A method for preparing sodium phosphate granules

Abstract

The invention provides a method for preparing sodium phosphate granules. The mass percentage of each component in the sodium phosphate granules is: 68.75% of sodium dihydrogen phosphate, 24.79% of disodium hydrogen phosphate, 0.79% to 4.81% of hydroxypropyl cellulose, 0.69% to 5.51% of low-substituted hydroxypropyl cellulose, and 0.16% to 0.96% of magnesium stearate. The preparation process is wet granulation. Binders, disintegrants and lubricants are added in a specific proportion to ensure the solubility, uniformity and fluidity of the granules. For sodium dihydrogen phosphate with larger particles, a suitable screen is used to screen them without crushing them, which not only saves preparation time, but also does not produce adhesion phenomenon in the preparation process of the granules, has good uniformity, and is more suitable for small-size packaging of sodium phosphate particles.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a method for preparing sodium phosphate granules. Background Art

[0002] Sodium phosphate can produce a significant osmotic effect on the large intestine, allowing water in the body to enter the intestine, softening the intestinal contents, thereby promoting excretion and achieving the purpose of cleaning the intestine. Phosphate granules can be dissolved in water and taken, quickly enter the intestine, and will not cause electrolyte disorders, and are very suitable for various types of patients. Patent CN111110697A provides a sodium phosphate powder and a preparation method thereof, the powder is composed of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium saccharin, lemon essence powder and xanthan gum, and the process steps are (1) firstly crushing sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium saccharin through an 80-mesh sieve; (2) respectively weighing the prescribed amount of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium saccharin, lemon essence powder and xanthan gum, adding them into a three-dimensional mixer, and mixing them thoroughly to make them uniform; (3) packaging the mixed materials with aluminum-plastic composite film. Research has found that during the grinding process of sodium dihydrogen phosphate, as the amount of material in the grinding chamber increases, the materials squeeze each other and are affected by the heat generated by the equipment, causing the material in the grinding chamber to melt and adhere to the grinding equipment. In addition, the particle size of the API not only affects the mixing uniformity, but also affects the dissolution rate of the granules.

[0003] Adding hydroxypropyl cellulose to sodium phosphate granules can not only play a bonding role, but also produce a sustained release effect on phosphates, reducing irritation to the intestines. Low-substituted hydroxypropyl cellulose has a certain viscosity and can be used as a binder under some conditions, but in most cases it is used as a disintegrant. Magnesium stearate has a lubricating effect and can enhance the fluidity of the granules. The applicant uses the compound phosphate granules listed in Japan as a reference preparation to develop generic drugs for sodium phosphate granules. The public prescription of the reference preparation is sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose and magnesium stearate. In order to ensure that the quality of generic drugs is consistent with that of the reference preparation, the material basis of the generic preparation should be kept consistent with that of the reference preparation as much as possible. During the preparation process, the applicant found that due to the strong adhesiveness of hydroxypropyl cellulose and the strong hydrophobicity of magnesium stearate, it is easy to produce problems such as difficult dissolution of granules, too coarse or too fine particles, and uneven particle size distribution, which is not suitable for the production of drugs.

[0004] In addition, since oral sodium phosphate has a certain irritating effect on the intestine, the tolerance of pediatric patients needs to be considered when developing specifications, so small-sized products have more advantages in clinical applications. However, small-sized packaging also means that there are higher requirements for the mixing uniformity of raw and auxiliary materials. The preparation process of sodium phosphate granules has not been studied in detail in the prior art. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing phosphate granules, which can effectively avoid the problem of raw material adhesion generated in the production process and enhance the mixing uniformity of raw and auxiliary materials; select a suitable auxiliary material ratio so that the solubility, fluidity, particle size distribution and uniformity of the sodium phosphate granules meet the requirements and can be used for actual production applications.

[0006] In order to achieve the above object, the technical solution adopted in the present invention is:

[0007] A method for preparing sodium phosphate granules. The contents of the components in the sodium phosphate granules are: 68.75% of sodium dihydrogen phosphate, 24.79% of disodium hydrogen phosphate, 0.79%-4.81% of hydroxypropyl cellulose, 0.69%-5.51% of low-substituted hydroxypropyl cellulose, and 0.16%-0.96% of magnesium stearate. The preparation process is wet granulation.

[0008] Preferably, the process comprises the following steps:

[0009] (1) Pretreatment: Sodium dihydrogen phosphate material is sieved through 12-20 mesh;

[0010] (2) Premixing: uniformly mixing sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose in a wet mixing granulator to obtain a premix;

[0011] (3) granulation: adding a wetting agent, ethanol, to the premix of step (2) for wet granulation, and then performing wet granulation after granulation;

[0012] (4) Drying: Drying the wet granules, and then performing dry granulation after drying;

[0013] (5) Blending: adding magnesium stearate to the dry granules for blending;

[0014] (6) Granule Packaging: The total mixed granules are packaged into granules.

[0015] Preferably, the content ratio of hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate is 5:5:1.

[0016] Preferably, the content ratio of hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate is 4:4:1.

[0017] Preferably, in the step (1), the sodium dihydrogen phosphate is sieved using a 20-mesh swing sieve.

