A polycarbophil calcium granule and a method for preparing the same

Abstract

The present application belongs to the field of oral medicine granules preparation, and provides a polycarbophil calcium granule and a preparation method thereof. The present application realizes wet dispersion and cross-compound granulation of polycarbophil calcium and corn-derived pre-gelatinized starch, so that the pre-gelatinized starch is distributed on the surface of the polycarbophil calcium and bridged between the granules. In combination with the sequential mixing of mannitol, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide and sucralose, a bagged granule with controlled particle size, moisture, calcium release and swelling performance is obtained, which takes into account the integrity of the granule structure, dispersibility, processing fluidity and exchangeable calcium release in an acid medium, solves the problems of bridging enhancement and dispersion reduction, roughening densification and release limitation, and is suitable for oral granule production and quality control.

Description

Technical Field

[0001] This invention relates to the field of oral drug granule preparation, specifically to a polycarboxylic acid calcium granule and its preparation method. Background Technology

[0002] Polycarboxylic acid calcium oral formulations have significant application value in intestinal moisture regulation, ease of swallowing, and dosage stability. Granules are easier to disperse and administer by sachet compared to tablets, but their industrial preparation requires meeting multiple formulation performance requirements simultaneously. On the one hand, the granules should have sufficient structural integrity to reduce the formation of fine powder during transportation, dispensing, and mixing, and maintain uniform content within the batch. On the other hand, the granules need to be rapidly wetted, dispersed, and swell upon entering aqueous or acidic environments to avoid forming hard clumps that are difficult to disperse. For granules containing a high proportion of hydrophilic crosslinked polymers, particle size, moisture content, bridging strength, excipient distribution, and post-mixing sequence all affect flowability, dispersibility, release behavior, and dosage stability. Therefore, it is necessary to establish a preparation system that can form a controllable particle structure during granulation, maintain flowability during post-mixing, and maintain dispersion and release capabilities during use.

[0003] Existing oral formulations of polycarboxymethyl calcium mainly focus on tablets, direct compression, or conventional granulation, often improving disintegration and processability through hydrophilic matrices, fillers, disintegrants, or flow aids. For example, Chinese patent CN112704664A discloses a polycarboxymethyl calcium tablet and its preparation method, which improves tablet disintegration by combining a solid micelle dispersion with fillers, disintegrants, flow aids, and lubricants; JP2004224758A also discloses a formulation containing polycarboxymethyl calcium and potentially pregelatinized starch. However, these disclosures focus more on tablet or general formulation forming and do not fully address the interplay between bridging enhancement, particle dispersion, particle size reduction, flowability, and exchangeable calcium release in acidic media in granules. If the bonding or bridging strength is simply increased, the particle structure may be more complete, but it is easy to form hard clumps after water enters. If the disintegration effect is simply increased, fine powder is easily generated during the packaging and transportation of the particles. If the particles are simply coarsened to improve flowability, the release and expansion performance may be weakened. Therefore, a particle preparation method that takes into account structure, dispersion, release and industrial mixing and packaging is still needed. Summary of the Invention

[0004] The purpose of this invention is to provide a polycarbohydrate calcium granule and its preparation method, which solves the problem that it is difficult to simultaneously achieve structural integrity, dispersibility, processing fluidity and calcium release in acidic media in current polycarbohydrate calcium granule.

[0005] This invention utilizes the wetting dispersion and cross-compound granulation of polycarboxymethyl cellulose and corn-derived pregelatinized starch to achieve a controlled distribution of pregelatinized starch on the particle surface and in the interparticle bridging regions. Furthermore, it incorporates cross-linked sodium carboxymethyl cellulose, colloidal silica, and sequential mixing to regulate the particle wetting, disintegration, flow, and release processes, thereby achieving a balance between particle structural integrity, dispersibility, processing fluidity, and exchangeable calcium release in acidic media.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A polycarboxylic acid calcium granule, based on a final dry basis total mass of 100 wt%, comprises the following components:

[0008] Polycarboxylic acid calcium 55–75 wt%;

[0009] 5–15 wt% pregelatinized starch, said pregelatinized starch being derived from corn;

[0010] Mannitol 10–30 wt%;

[0011] 0.5–3.0 wt% croscarmellose sodium;

[0012] Colloidal silica 0.2–0.8 wt%;

[0013] Sucralose 0–1.0 wt%

[0014] The total mass fraction of polycarboxymethyl cellulose, pregelatinized starch, mannitol, croscarmellose sodium, colloidal silica, and sucralose is 100 wt%, and the mass ratio of polycarboxymethyl cellulose to pregelatinized starch is 100:8 to 100:20. The polycarboxymethyl cellulose and pregelatinized starch form polycarboxymethyl cellulose-pregelatinized starch cross-composite particles. The pregelatinized starch is distributed on the surface of the polycarboxymethyl cellulose and in the interparticle bridging region. The D50 of the polycarboxymethyl cellulose-pregelatinized starch cross-composite particles is 300–850 μm, and the loss on drying is 2.0–5.0 wt%.

[0015] Furthermore, the exchangeable calcium release rate of the polycarboxymethyl calcium granules in 0.1 mol / L hydrochloric acid solution for 30 min is 80–98%, and the water absorption and swelling amount of the polycarboxymethyl calcium granules after treatment with the 0.1 mol / L hydrochloric acid solution is 25–60 g / g polycarboxymethyl calcium.

[0016] Furthermore, the polycarboxylic acid-pregelatinized starch cross-composite particles are prepared through the following steps:

[0017] A1. Raw material preparation: Weigh 100 parts by weight of polycarboxymethyl calcium and 8-20 parts by weight of pregelatinized starch, wherein the pregelatinized starch is derived from corn;

[0018] A2. Wetting and Dispersion: A portion of the pregelatinized starch is dispersed in purified water to obtain a pregelatinized starch aqueous dispersion;

[0019] A3. Cross-composite granulation: The polycarboxylic acid calcium is mixed with pregelatinized starch not used to prepare the pregelatinized starch aqueous dispersion, and then the pregelatinized starch aqueous dispersion is added. Granulation is carried out at 20–35°C, so that the pregelatinized starch is distributed on the surface of the polycarboxylic acid calcium and in the interparticle bridging region.

[0020] A4. Endpoint control: When the amount of the pregelatinized starch aqueous dispersion added is 8-18 wt% of the amount of the premixed material, granulation is stopped when the mass fraction of wet particles passing through the sieve after granulation is 70-95 wt%.

[0021] A5. Post-processing: The wet granules are dried and granulated to obtain polycarbohydrate calcium-pregelatinized starch cross-composite granules;

[0022] A6. Quality control: The D50 of the polycarboxylic acid calcium-pregelatinized starch cross-composite particles is 300–850 μm, and the loss on drying is 2.0–5.0 wt%.

[0023] Furthermore, in step A1, the polycarboxymethyl calcium undergoes the following pretreatment and premixing before granulation:

[0024] B1. The polycarbohydrate calcium is sieved to obtain polycarbohydrate calcium raw material;

[0025] B2. The polycarbohydrate calcium raw material is dried to a drying loss of 0.5–6.0 wt%.

[0026] B3. The dried polycarbohydrate calcium raw material is premixed with pregelatinized starch that was not used to prepare the pregelatinized starch aqueous dispersion to obtain a premix.

[0027] B4. The mass fraction of fine powder with a particle size of less than 75 μm in the premix is ​​10–45 wt%.

[0028] Furthermore, in step A2, the pregelatinized starch aqueous dispersion is prepared by the following method:

[0029] C1. Add a portion of the pregelatinized starch to purified water;

[0030] C2. Disperse at 20–35℃ to obtain a pregelatinized starch aqueous dispersion with a solid content of 5–15 wt% and a pH of 5.0–7.5;

[0031] C3. The pregelatinized starch aqueous dispersion is left to stand for 0–4 hours before being added in step A3;

[0032] C4. The pregelatinized starch aqueous dispersion does not contain organic solvents.

[0033] Furthermore, the mass fraction of hard agglomerates with a particle size greater than 2.00 mm formed after the polycarboxylic acid calcium granules are dispersed in water is 0–10 wt%, and the mass fraction of free fine powder with a particle size less than 75 μm is 0–8 wt%.

[0034] The term "polycarboxymethyl calcium-pregelatinized starch cross-composite granules" as used in this article refers to composite granules formed by wet granulation, drying, and sizing of polycarboxymethyl calcium and pregelatinized starch. The term "cross-composite" is used to describe the distribution of pregelatinized starch on the surface of polycarboxymethyl calcium granules and in the intergranular bridging regions, and does not indicate the formation of new covalent cross-links. The term "intergranular bridging regions" refers to the areas where adjacent granules form contact or connection after granulation and drying.

[0035] Furthermore, the polycarboxymethyl calcium granules are packaged in bags, with each bag containing 0.5–1.5 g of polycarboxymethyl calcium.

[0036] As a concept of this invention, the present invention employs a cross-composite particle design of polycarboxymethyl phosphate and corn-derived pregelatinized starch, primarily aimed at achieving a synergistic balance between particle structural integrity and water dispersibility. In existing technologies, enhancing particle structure typically involves increasing bridging or densification, but this method easily restricts water penetration into the particle interior and forms hard clumps. Conversely, improving dispersibility usually involves increasing disintegration or refining, which can weaken particle integrity during mixing, granulation, and packaging. This invention, by limiting the ratio of polycarboxymethyl phosphate to pregelatinized starch and pre-preparing a portion of the pregelatinized starch into an aqueous dispersion and distributing it on the surface of the polycarboxymethyl phosphate and in the inter-particle bridging regions, prevents the inter-particle bonding from concentrating into excessively dense areas. Simultaneously, mannitol, cross-linked sodium carboxymethyl cellulose, and colloidal silica are used to regulate wetting, disintegration, and flow processes, thereby achieving a synergistic balance between structural integrity, effective dispersion, and uniform quality.

