air pressure The pressure ranges from 0.5 MPa to 0.8 MPa. By adopting the above technical solution, the droplet size is controlled by a pressure of 0.1 MPa to 0.3 MPa, which promotes particle growth and reduces the generation of fine powder; the atomization kinetic energy is increased by a pressure of 0.5 MPa to 0.8 MPa, which improves the density and smoothness of the particle surface and further reduces the surface porosity.

[0011] Preferably, the spraying weight ratio of the first adhesive solution to the second adhesive solution is 2:1 to 4:1.

[0012] By adopting the above technical solution, the ratio of core construction materials to surface modification materials is controlled within an appropriate range to balance the internal mechanical strength of the particles and the surface moisture-proof performance, avoiding the problem of easy tablet compression due to too low core ratio or insufficient moisture-proof effect due to too low surface ratio.

[0013] Preferably, the adhesive in both the first adhesive solution and the second adhesive solution is sodium carboxymethyl cellulose, and the solvent is purified water.

[0014] By adopting the above technical solution and using an adhesive system with the same composition but different concentrations, material compatibility issues are avoided, and sodium carboxymethyl cellulose has good film-forming properties, which can meet the needs of structured granulation.

[0015] Preferably, in steps S1 to S3, the material temperature is controlled at 40℃~60℃; in step S4, the drying air temperature is controlled at 55℃~65℃, and the drying is controlled until the particle moisture content is ≤0.5%.

[0016] By adopting the above technical solution, the process temperature is controlled below the melting point of xylitol, preventing the material from softening or collapsing due to local overheating during fluidization, while ensuring effective evaporation of moisture, so that the finished product meets the low moisture standard.

[0017] Preferably, step S2 is implemented by continuously delivering the first adhesive solution via a peristaltic pump, using larger droplets to wet the xylitol powder to construct a framework; step S3 is implemented by immediately switching to the second adhesive solution after the first adhesive solution is sprayed, using fine droplets to spread and form a film on the particle surface.

[0018] By adopting the above technical solution and using a continuously switching liquid supply method, the continuity of the particle growth process and production efficiency are ensured.

[0019] Secondly, the present invention provides xylitol granules with high compressibility and low hygroscopicity, using the following technical solution: A highly compressible and low-hygroscopic xylitol granule is made from a raw material comprising xylitol and a binder, and the xylitol granule is prepared by the structured granulation method described in the first aspect.

[0020] By adopting the above technical solution, the obtained xylitol particles possess a structure characterized by strong core bonding and a dense surface. This structure results in a support network formed by a high concentration of binder inside the particles and a barrier layer formed by a low concentration of binder on the outside, thereby maintaining low hygroscopicity while exhibiting excellent compression molding performance.

[0021] Preferably, the raw material is composed of the following components in parts by weight: 100 parts xylitol and 0.3 to 0.4 parts sodium carboxymethyl cellulose.

[0022] By adopting the above technical solution, high-performance granulation was achieved with a low amount of adhesive (0.3% to 0.4%), which improved the distribution efficiency of the adhesive and reduced the proportion of auxiliary materials in the product.

[0023] Preferably, the granules have the following performance parameters: Karl Fischer index ≤ 16%; moisture absorption weight gain rate ≤ 0.75% after being placed at 25°C and 75%RH for 24 hours; and tablets pressed under a main pressure of 8kN and a rotation speed of 30rpm with a hardness ≥ 78N and no top cracking.

[0024] By employing the above technical solution, the physical properties of the particles were quantified. A Karl Fischer index ≤ 16% indicates that the particles have good flowability; a moisture absorption weight gain rate ≤ 0.75% confirms the barrier effect of the surface modification layer; and a hardness ≥ 78N with no top cracks confirms the mechanical support of the internal skeleton, indicating that the particles are suitable for high-speed tableting processes.