[0018] The beneficial effects achieved by the technical solution of the present invention are as follows: in the pretreatment process, only sodium dihydrogen phosphate is screened, which can shorten the preparation time and improve the efficiency; the selection of a suitable screen mesh number can avoid adhesion during the mixing process and ensure the mixing uniformity of the granules; low-substituted hydroxypropyl cellulose is selected as a disintegrant and added with hydroxypropyl cellulose and magnesium stearate in a specific proportion, which can significantly improve the mixing uniformity, fluidity and solubility of sodium phosphate salt particles; compared with the commercially available reference preparation, the solubility of the self-developed sample is similar, the particle size distribution is more concentrated, and it is more conducive to the control of the filling amount during the granule packaging, and can be used for the mass production of generic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 These are pictures of the solubility results of samples of Examples 1 to 6 described in the present invention.

[0020] Figure 2 These are pictures of the solubility results of samples of Examples 7 to 13 described in the present invention.

[0021] Figure 3 These are pictures of the solubility results of samples in Examples 14 to 16 of the present invention.

[0022] Figure 4 This is a picture of the solubility results of samples in Examples 17 to 20 of the present invention.

[0023] Figure 5 This is a picture of the solubility results of the sample in Example 21 of the present invention and a commercially available reference preparation. DETAILED DESCRIPTION

[0024] In order to better understand the technical solutions and advantages of the present invention, the present invention is further described below through specific implementation methods.

[0025] Process 1:

[0026] (1) Pretreatment: Sodium dihydrogen phosphate and disodium hydrogen phosphate are crushed and passed through an 80-mesh sieve.

[0027] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (if any), magnesium stearate, and ethanol (as a wetting agent).

[0028] (3) Premixing: Weighed amounts of sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose (if any) are added into a wet granulator for premixing to obtain a premix.

[0029] (4) Granulation: Slowly pour the wetting agent into the above premix, start stirring and cutting, and perform wet granulation.

[0030] (5) Drying: Dry the wet granules.

[0031] (6) Dry granulation: The dry granules are dry granulated using a portal granulator.

[0032] (7) Blending: Add magnesium stearate to the above dry granules and blend them.

[0033] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0034] The sodium phosphate granule sample was prepared according to the prescription and process flow 1 shown in Table 1.

[0035] Table 1

[0036]

[0037] Solubility test: Take 5 packets of sample (weighing about 2.25g), add 200ml of warm water, stir for 5 minutes, and observe immediately.

[0038] The results are as follows Figure 1 As shown, samples of Examples 1 to 6 all have more insoluble matter, and the greater the amount of hydroxypropyl cellulose used in the prescription, the more obvious the insoluble matter agglomerates are. When hydroxypropyl cellulose is mixed with low-substituted hydroxypropyl cellulose,

[0039] The solubility is improved, and as the proportion of low-substituted hydroxypropyl cellulose increases, the number of insoluble lumps is significantly reduced.

[0040] The sodium phosphate granule sample was prepared according to the prescription and process flow 1 shown in Table 2.

[0041] Table 2

[0042]

[0043] Solubility results such as Figure 2 As shown. The sample particles of Examples 7 to 13 can all be dissolved, meeting the solubility requirements, but there is a small amount of white floccules. From the key quality attributes of the sample such as bulk density and angle of repose, the fluidity of the sample increases with the increase of magnesium stearate content.

[0044] Table 3

[0045]

[0046]

[0047] Both sodium dihydrogen phosphate and disodium hydrogen phosphate in the prescription are active ingredients, and their particle sizes may affect the product quality. The particle sizes of the two were preliminarily investigated using the mechanical sieving method, and the test data are shown in Table 4.

[0048] Table 4

[0049]

[0050] From the data in Table 4, it can be seen that disodium hydrogen phosphate is a powder with a small particle size, and the proportion of fine powder below 100 mesh is close to 70%; while sodium dihydrogen phosphate is a crystalline powder or granule with a large particle size and a wide particle size distribution. Crushing will change the particle size and specific surface area of ​​the API, which directly affects the dissolution rate of the product. Sodium dihydrogen phosphate is crushed using 18 mesh, 40 mesh, and 60 mesh screens to obtain APIs of different particle sizes. During the crushing process, it was found that if a screen of 60 mesh or above is used for crushing, as the material in the crushing chamber increases, sodium dihydrogen phosphate squeezes each other and is affected by the heat generated by the equipment, and the material will melt in the crushing chamber and adhere to the crushing equipment. Sodium phosphate particles are prepared according to the prescription, crushing state and process flow 2 shown in Table 5.

[0051] Process 2:

[0052] (1) Pretreatment: Sodium dihydrogen phosphate is crushed or not.

[0053] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, and ethanol (as a wetting agent).

[0054] (3) Premixing: Weighed amounts of sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose are added into a wet granulator for premixing to obtain a premix.

[0055] (4) Granulation: Slowly pour the wetting agent into the above premix, start stirring and cutting, and perform wet granulation.

[0056] (5) Drying: Dry the wet granules and then perform dry granulation after drying.