[0037] This invention also discloses a method for preparing polycarboxylic acid calcium granules, comprising the following steps:

[0038] S1. Provides pre-prepared polycarboxylic acid calcium-pregelatinized starch cross-composite granules;

[0039] S2. The polycarbohydrate calcium-pregelatinized starch cross-composite particles are mixed with mannitol to obtain a first mixture;

[0040] S3. Add croscarmellose sodium to the first mixture and mix to obtain a second mixture;

[0041] S4. Add colloidal silica to the second mixture, and add sucralose when the polycarboxylic acid calcium granules contain sucralose, and mix to obtain a third mixture;

[0042] S5. The third mixture is granulated and then packaged to obtain the polycarboxylic acid calcium granules;

[0043] The intra-batch relative standard deviation of the polycarboxylic acid calcium content in the packaged polycarboxylic acid calcium granules is 0.5–5.0%.

[0044] Further, in step S1, when preparing the polycarbofi calcium-pregelatinized starch cross-composite particles, polycarbofi calcium is premixed with pregelatinized starch that is not used to prepare the pregelatinized starch aqueous dispersion to obtain a premix, and then the pregelatinized starch aqueous dispersion is added; the amount of the pregelatinized starch aqueous dispersion added is 8-18 wt% of the premix, and the D90 of the polycarbofi calcium-pregelatinized starch cross-composite particles is 600-1400 μm.

[0045] Furthermore, step S4 is the final mixing.

[0046] Furthermore, the polycarbohydrate non-calcium-pregelatinized starch cross-composite granules provided in step S1 are obtained by a high-shear wet granulation machine and a fluidized bed dryer, and step S5 is completed by a granulator and a granulation packaging machine, and the preparation method does not use organic solvents.

[0047] Furthermore, the batch size of the polycarboxylic acid calcium granules is 1–300 kg / batch, and the inter-batch coefficient of variation (D50) of three adjacent batches of polycarboxylic acid calcium-pregelatinized starch cross-composite granules is 0.5–10%.

[0048] Furthermore, in the preparation of polycarboxylic acid calcium-pregelatinized starch cross-composite granules, 100 parts by mass of polycarboxylic acid calcium and 8–20 parts by mass of pregelatinized starch are used as granulation raw materials; a portion of the pregelatinized starch is mixed with purified water and dispersed at 20–35°C for 5–30 min to obtain a pregelatinized starch aqueous dispersion with a solid content of 5–15 wt% and a pH of 5.0–7.5; the pregelatinized starch not used to prepare the pregelatinized starch aqueous dispersion is premixed with polycarboxylic acid calcium for 5–15 min to obtain a premix; within 0–4 h after obtaining the pregelatinized starch aqueous dispersion, the pregelatinized starch aqueous dispersion is added to the premix at 8–18 wt% of the premix mass to obtain a wet mixing system for granulation; the pregelatinized starch aqueous dispersion and the wet mixing system do not contain organic solvents.

[0049] Further, the wet mixture system is subjected to high-shear wet granulation at 20–35°C for 3–10 min; granulation is stopped when the mass fraction of wet particles passing through the sieve after granulation is 70–95 wt%; the obtained wet particles are dried at 40–55°C for 0.5–3.0 h and then granulated to obtain polycarbohydrate calcium-pregelatinized starch cross-composite particles, wherein the pregelatinized starch is distributed on the surface of the polycarbohydrate calcium particles and in the interparticle bridging region; the polycarbohydrate calcium-pregelatinized starch cross-composite particles are then mixed with mannitol in the subsequent step.

[0050] Further, after sieving, polycarboxymethyl calcium is dried at 35–55°C for 0.5–2.0 h to achieve a drying weight loss of 0.5–6.0 wt%. The dried polycarboxymethyl calcium raw material is premixed with pregelatinized starch not used in the preparation of the pregelatinized starch aqueous dispersion for 5–15 min to obtain a premix with a fine powder mass fraction of 10–45 wt% with a particle size less than 75 μm. The premix is ​​then used in the granulation step after adding the pregelatinized starch aqueous dispersion.

[0051] Further, the polycarboxymethyl cellulose-pregelatinized starch cross-composite granules are mixed with mannitol for 5–15 min to obtain a first mixture; cross-linked sodium carboxymethyl cellulose is added to the first mixture and mixed for 3–10 min to obtain a second mixture; colloidal silica is added to the second mixture, and sucralose is added when the polycarboxymethyl cellulose granules contain sucralose, and a final mixing is performed for 2–8 min to obtain a third mixture; the third mixture is granulated to obtain granules for packaging.

[0052] Furthermore, the granules used for repackaging are repackaged into bagged granules, with each bag containing 0.5–1.5 g of polycarboxymethyl calcium. The difference between the actual amount and the labeled amount of each bag of granules is taken as the percentage of the labeled amount, and the difference in amount does not exceed 10% of the labeled amount.

[0053] As another aspect of this invention, the present invention employs a sequential mixing and solvent-free preparation design, primarily used to achieve, fix, or amplify the aforementioned synergistic effects. If all excipients are mixed at once, fine powders, disintegrants, and flow aids may prematurely interfere with the surface bridging between polycarboxymethyl cellulose (PCCF) and pregelatinized starch, leading to unstable structural formation. Conversely, excessively extending wet granulation or increasing moisture content may densify the particles and affect subsequent release. This invention first prepares PCCF-pregelatinized starch cross-composite particles, then sequentially mixes them with mannitol, cross-linked sodium carboxymethyl cellulose, colloidal silica, and sucralose, placing the colloidal silica in the final mixing stage. This ensures that the particle structure forms first, the dispersion-regulating components are introduced later, and the flowability-regulating components are added last, thereby reducing the damage to the bridging structure during mixing and improving the uniformity of the packaging.

[0054] Polycarboxymethyl cellulose (PCCF) primarily functions to absorb water and swell, and release exchangeable calcium. However, its fine powder state and high hydrophilicity can lead to insufficient flowability, localized agglomeration, and uneven dispersion. Pregelatinized starch from corn can participate in surface coating and inter-particle bridging after wetting and dispersion, which is beneficial for improving particle structural integrity. However, if its proportion is too high or its distribution is too concentrated, it may cause excessive particle adhesion and restrict water penetration. Crosslinked sodium carboxymethyl cellulose (CCMC) helps with disintegration in water and the formation of wetting channels, but excessive dosage can weaken particle integrity and increase the risk of fine powder formation. This invention achieves a balance between inter-particle bonding, wetting disintegration, and flowability regulation by matching the ratio of PCCF to pregelatinized starch, sequentially adding a portion of the pregelatinized starch aqueous dispersion, and controlling the granulation endpoint and post-mixing sequence. This ultimately balances structural integrity, dispersibility, processing flowability, and acid media release.

[0055] Beneficial technical effects

[0056] 1. This invention constructs cross-composite particles by combining polycarboxylated calcium with corn-derived pregelatinized starch, allowing the pregelatinized starch to be distributed on the surface of polycarboxylated calcium and in the bridging areas between particles. This reduces the problems of uneven bonding and excessive fine powder in ordinary dry mixing, and enables the particles to maintain good structural integrity during mixing, granulation, and packaging.

[0057] 2. This invention achieves controlled distribution of interparticle bonding on the particle surface and in the interparticle region by wetting and dispersing a partially pregelatinized starch aqueous dispersion and adding it sequentially. This avoids excessive particle density caused by simply enhancing adhesion, thereby improving the dispersion state and control of hard clumps after adding water while maintaining the particle morphology.

[0058] 3. In this invention, mannitol, croscarmellose sodium, colloidal silica and sucralose are added in sequence. Croscarmellose sodium regulates the water ingress and disintegration process, and colloidal silica improves flowability in the final mixing stage, so that the granules achieve a good balance in terms of oral dispersion, uniform content and stable packaging.

[0059] 4. This invention controls the D50, D90, loss on drying, amount of pregelatinized starch aqueous dispersion added, and granulation endpoint of the cross-composite particles to match the particle size and drying state with the post-mixing process, thereby taking into account the processing fluidity, release behavior under acidic media, and water absorption and swelling capacity under the corresponding formulation and process conditions.

[0060] 5. The preparation process of this invention does not use organic solvents and can be completed using a high-shear wet granulation machine, fluidized bed dryer, granulator and granule packaging machine. The process path is clear and suitable for batch preparation, quality control and process scale-up of bagged granules. Attached Figure Description

[0061] Figure 1 The graph shows the effect of the mass ratio of polycarboxymethyl calcium to pregelatinized starch in the baseline formulation of Example 1 on the exchangeable calcium release rate and the mass fraction of hard masses.

[0062] Figure 2 The graph shows the effect of polycarbohydrate non-calcium-pregelatinized starch cross-composite particles D50 in the baseline formulation of Example 1 on the exchangeable calcium release rate and intra-batch relative standard deviation.

[0063] Figure 3 The graph shows the effect of the amount of pregelatinized starch aqueous dispersion added in the baseline formulation of Example 1 on the exchangeable calcium release rate and the mass fraction of hardened masses.

[0064] Figure 4 The graph shows the effect of the amount of cross-linked sodium carboxymethyl cellulose in the baseline formulation of Example 1 on the exchangeable calcium release rate and the mass fraction of free fine powder.