[0025] This invention provides a structured granulation method for highly compressible, low-hygroscopic xylitol particles. It offers the following advantages: 1. This invention effectively resolves the contradiction between compressibility and hygroscopicity in direct compression of xylitol granules through a dual coupling process of concentration gradient and pressure gradient. The process first-stage high-concentration low-pressure spray constructs a high-strength bonding skeleton inside the granules, ensuring the transmission of mechanical force during tableting and eliminating top cracking. The second-stage low-concentration high-pressure spray uses micro-droplets to form a dense and smooth modification layer on the granule surface, effectively blocking the intrusion of environmental moisture. The resulting granules maintain a tablet hardness greater than 78N while significantly reducing the moisture absorption weight gain rate, achieving appearance stability in high-humidity environments.

[0026] 2. This invention improves the surface morphology and sphericity of particles by stepwise controlling droplet size and viscosity, reducing interparticle friction, controlling the Karl Fischer index below 16%, achieving suitable bulk density, and exhibiting excellent flowability and filling properties, meeting the continuous production requirements of high-speed rotary tablet presses. Simultaneously, this process avoids the common problems of material sticking to the walls or excessive fine powder in conventional granulation, maintaining a stable yield of over 97%, making it suitable for industrial production. The resulting particles possess excellent powder properties and process reproducibility.

[0027] 3. This invention significantly improves the utilization efficiency of adhesives and achieves high-performance granulation with low additive amounts. By using a structured distribution strategy, the limited amount of adhesive is precisely distributed in the internal skeleton nodes and surface coating layer of the particles. Only 0.3% to 0.4% of adhesive is needed to achieve the molding effect that traditional processes require high additive amounts. The low additive amount formulation design not only reduces production costs but also preserves the high purity characteristics of xylitol to the greatest extent. Attached Figure Description

[0028] Figure 1 This is a flowchart of the method steps of the present invention. Detailed Implementation

[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0030] Please see the appendix Figure 1 The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products: Xylitol, CAS No. 87-99-0, is a white crystalline powder with a purity ≥99.0%, melting point 92℃~96℃, loss on drying ≤0.5%, and particle size distribution where all particles pass through a 60-mesh sieve and no more than 20% pass through a 200-mesh sieve. Sodium carboxymethyl cellulose, CAS No. 9004-32-4, is a white or off-white fibrous powder with a viscosity (2% aqueous solution, 25℃) of 300 mPa·s-800 mPa·s, a degree of substitution (DS) of 0.7-0.9, a pH value (1% aqueous solution) of 6.5-8.5, and a loss on drying ≤10.0%. Purified water, CAS No. 7732-18-5, meets the purified water standard of the 2020 edition of the Chinese Pharmacopoeia, with conductivity ≤5.1μS / cm (25℃) and total organic carbon ≤500ppb.

[0031] Preparation Example 1: This preparation example provides a high-concentration binder solution for core granulation with a concentration of 2.0%, comprising the following steps: accurately weighing 200g of sodium carboxymethyl cellulose (CMC-Na) and placing it in a mixing tank; adding 9800g of purified water to the mixing tank; turning on a mechanical stirrer and adjusting the speed to 300rpm to 500rpm, and stirring continuously at room temperature (25℃±2℃) for 30 to 45 minutes until the sodium carboxymethyl cellulose is completely dissolved, the solution is clear and transparent without lumps, thus obtaining a first binder solution with a concentration of 2.0% (w / w).

[0032] Preparation Example 2: This preparation example provides a low-concentration adhesive solution for surface modification with a concentration of 1.0%, comprising the following steps: accurately weighing 100g of sodium carboxymethyl cellulose (CMC-Na) and placing it in a mixing tank; adding 9900g of purified water to the mixing tank; turning on a mechanical stirrer and adjusting the speed to 300rpm to 500rpm, and stirring continuously at room temperature (25℃±2℃) for 20 to 30 minutes until the sodium carboxymethyl cellulose is completely dissolved, the solution is clear and transparent without lumps, thus obtaining a second adhesive solution with a concentration of 1.0% (w / w).