[0057] (6) Dry granulation: The dry granules are dry granulated using a portal granulator.

[0058] (7) Total mixing: Magnesium stearate is then added to the above dry granules for total mixing.

[0059] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0060] Table 5

[0061]

[0062] Comparing the test results of samples in Examples 14 to 16, the proportion of fine powder of the sample obtained after the sodium dihydrogen phosphate was crushed increased significantly, and the fluidity of the sample was worse than that of the un-crushed batch, resulting in unstable differences in the amount of subsequent packaging process. Figure 3As shown, samples of Examples 14 and 15 were completely dissolved, but the suspended flocs in the solution of the sample of Example 15 were more obvious than those of the un-crushed batches, and one or two undissolved white small lumps were visible on the liquid surface of the sample of Example 16.

[0063] The particle size distribution of sodium dihydrogen phosphate after sieving with different mesh sieves is shown in Table 6. According to the prescription shown in Table 7, sodium dihydrogen phosphate was sieved and sodium phosphate granules were prepared with reference to process flow 2. The solubility results of samples in Examples 17 to 20 are shown in Figure 4 The mixing uniformity results are shown in Table 8. The results show that after swing granulation with 12 mesh, 16 mesh, and 20 mesh iron sieves, there is no obvious difference in the particle size distribution of sodium dihydrogen phosphate. After manual screening, the particle size of sodium dihydrogen phosphate is mainly concentrated in the range of 40-80 mesh, while after swing granulation, the particle size is mainly between 60-100 mesh, and the particle size of the two treatment methods does not show a two-level differentiation. The granulation efficiency of the swing granulator is much greater than that of manual screening, which can greatly shorten the pretreatment time and is more conducive to actual production operations. In terms of product solubility, samples of Examples 17 to 20 can be completely dissolved without visible particles, but in terms of uniformity, the mixing uniformity of samples of Examples 17 and 20 is higher.

[0064] Table 6

[0065]

[0066] Table 7

[0067]

[0068] Table 8

[0069]

[0070] Embodiment 21

[0071] Prescription: Sodium dihydrogen phosphate 68.75%, disodium hydrogen phosphate 24.79%, hydroxypropyl cellulose 2.87%, low-substituted hydroxypropyl cellulose 2.87%, magnesium stearate 0.72%.

[0072] Process 3:

[0073] Pretreatment: Sodium dihydrogen phosphate was sieved using a 20-mesh disc sieve before weighing.

[0074] Ingredients: weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, and ethanol (as a wetting agent) according to the prescribed amount.

[0075] Premixing: Add the weighed sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose into a wet granulator for premixing. The speed is 3r / s for the stirring paddle and 40r / s for the cutting blade. The mixing time is 5min.

[0076] Granulation: Slowly pour ethanol into the above premix, start stirring and cutting, the speed is 3r / s for the stirring paddle and 50r / s for the cutting knife, and wet granulation is carried out for 1 min.

[0077] Drying: Pour the wet granules into a fluidized bed for drying at a temperature of 60°C. Stop drying when the moisture content of the granules meets the requirements.

[0078] Dry granulation: The above dry granules were dry granulated using a portal granulator with a 1.2 mm screen.

[0079] Total mixing: Pour the sized dry granules and the weighed magnesium stearate into a three-dimensional mixing barrel for total mixing.

[0080] Granule packing: pack the total mixed granules into granules.

[0081] The sample of Example 21 was compared with the commercially available reference preparation. The quality attribute results are shown in Table 9. The solubility results are shown in Figure 5 As shown. After adjusting the prescription process, there was no abnormality in the sample preparation process. Compared with the commercially available reference preparation, the particle size distribution of the sample of Example 21 is more concentrated, and the coarse particles and fine powder below 100 mesh are less than the commercially available reference preparation, which is more conducive to the control of the particle filling amount; the solubility of the sample of Example 21 is not significantly different from that of the commercially available reference preparation, and no flocs or precipitation are produced, which meets the requirements.

[0082] Table 9

[0083]

[0084] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments may still be modified, or some or all of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing sodium phosphate granules, characterized in that: The contents of the components in the sodium phosphate granules are: 68.75% sodium dihydrogen phosphate, 24.79% disodium hydrogen phosphate, 2.87% hydroxypropyl cellulose, 2.87% low-substituted hydroxypropyl cellulose, and 0.72% magnesium stearate. The preparation process is wet granulation. The preparation method comprises the following steps: (1) Pretreatment: Sodium dihydrogen phosphate material is passed through a 20-mesh sieve; (2) Premixing: uniformly mix sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose in a wet mixing granulator to obtain a premix; (3) Granulation: adding ethanol as a wetting agent to the premix in step (2) to perform wet granulation, and then wet granulation to obtain wet granules; (4) Drying: Drying the wet granules obtained in step (3), and after drying, performing dry granulation to obtain dry granules; (5) Mixing: adding magnesium stearate to the dry granules obtained in step (4) and mixing; (6) Granule packaging: The total mixed granules are packaged into granules.

2. The method for preparing the sodium phosphate granules according to claim 1, characterized in that: The content ratio of hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate is 4:4:1.

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