[0065] Figure 5 This is a diagram showing the surface pregelatinized starch coverage area ratios for Examples 1, 9, and 10.

[0066] Figure 6 This is a comparison diagram of the interparticle bridging region distribution in Example 1, Comparative Example 9, and Comparative Example 10.

[0067] Figure 7 This is a comparison diagram of the interparticle connectivity between Example 1 and Comparative Example 10 using scanning electron microscopy.

[0068] Figure 8 The image shows a comparison of particle aggregation states under scanning electron microscopy for Example 1 and Comparative Example 10.

[0069] Figure 9 The plot shows the particle size distribution curves of the cross-composite particles in Example 1, Comparative Example 5, and Comparative Example 6.

[0070] Figure 10 The cumulative particle size distribution curves of the cross-composite particles in Example 1, Comparative Example 5, and Comparative Example 6 are shown.

[0071] Figure 11 This is a comparison graph of drying weight loss and exchangeable calcium release rate between Example 1 and Comparative Example 8.

[0072] Figure 12 This is a comparison chart of the intra-batch relative standard deviations of Example 1, Comparative Example 3, and Comparative Example 4.

[0073] Figure 13 This is a comparison of macroscopic optical photographs of the final product of Example 1 and the final product of Comparative Example 10; wherein, Figure 13 Figure a in the image is a macroscopic optical photograph of the final bagged polycarbohydrate non-calcium granules of Example 1; Figure 13Figure b in the figure is a macroscopic optical photograph of the final granules of Comparative Example 10.

[0074] Figure 14 The images show a comparison of the scanning electron microscope (SEM) morphology and energy dispersive spectral distribution of the final product from Example 1 and Comparative Example 10; where, Figure 14 Figure a in the figure is a low-magnification scanning electron microscope image of the final product of Example 1; Figure 14 Figure b in the figure is a low-magnification scanning electron microscope image of the final product of Comparative Example 10; Figure 14 Figure c in the figure is a medium-magnification scanning electron microscope image of the final product of Example 1; Figure 14 Figure d in the figure is a medium-magnification scanning electron microscope image of the final product of Comparative Example 10; Figure 14 Figure e in the figure is a high-magnification scanning electron microscope image of the final product of Example 1; Figure 14 Figure f in the figure is a high-magnification scanning electron microscope image of the final product of Comparative Example 10; Figure 14 Figure g in the figure is the scanning electron microscope energy distribution diagram of the final product of Example 1; Figure 14 Figure h in the figure shows the scanning electron microscope energy distribution of the final product of Comparative Example 10. Detailed Implementation

[0075] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0076] Example 1

[0077] Overall production scale and product form

[0078] In this embodiment, 1.000 kg dry-battery bags of polycarboxymethyl cellulose granules were prepared, with each bag containing 0.5 g of polycarboxymethyl cellulose. Based on a final dry-battery total mass of 100 wt%, the granules in this embodiment comprise 55.0 wt% polycarboxymethyl cellulose, 11.0 wt% pregelatinized starch, 30.0 wt% mannitol, 3.0 wt% croscarmellose sodium, 0.8 wt% colloidal silica, and 0.2 wt% sucralose. The polycarboxymethyl cellulose is a pharmaceutical-grade commercially available raw material, the pregelatinized starch is a corn-derived pharmaceutical-grade commercially available raw material, and the mannitol, croscarmellose sodium, colloidal silica, and sucralose are all pharmaceutical-grade commercially available raw materials.

[0079] Raw materials, components or material specifications

[0080] Weigh out 550.0 g of polycarboxymethyl cellulose (PCCF), 110.0 g of pregelatinized starch, 300.0 g of mannitol, 30.0 g of croscarmellose sodium, 8.0 g of colloidal silica, and 2.0 g of sucralose on a dry basis. The mass ratio of PCCF to pregelatinized starch is 100:20. PCCF is first sieved through an 850 μm sieve and dried at 35°C under air circulation for 0.5 h, resulting in a drying loss of 0.5 wt%. The mass fraction of fine powder with a particle size less than 75 μm in the dried PCCF is determined to be 10 wt% by sieve analysis.

[0081] Step 1: Preparation of pregelatinized starch aqueous dispersion

[0082] 16.5 g of pregelatinized starch was added to 93.5 g of purified water and dispersed at 20 °C with mechanical stirring for 5 min at a stirring speed of 300 rpm to obtain a pregelatinized starch aqueous dispersion with a solid content of 15 wt% and a pH of 5.0. This aqueous dispersion does not contain organic solvents and was used immediately for subsequent granulation.

[0083] Step 2: Preparation of premix

[0084] 550.0 g of dried polycarboxymethyl phosphate and 93.5 g of pregelatinized starch (not used to prepare the pregelatinized starch aqueous dispersion) were added to the feed pan of a high-shear wet granulator and premixed at 20°C for 5 min to obtain a premix. The mass fraction of fine powder with a particle size less than 75 μm in the premix was 10 wt%.

[0085] Step 3: Cross-compound granulation

[0086] 110.0 g of the pregelatinized starch aqueous dispersion obtained in step 1 was added to the premix from step 2 within 2 min. The amount of pregelatinized starch aqueous dispersion added was 17.1 wt% of the premix. During the addition process, the stirring paddle speed was maintained at 250 rpm, the cutter speed at 800 rpm, and the feed pot temperature was controlled at 20℃. After the addition was completed, high-shear wet granulation was continued for 3 min to form a wet mixture and wet granules. An air environment was maintained during granulation at atmospheric pressure.

[0087] Step 4: Endpoint control, drying and granulation

[0088] After granulation, the wet granules were granulated through a 1.00 mm sieve, with a mass fraction of 70 wt% passing through the sieve. The wet granules were then transferred to a fluidized bed dryer and dried for 0.5 h at an inlet air temperature of 40 °C, atmospheric pressure, and an air atmosphere. Subsequently, they were granulated through an 850 μm sieve to obtain polycarbohydrate calcium-pregelatinized starch cross-linked granules. The resulting cross-linked granules had a D50 of 300 μm, a D90 of 600 μm, and a drying loss of 2.0 wt%.

[0089] Step 5: Post-mixing and dispensing

[0090] Polycarboxymethyl cellulose-pregelatinized starch cross-linked granules were mixed with 300.0 g of mannitol in a mixer for 5 min to obtain the first mixture. 30.0 g of croscarmellose sodium was added to the first mixture and mixed for 3 min to obtain the second mixture. 8.0 g of colloidal silica and 2.0 g of sucralose were added to the second mixture and mixed for a final 2 min to obtain the third mixture. The third mixture was granulated through an 850 μm sieve and then packaged to obtain bagged polycarboxymethyl cellulose granules with a fill weight variation of 3.0%.

[0091] Quality testing methods and results

[0092] The particle size and loss on drying of the polycarbohydrate calcium-pregelatinized starch cross-composite granule sample of this embodiment were tested; the dispersibility, exchangeable calcium release rate, water absorption swelling, and content uniformity of the bagged polycarbohydrate calcium granule sample were tested. D50 and D90 were analyzed by laser diffraction and verified by sieving. The cross-composite granule sample was measured by dry injection. The loss on drying was measured by drying at 105℃ to constant weight. The exchangeable calcium release rate was determined by complexometric titration after treatment with 0.1 mol / L hydrochloric acid solution for 30 min, and the calcium ion content in the acid-treated solution was calculated as a percentage of the total calcium in the same sample. The water absorption swelling was determined by weighing after water absorption following acid treatment. The test results are as follows: the D50 of the cross-composite particles is 300 μm, the D90 is 600 μm, and the loss on drying is 2.0 wt%; the exchangeable calcium release rate of the bagged polycarboxymethyl calcium granules in 0.1 mol / L hydrochloric acid solution for 30 min is 80.5%, the water absorption swelling after acid treatment is 25.8 g / g polycarboxymethyl calcium, the mass fraction of hard agglomerates with a particle size greater than 2.00 mm is 8.8 wt%, the mass fraction of free fine powder with a particle size less than 75 μm is 7.5 wt%, the intra-batch relative standard deviation of polycarboxymethyl calcium content after repackaging is 4.8%, and the inter-batch coefficient of variation of D50 of three adjacent batches of cross-composite particles is 0.5%.

[0093] Features and application scenarios of this embodiment

[0094] This embodiment uses a combination of low polycarboxylic acid non-calcium ratio, high bridging ratio of pregelatinized starch, mild granulation and short drying time. The particle size is in the low range, which is suitable for the production of bagged granules that require lower unit dosage, faster wetting and basic process operability evaluation.

[0095] Example 2

[0096] Raw materials and proportions

[0097] This embodiment prepares 300kg / batch dry-battery bagged polycarboxylic acid calcium granules, with each bag containing 1.5g of polycarboxylic acid calcium. Based on a final dry-battery total mass of 100wt%, the granules in this embodiment comprise 75.0wt% polycarboxylic acid calcium, 6.0wt% pregelatinized starch, 17.5wt% mannitol, 0.5wt% croscarmellose sodium, 0.2wt% colloidal silica, and 0.8wt% sucralose. 225.0kg of polycarboxylic acid calcium, 18.0kg of pregelatinized starch, 52.5kg of mannitol, 1.5kg of croscarmellose sodium, 0.6kg of colloidal silica, and 2.4kg of sucralose are weighed in batches of 300kg. The mass ratio of polycarboxylic acid calcium to pregelatinized starch is 100:8, and all raw materials and excipients are commercially available pharmaceutical-grade materials.