[0033] Preparation Example 3: This preparation example provides an intermediate concentration adhesive solution for comparative experiments, with a concentration of 1.5%, comprising the following steps: accurately weighing 150g of sodium carboxymethyl cellulose (CMC-Na) and placing it in a mixing tank; adding 9850g of purified water to the mixing tank; turning on a mechanical stirrer and adjusting the speed to 300rpm to 500rpm, and stirring continuously at room temperature (25℃±2℃) for 25 to 40 minutes until the sodium carboxymethyl cellulose is completely dissolved, the solution is clear and transparent without lumps, thus obtaining an adhesive solution with a concentration of 1.5% (w / w).

[0034] Example 1: This embodiment provides a structured granulation method for highly compressible and low-hygroscopic xylitol particles, including the following steps: (1) Put 100kg xylitol raw material into the material tank of the fluidized bed granulator (model: FLP-5), turn on the blower and heating system, set the air inlet temperature, and preheat the material to 50℃ in the fluidized state; (2) Core granulation step: Maintain the material temperature at 50℃±2℃, and deliver the first binder solution with a concentration of 2.0% prepared in Preparation Example 1 to the spray gun through a peristaltic pump, and adjust the atomizing air pressure. At a pressure of 0.2 MPa, 15 kg of the first adhesive solution was continuously sprayed in, causing the xylitol powder to aggregate into a particle core. (3) Surface modification step: After the first adhesive solution is sprayed, immediately switch to the second adhesive solution with a concentration of 1.0% prepared in Preparation Example 2, and adjust the atomizing air pressure. The pressure is 0.6 MPa, the material temperature is maintained at 50℃±2℃, and 5 kg of the second adhesive solution is continuously sprayed in. At this time, the weight ratio of the first adhesive solution to the second adhesive solution is 3:1. (4) Drying and granulation: After the spraying is completed, maintain the fluidized state, set the air inlet temperature to 60℃ for drying until the moisture content (drying loss) of the particles is ≤0.5%, discharge the material, and granulate it using a 20-mesh sieve to obtain xylitol particles.

[0035] Example 2: This embodiment provides a structured granulation method for high compressibility and low hygroscopicity xylitol particles, used as a verification of the lower limit of process parameters, including the following steps: (1) Put 100 kg of xylitol raw material into the fluidized bed granulator, turn on the blower and heating system, and preheat the material to 40°C in the fluidized state; (2) Core granulation step: Maintain the material temperature at 40℃±2℃, convey the first binder solution with a concentration of 2.0% obtained in Preparation Example 1, and adjust the atomizing air pressure. At a pressure of 0.1 MPa, 16 kg of the first adhesive solution was continuously sprayed in. (3) Surface modification step: Switch to the second binder solution with a concentration of 1.0% prepared in Preparation Example 2, and adjust the atomizing air pressure. The pressure is 0.5 MPa, the material temperature is maintained at 40℃±2℃, and 4 kg of the second adhesive solution is continuously sprayed in. At this time, the weight ratio of the first adhesive solution to the second adhesive solution is 4:1. (4) Drying and granulation: After the spraying is completed, maintain the fluidized state, set the air inlet temperature to 60℃ for drying until the moisture content of the particles is ≤0.5%, discharge the material, and granulate it using a 20-mesh sieve to obtain xylitol particles.

