A method for preparing compound phosphate granules

Abstract

The invention provides a preparation method of compound phosphate granules, the prescription is 68.75% of sodium dihydrogen phosphate, 24.79% of disodium hydrogen phosphate, 5.46%-5.96% of hydroxypropyl cellulose, 0.5%-1.0% of magnesium stearate, and the preparation process is: sodium dihydrogen phosphate is sieved through 20-40 meshes, disodium hydrogen phosphate is sieved through 40 meshes, and then ingredients are prepared, premixed and granulated, and during granulation, hydroxypropyl cellulose is first dissolved in a wetting agent, and then added to a wet granulator for granulation, and then dried, dry granulated, mixed and packaged. The method can increase the solubility and mixing uniformity of the granules, and the obtained product has the same raw materials and auxiliary materials as the commercially available reference preparation, similar solubility, more concentrated particle size distribution, is conducive to the control of the granule packaging amount, and is suitable for the production of generic drugs.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a method for preparing compound phosphate particles. 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. The applicant 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. When sodium dihydrogen phosphate and disodium hydrogen phosphate are pre-treated through an 80-mesh sieve, the proportion of fine powder is too high, affecting the fluidity of the material and clogging the screen, which is not conducive to actual production applications.

[0003] The publicly disclosed prescription of the reference preparation of compound phosphate is sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose and magnesium stearate, but the preparation method of compound phosphate granules is not disclosed in the prior art. 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 and the reference preparation should be kept consistent as much as possible. The applicant referred to the original prescription and found in the process of preparing granules that when hydroxypropyl cellulose was used as a binder, white lumps easily appeared when the granules were dissolved, and the solubility did not meet the requirements; if a certain proportion of low-substituted hydroxypropyl cellulose was added, the granules could be completely dissolved, but flocs would appear in the solution; if hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate were added in a specific proportion and the process was adjusted, the formation of flocs could be avoided, making the solubility results similar to those of the reference preparation, but the prescription was changed compared with the reference preparation, which was not conducive to the consistency evaluation study of generic drugs. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing compound phosphate particles, so as to fill the gap in the preparation method of phosphate particles.

[0005] In order to achieve the above object, the technical solution adopted in the present invention is:

[0006] A method for preparing compound phosphate granules, the prescription is 68.75% of sodium dihydrogen phosphate, 24.79% of disodium hydrogen phosphate, 5.46% to 5.96% of hydroxypropyl cellulose, and 0.5% to 1.0% of magnesium stearate, and the preparation process comprises the following steps:

[0007] (1) Pretreatment: Sodium dihydrogen phosphate is sieved through 20-40 mesh, and disodium hydrogen phosphate is sieved through 40 mesh.

[0008] ~60 mesh sieving process;

[0009] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate and a wetting agent, wherein the amount of the wetting agent is 2% to 5% of the total amount of the excipients;

[0010] (3) Premixing: adding weighed amounts of sodium dihydrogen phosphate and disodium hydrogen phosphate into a wet granulator for premixing to obtain a premix;

[0011] (4) Granulation: Dissolve hydroxypropyl cellulose in a wetting agent, add to a wet granulator, and start stirring and cutting;

[0012] (5) Drying: The wet granules are dried using a multifunctional fluidized bed, and then dry granulation is performed after the drying is completed;

[0013] (6) Dry granulation: Use a portal granulator for dry granulation;

[0014] (7) Blending: adding magnesium stearate to the dry granules for blending;

[0015] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0016] Preferably, in the step (1), the sodium dihydrogen phosphate is sieved through 20 mesh, and the disodium hydrogen phosphate is sieved through 40 mesh.

[0017] Preferably, the wetting agent in step (2) is ethanol or water.

[0018] Preferably, in step (4), hydroxypropyl cellulose and the wetting agent are added by spraying.

[0019] Preferably, the wetting agent in step (2) is ethanol, and the amount used is 2% of the total amount of the auxiliary materials.

[0020] The beneficial effects achieved by the technical solution of the present invention are: the prescription is consistent with that of the reference preparation, the particle uniformity, solubility and clarity of the dissolved solution can all meet the requirements, the solubility results are similar to those of the commercially available reference preparation, the particle size distribution is more concentrated than that of the reference preparation, and it is more conducive to the packaging of the particles, and can be used for the development and mass production of generic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a picture of the solubility results of samples in Examples 1 and 2 of the present invention.

[0022] Figure 2 This is a picture of the solubility results of samples in Examples 3 and 4 of the present invention.

[0023] Figure 3 These are pictures of the solubility results of samples of Examples 5 to 16 described in the present invention.

[0024] Figure 4 This is a picture of the solubility results of the sample in Example 23 of the present invention and a commercially available reference preparation. DETAILED DESCRIPTION

[0025] 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.

[0026] Process 1:

[0027] (1) Pretreatment: Grind sodium dihydrogen phosphate and disodium hydrogen phosphate and pass through an 80-mesh sieve.

[0028] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate, and ethanol (as a wetting agent).

[0029] (3) Premixing: Add weighed amounts of sodium dihydrogen phosphate, disodium hydrogen phosphate, and hydroxypropyl cellulose into a wet granulator for premixing to obtain a premix.

[0030] (4) Granulation: Slowly pour the wetting agent into the above premix, start stirring and cutting, and perform wet granulation.

[0031] (5) Drying: Dry the wet granules.

[0032] (6) Dry granulation: The dry granules are dry granulated using a portal granulator.

[0033] (7) Blending: Add magnesium stearate to the above dry granules and blend them.

[0034] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0035] Solubility test: Take 5 packets of sample (weighing about 2.25g), add 200ml of warm water, stir for 5 minutes, and observe immediately.