[0098] Preparation process

[0099] Polycarboxymethyl phosphate was sieved through an 850 μm sieve and dried at 55°C under air circulation for 2.0 h, resulting in a drying loss of 6.0 wt%. 2.7 kg of pregelatinized starch was added to 19.8 kg of purified water and dispersed at 35°C with mechanical stirring for 30 min at 500 rpm, yielding a pregelatinized starch aqueous dispersion with a solid content of 12 wt% and a pH of 7.5. The premix was added to the aqueous dispersion within 4.0 h after preparation. The aqueous dispersion contained no organic solvents.

[0100] Cross-compound granulation, drying and granulation

[0101] 225.0 kg of dried polycarboxymethyl phosphate and 15.3 kg of pregelatinized starch (not used to prepare the pregelatinized starch aqueous dispersion) were added to a high-shear wet granulator and premixed for 15 min to obtain a premix with a fine powder content of 45 wt% and a particle size less than 75 μm. 22.5 kg of the pregelatinized starch aqueous dispersion was added to the premix over 5 min, at a concentration of 9.4 wt% of the premix. Granulation was carried out at 35°C, atmospheric pressure, and air atmosphere for 10 min, with a stirring paddle speed of 350 rpm and a cutter speed of 1200 rpm. After granulation, the wet granules were sized through a 1.40 mm sieve, with a mass fraction of 95 wt% passing through the sieve. The wet granules were then dried in a fluidized bed dryer at an inlet air temperature of 55°C for 3.0 h and sized through a 1.40 mm sieve to obtain polycarboxymethyl phosphate-pregelatinized starch cross-composite granules.

[0102] Quality inspection or performance testing

[0103] In this embodiment, the cross-linked composite particles have a D50 of 850 μm, a D90 of 1400 μm, and a drying loss of 5.0 wt%. The cross-linked composite particles were mixed with 52.5 kg of mannitol for 15 min to obtain a first mixture; 1.5 kg of croscarmellose sodium was added and mixed for 10 min to obtain a second mixture; 0.6 kg of colloidal silica and 2.4 kg of sucralose were added, and a final mixing was performed for 8 min to obtain a third mixture. The third mixture was granulated and packaged with a fill weight variation of 8.0%. The test results of the obtained bagged polycarboxymethyl calcium granules are as follows: the exchangeable calcium release rate in 0.1 mol / L hydrochloric acid solution for 30 min is 97.2%; the water absorption swelling after acid treatment is 58.5 g / g polycarboxymethyl calcium; the mass fraction of hard agglomerates with a particle size greater than 2.00 mm is 1.2 wt%; the mass fraction of free fine powder with a particle size less than 75 μm is 0.9 wt%; the intra-batch relative standard deviation of polycarboxymethyl calcium content after repackaging is 0.8%; and the inter-batch coefficient of variation of D50 of cross-composite particles in three adjacent batches is 10.0%.

[0104] Features of the solution in this embodiment

[0105] This embodiment uses a combination of high polycarbohydrate calcium ratio, low pregelatinized starch ratio, high granulation temperature and long drying time, resulting in a relatively high particle size. It is suitable for the production of bagged granules with large batches, high polycarbohydrate calcium loading and strong flowability requirements.

[0106] Example 3

[0107] The key parameters and sample conditions in this embodiment are as follows: 50kg / batch dry-battery bagged polycarboxylic acid calcium granules were prepared, with each bag containing 1.0g of polycarboxylic acid calcium. The final dry-battery composition consisted of 62.5wt% polycarboxylic acid calcium, 5.0wt% pregelatinized starch, 30.0wt% mannitol, 1.5wt% croscarmellose sodium, 0.5wt% colloidal silica, and 0.5wt% sucralose. The mass ratio of polycarboxylic acid calcium to pregelatinized starch was 100:8. 31.25kg of polycarboxylic acid calcium, 2.50kg of pregelatinized starch, 15.00kg of mannitol, 0.75kg of croscarmellose sodium, 0.25kg of colloidal silica, and 0.25kg of sucralose were weighed in batches of 50kg each.

[0108] In the preparation process, polycarboxymethyl calcium was first sieved and dried at 45°C under air circulation for 1.0 h to achieve a drying weight loss of 3.0 wt%. 0.55 kg of pregelatinized starch was added to 4.95 kg of purified water and dispersed at 28°C for 15 min with a stirring speed of 400 rpm to obtain a pregelatinized starch aqueous dispersion with a solid content of 10 wt% and a pH of 6.2. This aqueous dispersion was allowed to stand for 2.0 h before adding the premix. No organic solvents were used in either the preparation or addition process.

[0109] 31.25 kg of dried polycarboxymethyl phosphate was premixed with 1.95 kg of pregelatinized starch for 10 min to obtain a premix containing 25 wt% fine powder with a particle size less than 75 μm. 5.50 kg of pregelatinized starch aqueous dispersion was added to the premix, representing 16.6 wt% of the premix mass. High-shear wet granulation was performed at 28 °C for 6 min, with a stirring paddle speed of 300 rpm, a cutter speed of 1000 rpm, atmospheric pressure, and an air atmosphere.

[0110] After granulation, the wet granules were sized through a 1.18 mm sieve, with a mass fraction of 80 wt% passing through the sieve. The wet granules were then placed in a fluidized bed dryer and dried at an inlet air temperature of 48°C for 1.5 hours. After sizing through a 1.00 mm sieve, polycarboxymethyl methacrylate (PCM) calcium-pregelatinized starch cross-linked granules were obtained. The cross-linked granules were mixed with mannitol for 10 minutes, followed by the addition of croscarmellose sodium and mixing for 6 minutes. Finally, colloidal silica and sucralose were added and mixed for 5 minutes to obtain granules for packaging.

[0111] Quality testing methods and results: In this embodiment, the cross-composite particles had a D50 of 520 μm, a D90 of 900 μm, and a drying loss of 3.2 wt%. The test results of the obtained bagged polycarboxylic acid calcium granules were as follows: the exchangeable calcium release rate in 0.1 mol / L hydrochloric acid solution for 30 min was 90.4%, and the water absorption swelling after acid treatment was 42.6 g / g polycarboxylic acid calcium. After water dispersion, the mass fraction of hard agglomerates with a particle size greater than 2.00 mm was 5.0 wt%, and the mass fraction of free fine powder with a particle size less than 75 μm was 4.0 wt%. The intra-batch relative standard deviation of polycarboxylic acid calcium content after packaging was 2.5%, the packaging weight difference was 5.0%, and the inter-batch coefficient of variation of D50 of three adjacent batches of cross-composite particles was 4.0%.

[0112] Applicable scenarios of this embodiment

[0113] This embodiment uses a combination of low pregelatinized starch ratio, high mannitol ratio, and intermediate process strength. The particle size, moisture content, and post-mixing time are in the intermediate range, making it suitable for the production of conventional bagged granules where taste, dispersibility, and production stability are all required.

[0114] Example 4

[0115] I. Preparation Object and Batch Size

[0116] Using 180kg / batch dry-battery bagged polycarboxylic acid calcium granules as the preparation material, each bag contains 1.2g of polycarboxylic acid calcium. The final dry-battery composition of this example includes 74.0wt% polycarboxylic acid calcium, 14.8wt% pregelatinized starch, 10.0wt% mannitol, 0.5wt% croscarmellose sodium, 0.2wt% colloidal silica, and 0.5wt% sucralose. 133.20kg of polycarboxylic acid calcium, 26.64kg of pregelatinized starch, 18.00kg of mannitol, 0.90kg of croscarmellose sodium, 0.36kg of colloidal silica, and 0.90kg of sucralose were weighed in batches. The mass ratio of polycarboxylic acid calcium to pregelatinized starch was 100:20.

[0117] II. Raw material pretreatment and aqueous dispersion

[0118] Polycarboxymethyl phosphate was sieved through an 850 μm sieve and dried at 52°C under air circulation for 1.8 h, resulting in a drying loss of 4.5 wt%. 3.60 kg of pregelatinized starch was added to 20.40 kg of purified water and dispersed at 32°C for 25 min with a stirring speed of 450 rpm, yielding a pregelatinized starch aqueous dispersion with a solid content of 15 wt% and a pH of 7.0. This aqueous dispersion was then used for granulation after standing for 3.5 h. Neither the aqueous dispersion nor the subsequent wet mixing system contained organic solvents.

[0119] III. Preparation of Cross-linked Composite Particles

[0120] 133.20 kg of dried polycarboxymethyl phosphate and 23.04 kg of pregelatinized starch (not used to prepare the pregelatinized starch aqueous dispersion) were added to a high-shear wet granulator and premixed for 12 min to obtain a premix. The premix contained 35 wt% fine powder with a particle size less than 75 μm. 24.00 kg of the pregelatinized starch aqueous dispersion was added to the premix, at a concentration of 15.4 wt%. Granulation was performed at 32°C, atmospheric pressure, and air atmosphere for 8 min, with a stirring paddle speed of 320 rpm and a cutter speed of 1100 rpm.

[0121] IV. Drying, Granulation, and Post-mixing

[0122] After granulation, the wet granules were sized through a 1.25mm sieve, with a mass fraction of 90wt% passing through the sieve. The wet granules were then dried in a fluidized bed dryer at an inlet air temperature of 52℃ for 2.5 hours. After granulation through a 1.25mm sieve, polycarboxymethyl methacrylate (PCM) calcium-pregelatinized starch cross-linked granules were obtained. The cross-linked granules were mixed with 18.00 kg of mannitol for 12 minutes, followed by the addition of 0.90 kg of croscarmellose sodium and mixing for 8 minutes. Finally, 0.36 kg of colloidal silica and 0.90 kg of sucralose were added and mixed for 6 minutes. After granulation, the granules were packaged with a fill weight variation of 6.0%.