[0036] Example 3: This embodiment provides a structured granulation method for high compressibility and low hygroscopicity xylitol particles, which serves as a verification of the upper limit of process parameters, and includes the following steps: (1) Put 100 kg of xylitol raw material into the fluidized bed granulator, turn on the blower and heating system, and preheat the material to 60°C in the fluidized state; (2) Core granulation step: Maintain the material temperature at 60℃±2℃, convey the first binder solution with a concentration of 2.0% obtained in Preparation Example 1, and adjust the atomizing air pressure. At a pressure of 0.3 MPa, 13.3 kg of the first adhesive solution was continuously sprayed in. (3) Surface modification step: Switch to the second binder solution with a concentration of 1.0% prepared in Preparation Example 2, and adjust the atomizing air pressure. The pressure is 0.8 MPa, the material temperature is maintained at 60℃±2℃, and 6.7 kg of the second adhesive solution is continuously sprayed. At this time, the weight ratio of the first adhesive solution to the second adhesive solution is approximately 2:1. (4) Drying and granulation: After the spraying is completed, maintain the fluidized state, set the air inlet temperature to 60℃ for drying until the moisture content of the particles is ≤0.5%, discharge the material, and granulate it using a 20-mesh sieve to obtain xylitol particles.

[0037] Example 4: This embodiment provides a structured granulation method for highly compressible and low-hygroscopic xylitol particles, aiming to verify the granulation effect under high kernel ratio conditions, including the following steps: (1) Put 100 kg of xylitol raw material into the fluidized bed granulator, turn on the blower and heating system, and preheat the material to 55°C in the fluidized state; (2) Core granulation step: Maintain the material temperature at 55℃±2℃, convey the first binder solution with a concentration of 2.0% obtained in Preparation Example 1, and adjust the atomizing air pressure. The pressure is 0.25 MPa, and 16 kg of the first adhesive solution is continuously sprayed in. (3) Surface modification step: Switch to the second binder solution with a concentration of 1.0% prepared in Preparation Example 2, and adjust the atomizing air pressure. The pressure is 0.7 MPa, the material temperature is maintained at 55℃±2℃, and 4 kg of the second adhesive solution is continuously sprayed in. At this time, the weight ratio of the first adhesive solution to the second adhesive solution is 4:1. (4) Drying and granulation: After the spraying is completed, maintain the fluidized state, set the air inlet temperature to 60℃ for drying until the moisture content of the particles is ≤0.5%, discharge the material, and granulate it using a 20-mesh sieve to obtain xylitol particles.

[0038] Example 5: This embodiment provides a structured granulation method for highly compressible and low-hygroscopic xylitol particles, aiming to verify the granulation effect under conditions of high surface modification ratio, including the following steps: (1) Put 100 kg of xylitol raw material into the fluidized bed granulator, turn on the blower and heating system, and preheat the material to 45°C in the fluidized state; (2) Core granulation step: Maintain the material temperature at 45℃±2℃, convey the first binder solution with a concentration of 2.0% obtained in Preparation Example 1, and adjust the atomizing air pressure. The pressure was 0.15 MPa, and 13.4 kg of the first adhesive solution was continuously sprayed in. (3) Surface modification step: Switch to the second binder solution with a concentration of 1.0% prepared in Preparation Example 2, and adjust the atomizing air pressure. The pressure is 0.65 MPa, the material temperature is maintained at 45℃±2℃, and 6.6 kg of the second adhesive solution is continuously sprayed. At this time, the weight ratio of the first adhesive solution to the second adhesive solution is approximately 2.03:1 (within the range of 2:1 to 4:1). (4) Drying and granulation: After the spraying is completed, maintain the fluidized state, set the air inlet temperature to 60℃ for drying until the moisture content of the particles is ≤0.5%, discharge the material, and granulate it using a 20-mesh sieve to obtain xylitol particles.

[0039] Comparative Example 1: This comparative example simulates the traditional one-step granulation method. The difference from Example 1 is that the step-by-step granulation operation is eliminated, and a single-stage granulation is used. Specifically, 20 kg of the 1.5% binder solution obtained in Preparation Example 3 is continuously sprayed into a fluidized bed at a constant atomized air pressure of 0.4 MPa for granulation. The remaining raw material amounts, temperature control, and drying and granulation steps are the same as in Example 1.