[0123] V. Quality Inspection Methods and Results

[0124] In this embodiment, the cross-composite particles have a D50 of 830 μm, a D90 of 1300 μm, and a drying loss of 4.8 wt%. The test results of the obtained bagged polycarboxylic acid calcium granules are as follows: the exchangeable calcium release rate in 0.1 mol / L hydrochloric acid solution for 30 min is 94.0%, and the water absorption swelling after acid treatment is 54.2 g / g polycarboxylic acid calcium; after water dispersion, the mass fraction of hard agglomerates with a particle size greater than 2.00 mm is 2.0 wt%, and the mass fraction of free fine powder with a particle size less than 75 μm is 1.5 wt%; the intra-batch relative standard deviation of polycarboxylic acid calcium content after packaging is 1.6%, and the inter-batch coefficient of variation of D50 of three adjacent batches of cross-composite particles is 7.0%.

[0125] The process features and application directions of this embodiment

[0126] This embodiment employs a high proportion of polycarboxymethyl calcium, a high bridging ratio of pregelatinized starch, a low proportion of mannitol, and a relatively high particle size scheme, which is suitable for the production of bagged granules with high requirements for high drug loading, particle structure stability, flowability, and uniformity of packaging.

[0127] Comparative Example 1: Basically the same as Example 1, except that the amount of pregelatinized starch was adjusted to 3.0 wt%, polycarboxymethyl cellulose calcium to 55.0 wt%, mannitol was adjusted to 38.0 wt% as a formula balancing agent, croscarmellose sodium to 3.0 wt%, colloidal silica to 0.8 wt%, sucralose to 0.2 wt%, polycarboxymethyl cellulose calcium was dried at 35°C for 0.5 h, the solid content of the pregelatinized starch aqueous dispersion was 15 wt%, the pH was 5.0, granulation was carried out at 20°C for 3 min, the wet granules after granulation were dried at 40°C for 0.5 h, and the subsequent mixing times were 5 min, 3 min, and 2 min respectively.

[0128] Comparative Example 2: Basically the same as Example 1, except that the amount of pregelatinized starch was adjusted to 16.0 wt%, polycarboxymethyl cellulose calcium to 55.0 wt%, mannitol was adjusted to 25.0 wt% as a formula balancing agent, croscarmellose sodium to 3.0 wt%, colloidal silica to 0.8 wt%, sucralose to 0.2 wt%, and polycarboxymethyl cellulose calcium was dried at 35°C for 0.5 h. The solid content of the pregelatinized starch aqueous dispersion was 15 wt%, the pH was 5.0, granulation was performed at 20°C for 3 min, the wet granules after granulation were dried at 40°C for 0.5 h, and the subsequent mixing times were 5 min, 3 min, and 2 min respectively.

[0129] Comparative Example 3: Basically the same as Example 1, except that the amount of cross-linked sodium carboxymethyl cellulose was adjusted to 0.2 wt%, polycarboxymethyl cellulose calcium to 55.0 wt%, pregelatinized starch to 11.0 wt%, mannitol to 32.8 wt% as a formula balancing agent, colloidal silica to 0.8 wt%, sucralose to 0.2 wt%, polycarboxymethyl cellulose calcium to be dried at 35°C for 0.5 h, the pregelatinized starch aqueous dispersion to have a solid content of 15 wt% and a pH of 5.0, to be granulated at 20°C for 3 min, the wet granules after granulation to be dried at 40°C for 0.5 h, and the subsequent mixing times to be 5 min, 3 min, and 2 min respectively.

[0130] Comparative Example 4: Basically the same as Example 1, except that the amount of colloidal silica was adjusted to 0.05 wt%, polycarboxymethyl cellulose to 55.0 wt%, pregelatinized starch to 11.0 wt%, mannitol to 30.75 wt% as a formula balancing agent, croscarmellose sodium to 3.0 wt%, sucralose to 0.2 wt%, polycarboxymethyl cellulose to be dried at 35°C for 0.5 h, the pregelatinized starch aqueous dispersion to have a solid content of 15 wt% and a pH of 5.0, to be granulated at 20°C for 3 min, and the wet granules after granulation to be dried at 40°C for 0.5 h, with subsequent mixing times of 5 min, 3 min, and 2 min respectively.

[0131] Comparative Example 5: Basically the same as Example 1, except that a 250μm sieve was used to control the cross-linked composite particles D50 to 220μm during granulation, the polycarboxymethyl cellulose was 55.0wt%, the pregelatinized starch was 11.0wt%, the mannitol was 30.0wt%, the cross-linked sodium carboxymethyl cellulose was 3.0wt%, the colloidal silica was 0.8wt%, and the sucralose was 0.2wt%. Granulation was carried out at 20℃ for 3min, and the wet granules after granulation were dried at 40℃ for 0.5h. The subsequent mixing times were 5min, 3min, and 2min respectively.

[0132] Comparative Example 6: Basically the same as Example 1, except that a 1.60mm sieve was used to control the cross-linked composite particle D50 to 1000μm during granulation, the polycarboxymethyl cellulose was 55.0wt%, the pregelatinized starch was 11.0wt%, the mannitol was 30.0wt%, the cross-linked sodium carboxymethyl cellulose was 3.0wt%, the colloidal silica was 0.8wt%, and the sucralose was 0.2wt%. Granulation was carried out at 20℃ for 3min, and the wet granules after granulation were dried at 40℃ for 0.5h. The subsequent mixing times were 5min, 3min, and 2min respectively.

[0133] Comparative Example 7: Basically the same as Example 1, except that the cross-compound granulation temperature was adjusted to 45°C, the amount of polycarboxymethyl cellulose calcium was 55.0 wt%, the amount of pregelatinized starch was 11.0 wt%, the amount of mannitol was 30.0 wt%, the amount of cross-linked sodium carboxymethyl cellulose was 3.0 wt%, the amount of colloidal silica was 0.8 wt%, the amount of sucralose was 0.2 wt%, the amount of pregelatinized starch aqueous dispersion was 15 wt%, the pH was 5.0, the granulation time was 3 min, the wet granules after granulation were dried at 40°C for 0.5 h, and the subsequent mixing times were 5 min, 3 min, and 2 min respectively.

[0134] Comparative Example 8: Basically the same as Example 1, except that the drying weight loss of the cross-linked composite particles after drying was controlled at 6.5 wt%, the calcium polycarboxymethyl ether was 55.0 wt%, the pregelatinized starch was 11.0 wt%, the mannitol was 30.0 wt%, the croscarmellose sodium was 3.0 wt%, the colloidal silica was 0.8 wt%, the sucralose was 0.2 wt%, the granulation was carried out at 20°C for 3 min, and the fluidized bed drying was carried out until the drying weight loss of the cross-linked composite particles was 6.5 wt%, and the subsequent mixing times were 5 min, 3 min, and 2 min respectively.

[0135] Comparative Example 9: Essentially the same as Example 1, except that pregelatinized starch was removed. The composition of polycarboxylic acid calcium was 55.0 wt%, mannitol was adjusted to 41.0 wt% as a formulation balancer, croscarmellose sodium was 3.0 wt%, colloidal silica was 0.8 wt%, and sucralose was 0.2 wt%. No pregelatinized starch aqueous dispersion was prepared. Polycarboxylic acid calcium was dried at 35°C for 0.5 h and then directly wetted and granulated. Granulation was carried out at 20°C for 3 min, and the wet granules were dried at 40°C for 0.5 h. The subsequent mixing times were 5 min, 3 min, and 2 min, respectively. This comparative example was used to investigate the synergistic relationship between polycarboxylic acid calcium and corn-derived pregelatinized starch.

[0136] Comparative Example 10: Essentially the same as Example 1, except that a pregelatinized starch aqueous dispersion was not prepared. 110.0 g of pregelatinized starch was premixed with 550.0 g of polycarboxymethyl cellulose (PCMC) in a dry state. The PCMCs composition was 55.0 wt%, pregelatinized starch 11.0 wt%, mannitol 30.0 wt%, croscarmellose sodium 3.0 wt%, colloidal silica 0.8 wt%, and sucralose 0.2 wt%. 110.0 g of purified water was added during granulation, and granulation was carried out at 20°C for 3 min. The wet granules were then dried at 40°C for 0.5 h. Post-mixing times were 5 min, 3 min, and 2 min, respectively. This comparative example was used to investigate the synergistic relationship between the pregelatinized starch aqueous dispersion and surface coating and interparticle bridging.

[0137] Comparative Example 11: Essentially the same as Example 1, except that corn-derived pregelatinized starch was replaced with corn-derived unpregelatinized starch at an amount of 11.0 wt%, polycarboxymethyl cellulose calcium at 55.0 wt%, mannitol at 30.0 wt%, croscarmellose sodium at 3.0 wt%, colloidal silica at 0.8 wt%, and sucralose at 0.2 wt%. 16.5 g of the unpregelatinized starch was added to 93.5 g of purified water, dispersed at 20°C for 5 min, and then the premix was added. Granulation was carried out at 20°C for 3 min, and the wet granules were dried at 40°C for 0.5 h. The subsequent mixing times were 5 min, 3 min, and 2 min. This comparative example was used to investigate the synergistic relationship between corn-derived pregelatinized starch and polycarboxymethyl cellulose calcium.

[0138] Characterization and performance testing:

[0139] Particle size distribution and fine powder agglomerate testing: The test subjects were granulated polycarbohydrate calcium-pregelatinized starch cross-composite granules from Examples 1–4 and all comparative examples, as well as the corresponding bagged granules. The purpose was to evaluate the D50 and D90 of the cross-composite granules, and the formation of free fine powder and agglomerates after water dispersion in the bagged granules. Samples used for D50, D90, and free fine powder determination were tested after equilibration for 24 hours at 25°C and 50% relative humidity. D50 and D90 were determined by laser diffraction particle size analysis and sieve verification. The mass fraction of free fine powder was determined by 75 μm sieve weighing, and the mass fraction of agglomerates after water dispersion was determined by 2.00 mm sieve weighing. The inter-batch coefficient of variation of D50 for three adjacent batches of cross-composite granules was the percentage of the standard deviation to the mean of the three batches of D50 measurements.

[0140] Loss on drying test: The test subjects were the granulated particles from Examples 1–4 and all comparative examples. The purpose was to evaluate the effect of the drying endpoint on the moisture content of the particles. The principle is that the mass reduction after heating to constant weight reflects the residual moisture and volatile components. Approximately 2g of sample was taken and dried at 105℃ until the difference between two consecutive weighings did not exceed 0.3mg.

[0141] Exchangeable calcium release test: The test subjects were the bagged granules of Examples 1–4 and all comparative examples. The purpose was to evaluate the exchangeable calcium release capacity under acidic conditions. The principle was to calculate the release rate of calcium ions released after polycarboxymethyl calcium was treated in 0.1 mol / L hydrochloric acid solution for 30 min using a complexometric titration method. Each sample was calculated to contain 0.5 g of polycarboxymethyl calcium. After shaking at 37°C for 30 min, the amount of calcium ions in the acid-treated solution was determined by complexometric titration. The exchangeable calcium release rate was calculated as the percentage of calcium ions in the acid-treated solution relative to the total calcium in the same sample.

[0142] Acid-treated water absorption and swelling test: The test subjects were particulate samples from Examples 1–4 and all comparative examples treated with 0.1 mol / L hydrochloric acid solution. The purpose was to evaluate the water absorption and swelling capacity of the polycarbohydrate calcium system after acid treatment. The principle is that the ratio of the mass difference of the sample before and after water absorption to the mass of polycarbohydrate calcium reflects the swelling behavior. The acid treatment used the same 0.1 mol / L hydrochloric acid solution, 37°C, and 30 min treatment conditions as the exchangeable calcium release test. After filtering, the acid-treated samples were placed in purified water to absorb water for 30 min, then placed on a filter to drain until the filtrate no longer dripped continuously, and then weighed.

[0143] Content Uniformity and Fill Weight Variation Test: The test subjects were the repackaged granules from Examples 1–4 and all comparative examples. The purpose was to evaluate the uniformity of the post-mixing and repackaging process. The principle is that the fluctuation of polycarboxymethyl phosphate content and the deviation of actual fill weight in different bag samples reflect the stability of intra-batch mixing and repackaging. Twenty bags were randomly selected from each batch, and the polycarboxymethyl phosphate content of each bag was measured and the intra-batch relative standard deviation was calculated. Simultaneously, the actual fill weight was weighed and the fill weight variation was calculated. The intra-batch relative standard deviation is the percentage of the standard deviation of the polycarboxymethyl phosphate content of the 20 bags to the average value.

[0144] Characterization of Pregelatinized Starch Distribution in the Surface: Representative particles from Examples 1, 9, 10, and 11 were used as test subjects to evaluate the distribution of pregelatinized starch on the surface of polycarboxylic acid and in the interparticle bridging regions. The principle was to use iodine staining microscopy and scanning electron microscopy (SEM) images to observe the starch-stained areas and interparticle connectivity. At least 100 particles were analyzed. The percentage of the iodine-stained area relative to the particle's projected area was used to represent the pregelatinized starch coverage area. SEM images were used to compare interparticle connectivity and particle aggregation.

[0145] Figures 1 to 4 The results shown are all derived from univariate comparisons where only one variable was changed under the corresponding baseline formulation and process conditions. The formulation composition, granulation conditions and post-mixing conditions of Examples 1 to 4 are not exactly the same. The data of each example in Table 1 are not used to characterize the causal relationship between any single variable and the performance index.

[0146] Figure 1This diagram illustrates the effect of the mass ratio of polycarboxymethyl phosphate (PCPF) to pregelatinized starch on the exchangeable calcium release rate and the mass fraction of hard clumps in this invention. Based on the basic formulation and preparation process of Example 1, only the amount of pregelatinized starch relative to 100 parts by mass of PCPF was varied. The exchangeable calcium release rate and the mass fraction of hard clumps larger than 2.00 mm in the granules were investigated under conditions of approximately 6, 8, 11, 14, 17, 20, and 23 parts by mass. The results show that when the amount of pregelatinized starch added is low, the effective bridging structure in the system is insufficient, and the surface adhesion and intergranular composite degree are inadequate, easily leading to the coexistence of hard clumps or loose granules. When the amount of pregelatinized starch added is too high, the local adhesion is enhanced, and excessive aggregation between granules easily occurs, which is also not conducive to rapid dispersion and stable release. An intermediate addition level can maintain a high exchangeable calcium release rate while keeping the mass fraction of hard clumps low, indicating that simply increasing the amount of pregelatinized starch does not improve performance; rather, it needs to form a moderately cross-composite structure with the PCPF main granules. These results, from a formulation composition perspective, demonstrate that, within the range of 8–20 parts by weight, corn-derived pregelatinized starch can achieve a balance between granule structure integrity and acid media release.

[0147] Figure 2 This diagram illustrates the effect of the D50 of the cross-composite particles of this invention on the exchangeable calcium release rate and intra-batch relative standard deviation. Based on the formulation ratio, wetting and dispersion method, and sequential mixing process of Example 1, only the D50 of the cross-composite particles was changed, and the acid medium release performance and intra-batch uniformity were investigated under conditions of approximately 250, 300, 450, 600, 720, 850, and 950 μm. The results show that when the D50 is too small, the particle specific surface area is large, making local differences more likely to occur in the liquid absorption and bonding processes, thus increasing the intra-batch relative standard deviation. When the D50 is too large, the internal wetting and disintegration paths of the particles are prolonged, limiting the effective contact between the acid medium and polycarbohydrate calcium, and decreasing the exchangeable calcium release rate. When the D50 is in the medium particle size range of approximately 300–600 μm, the particles exhibit both good processing stability and maintain sufficient medium contact and low intra-batch fluctuations, indicating that particle size control is an important foundation for achieving synergistic improvement in dispersion uniformity, dosage stability, and release stability.

[0148] Figure 3This diagram illustrates the effect of the amount of pregelatinized starch aqueous dispersion added on the exchangeable calcium release rate and the mass fraction of hard agglomerates. Based on the solid component ratio, mixing sequence, and granulation conditions of Example 1, only the amount of pregelatinized starch aqueous dispersion relative to the premix was varied, and particle formation and calcium release were investigated at approximately 6.0, 8.0, 11.0, 14.0, 17.1, 18.0, and 20.0 wt%. The results show that when the amount of aqueous dispersion added is too low, the pregelatinized starch is difficult to fully expand and distribute on the surface of the polycarboxylated calcium particles and in the contact area between particles, resulting in insufficient bridging structure formation and uneven particle structure. When the amount of aqueous dispersion added is too high, local over-wetting occurs, particle adhesion is enhanced, and the mass fraction of hard agglomerates increases. An addition amount in the range of 8–18 wt% can create a more uniform wetted state, allowing the pregelatinized starch to be distributed in a controlled manner on the particle surface and in the bridging area, thus achieving both a high exchangeable calcium release rate and a low proportion of hard agglomerates. The results show that the proposed method, by introducing pregelatinized starch through an aqueous dispersion, not only improves the bonding efficiency but also avoids the agglomeration side effect caused by simply enhancing bridging.

[0149] Figure 4 This diagram illustrates the effect of the amount of crosslinked sodium carboxymethyl cellulose (CMC) on the release rate of exchangeable calcium and the mass fraction of free fine powder. Based on the amounts of polycarboxymethyl cellulose (PCC), pregelatinized starch, and aqueous dispersion, as well as the post-mixing process in Example 1, only the amount of CMC was varied. The release in acidic media and the mass fraction of free fine powder smaller than 75 μm were investigated under conditions of approximately 0.2, 0.5, 1.2, 1.8, 2.4, 3.0, and 3.5 wt%. The results show that when the amount of CMC is insufficient, the disintegration and hydration diffusion capacity of the particles after entering the acidic medium is limited, resulting in insufficient release of exchangeable calcium. When added in the range of 0.5–3.0 wt%, it promotes rapid liquid absorption, disintegration, and dispersion of the particles, ensuring sufficient contact between the PCC and the acidic medium. However, when the amount is too high, the particle structure is prone to excessive disintegration and fine powder shedding, leading to an increase in the mass fraction of free fine powder and potentially affecting the flowability of subsequent packaging. This indicates that croscarmellose sodium mainly plays a role in regulating disintegration and dispersion release in this scheme. Its dosage needs to be matched with the bridging strength formed by pregelatinized starch in order to achieve a balance between structural integrity and rapid dispersion.