[0040] Comparative Example 2: This comparative example aims to verify the necessity of the variable pressure process. The difference compared to Example 1 is that the atomizing air pressure remains constant throughout the granulation process. Specifically, the atomizing air pressure is constant during both the core granulation and surface modification steps. and All were set to 0.4 MPa, and the remaining steps and parameters (including concentration gradients of 2% and 1%, solution volume and switching operation) were the same as in Example 1.

[0041] Comparative Example 3: This comparative example aims to verify the necessity of a variable concentration process. The difference from Example 1 is that a single concentration of binder is used throughout the granulation process. Specifically, in both the core granulation and surface modification steps, a 1.5% binder solution prepared in Preparation Example 3 is used (15 kg is sprayed in the first stage, and 5 kg is sprayed in the second stage). All other steps and parameters (including pressure gradients of 0.2 MPa and 0.6 MPa, and temperature control) are the same as in Example 1.

[0042] Comparative Example 4: This comparative example aims to verify the necessity of the "core-first, surface-second" process sequence. The difference from Example 1 is that the order of the granulation steps is reversed. Specifically, surface modification is performed first (5 kg of a 1.0% concentration second binder solution is sprayed at a pressure of 0.6 MPa), followed by core granulation (15 kg of a 2.0% concentration first binder solution is sprayed at a pressure of 0.2 MPa). The remaining raw material amounts and drying / granulation steps are the same as in Example 1.

[0043] Comparative Example 5: This comparative example aims to verify the necessity of the surface modification step. The difference from Example 1 is that the surface modification step was omitted. Specifically, only the core granulation step was performed (spraying in 20 kg of a 2.0% concentration first binder solution at a pressure of 0.2 MPa). After spraying, drying and granulation were carried out directly. The remaining raw material amounts and temperature control were the same as in Example 1.

[0044] Test Example 1: The xylitol granules prepared in Examples 1 to 5 were used as test samples. First, the yield was determined by collecting and weighing the final granulated product, and calculating its percentage relative to the total weight of the input raw materials (the sum of xylitol raw material and binder solids). Next, the loss on drying (LOD) was determined by spreading approximately 2g of the finished product granules evenly in a weighing bottle and drying it in a 105°C drying oven until constant weight, calculating the percentage of weight loss. Finally, the particle size distribution was determined using the standard sieve method. 100g of granules was weighed and placed on a vibrating sieve and vibrated for 10 minutes, and the median particle size (D50) was recorded.

[0045] Table 1. Test results of basic physical properties of particles in Examples 1-5

[0046] Data show that the product yields of Examples 1 to 5 ranged from 97.1% to 98.8%, and the loss on drying values ​​ranged from 0.28% to 0.45%, all below the control limit of 0.5%. The median particle size D50 ranged from 268 μm to 312 μm. These results demonstrate that, within the set parameter range, the stepwise granulation process can stably produce particles with low moisture content and suitable particle size, without excessive material adhesion to the walls or failure to dry, indicating good reproducibility of the process.

[0047] Test Example 2: The granules prepared in Examples 1 to 5 and Comparative Examples 1 to 5 were used as test samples. The bulk density and tap density of each group of granules were measured and the Karl Fischer index was calculated. A quantitative amount of granules was weighed and placed in a constant temperature and humidity chamber at 25°C and 75% relative humidity. After 24 hours, the moisture absorption weight gain rate was measured. Using a rotary tablet press, under a main pressure of 8 kN and a rotation speed of 30 rpm, each group of granules was compressed into tablets with a weight of 0.5 g, and samples were taken to measure the tablet hardness.

[0048] Table 2. Test results of particle properties and tableting performance of the examples and comparative examples

[0049] Data show that the Karl Fischer index of Examples 1 to 5 ranged from 13.5% to 15.8%, the moisture absorption weight gain was controlled between 0.58% and 0.71%, and the tablet hardness was maintained between 78.9 N and 88.2 N.