[0150] After the formulation factors and process parameters were determined, the internal and surface structures of the particles were further observed through quantitative imaging and scanning electron microscopy. Figure 5This diagram illustrates the proportion of pregelatinized starch coverage on the surface of the particles in this invention. Image analysis of iodine-stained microscopic images of the particle surfaces from Examples 1, 9, and 10 was performed to statistically determine the proportion of pregelatinized starch covering the particle surface. The results show that the proportion of pregelatinized starch coverage in Example 1 is significantly higher than that of the sample that failed to form an effective surface composite structure, and also higher than that of the control sample obtained using unfavorable dispersion methods. This indicates that after being wetted and dispersed with an aqueous dispersion, the pregelatinized starch can be more continuously distributed on the surface of the polycarboxylic acid calcium particles, forming a more stable surface adhesion and coating area. This surface coating structure helps reduce particle breakage and fine powder generation, while avoiding insufficient local coverage or uneven component distribution caused by direct dry mixing.

[0151] Figure 6 This is a comparative diagram showing the distribution of interparticle bridging regions in this invention. Microscopic images of Example 1, Comparative Example 9, and Comparative Example 10 were compared to illustrate the distribution of these bridging regions. The results show that the interparticle bridging regions in Example 1 are more continuous, indicating that the pregelatinized starch, in its aqueous dispersion state, can enter the particle contact area and form a relatively uniformly distributed connection structure during drying. The control samples, on the other hand, have insufficient bridging regions or discontinuous distributions, leading to a tendency for the particle structure to become loose, powdery, or locally agglomerated. These results are consistent with... Figure 1 and Figure 3 The effects of the amount of pregelatinized starch and the amount of aqueous dispersion added on the mass fraction of hard agglomerates corroborate each other, indicating that this scheme does not rely on strong adhesion to form hard agglomerates, but rather forms a particle network with both integrity and dispersibility through controlled bridging.

[0152] Figure 7 This is a comparison of the interparticle connectivity under scanning electron microscopy (SEM) of the present invention. By comparing the SEM images of Example 1 and Comparative Example 10, the continuity of the connectivity region at the particle contact boundary is compared. The results show that the connectivity at the particle contact boundary in Example 1 is more continuous than that in Comparative Example 10, indicating that when a pregelatinized starch aqueous dispersion is used in cross-composite granulation, the interparticle connectivity is more continuous and the local interface is more stable. In contrast, in Comparative Example 10, the pregelatinized starch was added entirely in a dry state, making it difficult to form a sufficient and uniform bridging structure in the particle contact area. This result further illustrates that the wetting and dispersion step is an important process step in forming an effective composite particle structure.

[0153] Figure 8This is a comparison of the particle aggregation state under scanning electron microscopy (SEM) of the present invention. The particle aggregation state was observed by comparing the particle boundaries, number of agglomerates, and local clustering in the SEM images of Example 1 and Comparative Example 10. The results show that the particle boundaries in Example 1 are relatively clear, with fewer large local agglomerates; in Comparative Example 10, local agglomeration is more obvious, indicating that the addition of pregelatinized starch in the dry state easily leads to both insufficient local adhesion and local aggregation. Combined with… Figures 5-7 It can be seen that this scheme achieves a balance between enhancing particle structure and avoiding excessive aggregation through the controlled surface coverage and bridging distribution of pregelatinized starch, supporting its role in improving dispersibility and structural integrity from the microscopic morphology level.

[0154] Figure 9 The particle size distribution curves of the cross-composite particles of this invention are shown. The particle size distributions of Example 1, Comparative Example 5, and Comparative Example 6 are compared, with a focus on observing the position of the main particle size peak, the distribution width, and the tailing of large particles. The results show that the main peak of the particle size distribution in Example 1 is located in the medium particle size range and is relatively concentrated, indicating that its granulation process can form a particle system with a clearly defined main particle size and controlled fine powder and coarse agglomerates. The particle size distribution of Comparative Example 5 is biased towards the fine particle size range, suggesting insufficient particle structural strength or inadequate granulation aggregation, which can easily affect processing flowability and filling stability. The particle size distribution of Comparative Example 6 is biased towards the coarse particle size range and may be accompanied by large particle tailing, suggesting excessive local adhesion or enhanced agglomeration, which is not conducive to rapid and uniform dispersion in acidic media. These results indicate that the particle size control in Example 1 is beneficial for simultaneously reducing the risk of free fine powder and hard agglomerates.

[0155] Figure 10 This is a cumulative particle size distribution curve of the cross-composite particles of the present invention. The cumulative particle size distributions of Example 1, Comparative Example 5, and Comparative Example 6 are compared, with a focus on the particle size ranges corresponding to D10, D50, and D90. The results show that the cumulative distribution curve of Example 1 is in a moderate position, reflecting a reasonable configuration of D10, D50, and D90; the cumulative curve of Comparative Example 5 shifts to the left overall, indicating a higher proportion of fine particles; the cumulative curve of Comparative Example 6 shifts to the right overall, indicating a higher proportion of coarse or agglomerated particles. Combined with… Figure 9 It can be seen that, in Example 1, by adjusting the main particle size of polycarboxylic acid, the amount of pregelatinized starch aqueous dispersion, and the post-mixing additives, the cross-composite particles have a moderate main particle size and a narrow particle size distribution, thereby providing a structural basis for subsequent mixing, packaging, resolution dispersion, and acid medium release.

[0156] Figure 11This diagram compares the drying loss and exchangeable calcium release rate of the present invention. By analyzing the drying loss of the cross-composite granules of Example 1 and Comparative Example 8 and the corresponding exchangeable calcium release rate of their bagged granules, the particle release performance under different drying endpoints or residual moisture conditions was compared. The results show that Example 1 and Comparative Example 8 differ in both drying loss and exchangeable calcium release rate. This comparison demonstrates that the drying endpoint and exchangeable calcium release performance under acidic media need to be controlled in conjunction with the formulation and granulation conditions; changes in storage stability or flowability cannot be inferred solely from this.

[0157] Figure 12 This is a comparison chart of the intra-batch relative standard deviations of the present invention, statistically comparing the intra-batch content fluctuations of Example 1, Comparative Example 3, and Comparative Example 4. The results show that Example 1 has a lower intra-batch relative standard deviation, indicating that its formulation, wetting dispersion, cross-compound granulation, and post-mixing processes enable a relatively uniform distribution of polycarboxymethyl cellulose calcium, pregelatinized starch, cross-linked sodium carboxymethyl cellulose, and colloidal silica within the batch. Comparative Examples 3 and 4 exhibit larger intra-batch fluctuations, suggesting that relying solely on adhesive enhancement or rapid disintegration may lead to unstable component distribution and particle properties. These results, from the perspective of intra-batch consistency, demonstrate that this method can improve the controllability of the preparation process and contribute to improving performance stability during packaging and use.

[0158] Based on the above formulation parameters, particle size control and intra-batch consistency results, the overall effect of this scheme is further observed by comparing the macroscopic optical photographs and microscopic morphology of the final product. Figure 13 The image shows a macroscopic optical photograph comparison between the final product of Example 1 and the final product of Comparative Example 10, used to evaluate the effect of pregelatinized starch aqueous dispersion participating in cross-compound granulation on the macroscopic uniformity of bagged polycarboxylic acid calcium granules. Figure 13 Image a is a macroscopic optical photograph of the final bagged polycarbohydrate calcium granules from Example 1. This sample consists of 55.0 wt% polycarbohydrate calcium, 11.0 wt% pregelatinized starch, 30.0 wt% mannitol, 3.0 wt% croscarmellose sodium, 0.8 wt% colloidal silica, and 0.2 wt% sucralose. The cross-linked composite particles obtained during preparation have a D50 of 300 μm, a D90 of 600 μm, and a drying loss of 2.0 wt%. The final bagged granules contain 7.5 wt% free fine powder (less than 75 μm) and 8.8 wt% hard agglomerates (greater than 2.00 mm). These parameters indicate that, under the test conditions, the mass fractions of free fine powder and hard agglomerates in this sample are within the range described in this application. Figure 13b is a macroscopic optical photograph of the final granules of Comparative Example 10. Comparative Example 10 has the same formulation as Example 1, but the pregelatinized starch was added entirely in a dry state, without participating in wetting dispersion and cross-compounding through an aqueous dispersion. The comparison shows that even with the same formulation, the method of adding pregelatinized starch significantly affects wetting, bridging, and macroscopic uniformity during granulation; using an aqueous dispersion results in more uniform granule appearance and reduces the risk of localized agglomeration and fine powdering.

[0159] Figure 14 The images show a comparison of the scanning electron microscope (SEM) morphology and energy dispersive spectral distribution of the final product of Example 1 and the final product of Comparative Example 10. This comparison is used to compare the effects of the participation of pregelatinized starch aqueous dispersion in granulation on particle surface bridging, particle integrity, and the spatial distribution of multiple components. Figure 14 a is a low-magnification scanning electron microscope image of the final product of Example 1, showing that the overall particle group is within the range of a hundred micrometers in terms of main particle size, and the particle distribution is relatively uniform. Figure 14 b is a low-magnification scanning electron microscope image of the final product of Comparative Example 10, used to compare the differences in overall particle distribution, fine powder residue, and agglomeration state with Example 1. Low-magnification image comparison can be used to compare the differences in the overall structure of the particle group before and after the pregelatinized starch aqueous dispersion was used for granulation.

[0160] Figure 14 c is a scanning electron microscope image of the final product of Example 1, showing the outline and surface coverage of single or a few polycarbohydrate non-calcium-pregelatinized starch cross-composite particles, and the connection areas between particles can be observed. Figure 14 Image d is a medium-magnification scanning electron microscope image of the final product of Comparative Example 10, used to observe the inadequacy of particle surface coverage and bridging continuity when pregelatinized starch is added in the dry state. The comparison of medium-magnification images shows that after the pregelatinized starch is introduced by the aqueous dispersion, it is more easily distributed on the particle surface and particle contact area, thus forming a stable but not excessively dense composite structure.

[0161] Figure 14 e is a high-magnification scanning electron microscope image of the final product of Example 1, showing the rough structure of the particle surface, local bridging traces, micropores, and the adhesion state of the post-mixed fine particles. Figure 14 f is a high-magnification scanning electron microscope image of the final product of Comparative Example 10, used to compare differences in particle surface cracks, loose fine powder, or insufficient local bridging. High-magnification image comparison can be used to observe the surface micropores and rough structures retained in this scheme while maintaining particle integrity.

[0162] Figure 14g is the scanning electron microscope energy distribution map of the final product of Example 1. The element channels include Ca, Si, Na, O and C. Ca, Si and Na are used to reflect the spatial distribution of calcium-containing components, silicon-containing components and sodium-containing components, respectively, while O and C are used to reflect the overall distribution of organic components. Figure 14 h represents the scanning electron microscope energy dispersive spectroscopy (EDS) pattern of the final product in Comparative Example 10, used to compare the differences in the distribution of Ca, Si, Na, O, and C elements on the particle surface and in the interparticle regions with that in Example 1. This comparison provides observational results of the spatial distribution differences of multiple components under different pregelatinized starch addition methods.

[0163] In conclusion, Figures 1-4 The effects of key parameters of this scheme on calcium release, hardening, fine powder and intra-batch fluctuations were explained by the formulation ratio, main particle size, amount of wetted dispersion added and amount of disintegration regulator. Figures 5-8 The structural role of pregelatinized starch aqueous dispersion in cross-composite granulation was observed from the aspects of surface coverage, bridging distribution, interparticle connection state and aggregation state. Figures 9-12 The particle size distribution, loss on drying, and intra-batch consistency reflect the coordination between the processing performance and release stability of granules; Figure 13 and Figure 14 The overall color difference between Example 1 and the comparative example was compared by examining the macroscopic appearance, scanning electron microscope morphology, and energy dispersive spectroscopy (EDS) distribution of the final product. The results, under the stated experimental conditions, indicate that this method can enhance particle structure integrity while avoiding excessive agglomeration and slow dispersion, and simultaneously ensures processing flowability, intra-batch uniformity, and the release of exchangeable calcium in acidic media.

[0164] Table 1 Performance of Examples and Comparative Examples

[0165]

[0166] In Table 1, D50 represents the measured value of the corresponding polycarbohydrate calcium-pregelatinized starch cross-composite granules after granulation; exchangeable calcium release rate, water absorption and swelling, mass fraction of hardened agglomerates, mass fraction of free fine powder, and intra-batch relative standard deviation represent the measured values ​​of the corresponding bagged polycarbohydrate calcium granules.

[0167] As can be seen from the performance of the examples and comparative examples in Table 1, Examples 1–4 show a relatively balanced trend in terms of D50, agglomerates, free fine powder, exchangeable calcium release rate, water absorption swelling, and intra-batch relative standard deviation. In the conventional comparative examples, insufficient pregelatinized starch, insufficient cross-linked sodium carboxymethyl cellulose, insufficient colloidal silica, excessively fine particle size, excessively coarse particle size, excessively high granulation temperature, or excessively high drying weight loss will cause at least one key performance to deviate from the target state. The synergistic effect comparative examples 9–11 show that after removing pregelatinized starch, eliminating the participation of aqueous dispersion, or replacing it with non-pregelatinized starch, agglomerates, fine powder, and release swelling index all showed adverse changes, indicating that there is a corresponding relationship between the cross-complexation of polycarboxymethyl cellulose and corn-derived pregelatinized starch and its addition order and structural integrity, dispersibility, and release behavior.

[0168] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A polycarboxylic acid calcium granule, characterized in that, Based on a final dry basis total mass of 100 wt%, the polycarboxylic acid calcium granules comprise the following components: Polycarboxylic acid calcium 55–75 wt%; 5–15 wt% pregelatinized starch, said pregelatinized starch being derived from corn; Mannitol 10–30 wt%; 0.5–3.0 wt% croscarmellose sodium; Colloidal silica 0.2–0.8 wt%; Sucralose 0–1.0 wt% The total mass fraction of polycarboxymethyl cellulose, pregelatinized starch, mannitol, croscarmellose sodium, colloidal silica, and sucralose is 100 wt%, and the mass ratio of polycarboxymethyl cellulose to pregelatinized starch is 100:8 to 100:

20. The polycarboxymethyl cellulose and pregelatinized starch form polycarboxymethyl cellulose-pregelatinized starch cross-composite particles. The pregelatinized starch is distributed on the surface of the polycarboxymethyl cellulose and in the interparticle bridging region. The D50 of the polycarboxymethyl cellulose-pregelatinized starch cross-composite particles is 300–850 μm, and the loss on drying is 2.0–5.0 wt%.

2. The polycarboxylic acid non-calcium granule according to claim 1, characterized in that, The polycarbohydrate-calcium-pregelatinized starch cross-composite granules are prepared by the following steps: A1. Raw material preparation: Weigh 100 parts by weight of polycarboxymethyl calcium and 8-20 parts by weight of pregelatinized starch, wherein the pregelatinized starch is derived from corn; A2. Wetting and Dispersion: A portion of the pregelatinized starch is dispersed in purified water to obtain a pregelatinized starch aqueous dispersion; A3. Cross-composite granulation: The polycarboxylic acid calcium is mixed with pregelatinized starch not used to prepare the pregelatinized starch aqueous dispersion, and then the pregelatinized starch aqueous dispersion is added. Granulation is carried out at 20–35°C, so that the pregelatinized starch is distributed on the surface of the polycarboxylic acid calcium and in the interparticle bridging region. A4. Endpoint control: Under the condition that the amount of the pregelatinized starch aqueous dispersion added is 8-18 wt% of the amount of the premixed substance, granulation is stopped when the mass fraction of wet particles passing through the sieve after granulation is 70-95 wt%. A5. Post-processing: The wet granules are dried and granulated to obtain the polycarbohydrate calcium-pregelatinized starch cross-composite granules; A6. Quality control: The D50 of the polycarboxylic acid calcium-pregelatinized starch cross-composite particles is 300–850 μm, and the loss on drying is 2.0–5.0 wt%.

3. The polycarboxylic acid non-calcium granule according to claim 2, characterized in that, In step A1, the polycarboxymethyl calcium undergoes the following pretreatment and premixing before granulation: B1. The polycarbohydrate calcium is sieved to obtain polycarbohydrate calcium raw material; B2. The polycarbohydrate calcium raw material is dried to a drying loss of 0.5–6.0 wt%. B3. The dried polycarbohydrate calcium raw material is premixed with pregelatinized starch that was not used to prepare the pregelatinized starch aqueous dispersion to obtain a premix. B4. The mass fraction of fine powder with a particle size of less than 75 μm in the premix is ​​10–45 wt%.

4. The polycarboxylic acid non-calcium granule according to claim 2, characterized in that, In step A2, the pregelatinized starch aqueous dispersion is prepared by the following method: C1. Add a portion of the pregelatinized starch to purified water; C2. Disperse at 20–35℃ to obtain a pregelatinized starch aqueous dispersion with a pH of 5.0–7.5; C3. The pregelatinized starch aqueous dispersion is left to stand for 0–4 hours before being added in step A3; C4. The pregelatinized starch aqueous dispersion does not contain organic solvents.

5. The polycarboxylic acid non-calcium granule according to claim 1, characterized in that, The mass fraction of hard agglomerates with a particle size greater than 2.00 mm formed by dispersing the polycarboxylic acid granules in water is 0–10 wt%, and the mass fraction of free fine powder with a particle size less than 75 μm is 0–8 wt%.

6. The polycarboxylic acid non-calcium granule according to claim 1, characterized in that, The polycarboxymethyl calcium granules are packaged in bags, with each bag containing 0.5–1.5 g of polycarboxymethyl calcium.

7. A method for preparing polycarboxylic acid calcium granules as described in any one of claims 1-6, characterized in that, Includes the following steps: S1. Provides pre-prepared polycarboxylic acid calcium-pregelatinized starch cross-composite granules; S2. The polycarbohydrate calcium-pregelatinized starch cross-composite particles are mixed with mannitol to obtain a first mixture; S3. Add croscarmellose sodium to the first mixture and mix to obtain a second mixture; S4. Add colloidal silica to the second mixture, and add sucralose when the polycarboxylic acid calcium granules contain sucralose, and mix to obtain a third mixture; S5. The third mixture is granulated and then packaged to obtain the polycarboxylic acid calcium granules; The intra-batch relative standard deviation of the polycarboxylic acid calcium content in the packaged polycarboxylic acid calcium granules is 0.5–5.0%.

8. The preparation method according to claim 7, characterized in that, The D90 of the polycarboxylic acid-pregelatinized starch cross-composite particles provided in step S1 is 600–1400 μm.

9. The preparation method according to claim 7, characterized in that, The polycarbohydrate-pregelatinized starch cross-composite granules provided in step S1 are obtained by a high-shear wet granulation machine and a fluidized bed dryer. Step S5 is completed by a granulator and a granulation packaging machine. The preparation method does not use organic solvents.

10. The preparation method according to claim 7, characterized in that, The preparation batch of the polycarboxylic acid calcium granules is 1–300 kg / batch, and the inter-batch coefficient of variation of D50 for three adjacent batches of polycarboxylic acid calcium-pregelatinized starch cross-composite granules is 0.5–10%.

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