[0050] Comparative Example 5, which only underwent the first stage of high-concentration, low-pressure granulation, produced tablets with the highest hardness (92.1 N), but also exhibited a moisture absorption weight gain rate as high as 2.15%. This result confirms that a high-concentration binder combined with low atomization pressure can construct a high-strength particle skeleton, significantly improving compressibility. However, due to the large pores on the particle surface and the uneven distribution of the hydrophilic binder, the particles are highly susceptible to moisture absorption.

[0051] Compared with Comparative Example 5, the hardness value of the Example Group decreased slightly but still met the tableting requirements, while the moisture absorption weight gain rate decreased by more than 60%. This indicates that the low-concentration, high-atomization-pressure process used in the second stage promoted the micronization of the adhesive droplets, and formed a denser modification layer on the particle surface while maintaining the strength of the internal skeleton, thus blocking the intrusion of environmental moisture.

[0052] Comparative Example 4, with a reversed process order, exhibited a higher moisture gain rate (1.82%) and the lowest tablet hardness (55.6 N). The initial surface modification process (high pressure, low concentration) resulted in a compact initial particle structure but weak internal binding force. Consequently, the subsequent high-concentration binder could not effectively penetrate the interior to build the skeleton, instead accumulating on the surface and increasing moisture absorption.

[0053] Comparative Example 1 (single parameter), Comparative Example 2 (no pressure gradient), and Comparative Example 3 (no concentration gradient) all outperformed Comparative Example 4 but were inferior to the Example Group. Data from Comparative Examples 2 and 3 showed that single-dimensional gradient control (concentration only or pressure only) could not simultaneously achieve both moisture resistance and compressibility. This invention achieves a balance between the internal structural strength of the particles and the surface physical barrier performance through a dual gradient coupling of concentration and pressure: the first stage involves strong adhesion of large droplets to construct the core, and the second stage involves microdroplet film formation to modify the surface.

[0054] Test Example 3: Take the granular samples prepared in Examples 1 to 5 and Comparative Examples 1 to 5. The sieved granules were naturally filled into a fixed-volume cylinder, and the bulk density was calculated using the mass-to-volume ratio. Each group of granules was compressed into tablets under the same compression parameters as in Test Example 2, and the presence of top cracking was observed during and after tablet disassembly. Whole tablets were taken and their disintegration time was determined in a 37°C water bath according to the disintegration time test method specified in the pharmacopoeia. Another tablet was placed in an environment of 40°C and 75% relative humidity for 24 hours, and the changes in the tablet's appearance were observed.

[0055] Table 3. Results of the comprehensive test on particle filling properties and tablet quality

[0056] Data show that the bulk density of Examples 1 to 5 ranges from 0.67 g / ml to 0.72 g / ml, the disintegration time is controlled between 26 seconds and 31 seconds, and the structure is intact and the appearance is stable during tableting and stability tests.

[0057] Comparative Example 1 had a bulk density of 0.66 g / ml and exhibited slight top cracking and moisture absorption. Granulation with a single-concentration binder resulted in voids within the particles, and no effective barrier layer was formed on the surface. Air trapping during tableting caused top cracking, and moisture easily penetrated in high-humidity environments.

[0058] Comparative Example 4 had the lowest bulk density (0.58 g / ml) and obvious top cracking. The process sequence of surface modification followed by core granulation resulted in weak internal bonding of the particles, failing to form a compact entity. Furthermore, the high-concentration adhesive layer on the outside became sticky due to moisture absorption under high humidity. In addition, due to the large difference in density between the internal and external structures, lamellar delamination easily occurred after tableting under stress.

[0059] Comparative Example 5 had a high bulk density (0.71 g / ml) and no top cracking, but surface liquefaction points appeared in the stability test. Although the internal skeleton constructed with high-concentration binder improved the bulk density and resistance to top cracking, it lacked the surface sealing effect of low-concentration fine droplets, and the direct exposure of xylitol and high-concentration CMC-Na resulted in insufficient moisture resistance.

[0060] In the first stage, this invention utilizes high-concentration, low-pressure spraying to reduce interparticle voids and achieve high bulk density; in the second stage, it utilizes low-concentration, high-pressure spraying to form a dense layer on the particle surface. This structure ensures the transfer of mechanical forces during tableting, eliminates top cracking, prevents moisture intrusion, and maintains an appropriate disintegration time.

Claims

1. A structured granulation method for high compressibility and low hygroscopicity xylitol particles, characterized in that, Includes the following steps: S1: Add xylitol raw material into the fluidized bed, start the fluidization process and preheat; S2: Core granulation step: Maintaining the material in a fluidized state, a first binder solution is sprayed into the xylitol raw material. The concentration of the first binder solution is... The atomizing air pressure is This causes the xylitol powder to aggregate into particle cores; S3: Surface finishing step: After the first adhesive solution spraying is completed, switch to spraying the second adhesive solution, the concentration of which is... The atomizing air pressure is A modification layer is formed on the surface of the particle core; S4: Drying and Granulation: After spraying, dry until the moisture content of the particles meets the requirements, then granulate to obtain the final product; wherein, the concentration... And the atomizing air pressure .

2. The structured granulation method for high compressibility and low hygroscopicity xylitol particles according to claim 1, characterized in that, In step S2, the concentration of the first adhesive solution The concentration is 1.5% to 2.5% (w / w); in step S3, the concentration of the second adhesive solution... It ranges from 0.5% to 1.5% (w / w).

3. The structured granulation method for high compressibility and low hygroscopicity xylitol particles according to claim 1, characterized in that, In step S2, the atomizing air pressure The pressure ranges from 0.1 MPa to 0.3 MPa. In step S3, the atomizing air pressure The pressure ranges from 0.5 MPa to 0.8 MPa.

4. The structured granulation method for high compressibility and low hygroscopicity xylitol particles according to claim 1, characterized in that, The spraying weight ratio of the first adhesive solution to the second adhesive solution is 2:1 to 4:

1.

5. The structured granulation method for high compressibility and low hygroscopicity xylitol particles according to claim 1, characterized in that, The adhesive in both the first and second adhesive solutions is sodium carboxymethyl cellulose, and the solvent in both is purified water; the concentration of the first adhesive solution... The concentration of the second adhesive solution is 2.0%. It is 1.0%.

6. The structured granulation method for high compressibility and low hygroscopicity xylitol particles according to claim 1, characterized in that, In steps S1 to S3, the material temperature is controlled at 40℃~60℃; in step S4, the drying air temperature is controlled at 55℃~65℃, and the drying is controlled until the particle moisture content is ≤0.5%.

7. The structured granulation method for high compressibility and low hygroscopicity xylitol particles according to claim 1, characterized in that, In step S2, a first adhesive solution is continuously delivered by a peristaltic pump, using larger droplets to wet xylitol powder to build a framework; in step S3, immediately after the first adhesive solution is sprayed, a second adhesive solution is switched on, using smaller droplets to spread and form a film on the particle surface.

8. A type of xylitol granules with high compressibility and low hygroscopicity, characterized in that, Made from raw materials containing xylitol and binders, wherein the xylitol particles are prepared by the structured granulation method as described in any one of claims 1-7.

9. The xylitol granules with high compressibility and low hygroscopicity according to claim 8, characterized in that, The raw material consists of the following components in parts by weight: 100 parts xylitol and 0.3 to 0.4 parts sodium carboxymethyl cellulose.

10. The structured granulation method for high compressibility and low hygroscopicity xylitol particles according to claim 1, characterized in that, The particles have the following performance parameters: Carr's exponent ≤ 16%; The moisture absorption weight gain rate after being placed at 25℃ and 75%RH for 24 hours is ≤0.75%; The tablets pressed under a main pressure of 8kN and a rotation speed of 30rpm have a hardness of ≥78N and no top cracking.

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