[0036] The compound phosphate granules sample was prepared according to the prescription and process flow 1 shown in Table 1.

[0037] Table 1

[0038]

[0039] The solubility test results of Examples 1 and 2 are as follows: Figure 1 As shown, both the samples of Examples 1 and 2 have more agglomerated insoluble matter, and as the amount of hydroxypropylcellulose in the formulation increases, the insoluble matter becomes more obvious.

[0040] Process 2:

[0041] (1) Pretreatment: Grind sodium dihydrogen phosphate and disodium hydrogen phosphate and pass through an 80-mesh sieve.

[0042] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate, and ethanol (as a wetting agent).

[0043] (3) Premixing: Add weighed amounts of sodium dihydrogen phosphate and disodium hydrogen phosphate into a wet granulator for premixing to obtain a premix.

[0044] (4) Granulation: Dissolve hydroxypropyl cellulose in ethanol, slowly pour into the above premix, start stirring and cutting, and perform wet granulation.

[0045] (5) Drying: Dry the wet granules.

[0046] (6) Dry granulation: Use a portal granulator for dry granulation.

[0047] (7) Blending: Add magnesium stearate to the above dry granules and blend them.

[0048] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0049] According to the prescription shown in Table 2, process flow 2 prepares the compound phosphate granules.

[0050] Table 2

[0051]

[0052] Solubility test results Figure 2 As shown, the soluble particles of the sample of Example 3 dissolved rapidly, and after 5 minutes, the solution was slightly turbid with a small amount of fine flocs suspended in the solution. The particles of the sample of Example 4 dissolved completely within 40 seconds, and after 5 minutes, a small amount of undissolved flocs were suspended in the solution.

[0053] Process 3:

[0054] (1) Pretreatment: Grind sodium dihydrogen phosphate and disodium hydrogen phosphate and pass through an 80-mesh sieve.

[0055] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate, and a wetting agent, wherein the amount of the wetting agent is 2% to 5% of the total amount of the excipients.

[0056] (3) Premixing: Add weighed amounts of sodium dihydrogen phosphate and disodium hydrogen phosphate into a wet granulator for premixing to obtain a premix.

[0057] (4) Granulation: Dissolve the binder (hydroxypropyl cellulose) in the wetting agent (ethanol or water) and add it to the above premix, start stirring and cutting, and perform wet granulation.

[0058] (5) Drying: Dry the wet granules and then perform dry granulation after drying.

[0059] (6) Dry granulation: The dry granules are granulated using a portal granulator.

[0060] (7) Blending: Add magnesium stearate to the above dry granules and blend them.

[0061] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0062] Process parameters:

[0063] Table 3

[0064]

[0065] According to the process flow 3 and the process parameters shown in Table 3, the compound phosphate granules were prepared with a prescription of 68.75% of monosodium phosphate, 24.79% of disodium hydrogen phosphate, 5.46% of hydroxypropyl cellulose and 1.0% of magnesium stearate.

[0066] Determine the solubility of the sample, the result is as follows Figure 3 shown.

[0067] Example 5: The particles dissolved rapidly in about 30 seconds, there was no precipitant flocs, and the solution was clear and transparent.

[0068] Example 6: After 5 minutes, the particles were completely dissolved, with a small amount of floccules suspended in the solution and no precipitation.

[0069] Example 7: After 5 minutes, the particles were completely dissolved without obvious floccules or precipitation.

[0070] Example 8: After about 2 minutes, there were no obvious large particles and flocs, but there were still many small clumps of flocs. After 5 minutes, the solution was slightly turbid with a small amount of fine flocs.

[0071] Example 9: All particles dissolved in about 2 minutes. After 5 minutes, the solution was slightly turbid without precipitation. After standing, there was a small amount of thin layer of undissolved matter in the center of the liquid surface.

[0072] Example 10: All particles dissolved in about 2 minutes. After 5 minutes, the solution was slightly turbid without precipitation. After standing at the center of the liquid surface, there was a small amount of a thin layer of undissolved matter.

[0073] Example 11: All particles dissolved in about 2min15s. After 5min, there was no precipitation in the solution, but a thin layer of undissolved matter floated on the liquid surface.

[0074] Example 12: After 5 minutes, it can be seen that all the particles are dissolved, the solution is clear, and a small amount of floccules are suspended in the solution.

[0075] Example 13: After 5 minutes, it can be seen that all the particles are dissolved, the solution is clear, and a small amount of floccules are suspended in the solution.

[0076] Example 14: All particles dissolved in about 2min20s, and after 5min the solution was slightly turbid with slight floccules.

[0077] Example 15: The particles were basically dissolved in about 1 minute. After 5 minutes, the solution was slightly turbid, without precipitation, and with a small amount of fine floccules.

[0078] Example 16: All particles dissolved in about 1min 50s, and there was a small amount of undissolved floccules in the solution after 5min.

[0079] The results show that the solubility of the particles can be increased by dissolving the binder in the wetting agent before granulation. When ethanol is used as the wetting agent, the solution is clearer after the particles are dissolved; if the wetting agent is water, the solution is turbid after the particles are dissolved.

[0080] During the grinding process of sodium dihydrogen phosphate and disodium hydrogen phosphate, as the material in the grinding chamber increases, the materials squeeze each other and are affected by the heat generated by the equipment. The materials in the grinding chamber will melt and adhere to the grinding equipment, which is not conducive to mass production of the product.

[0081] Process 4:

[0082] (1) Pretreatment: Sodium dihydrogen phosphate and disodium hydrogen phosphate are sieved.

[0083] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate, and ethanol (as a wetting agent, the amount used is 2% of the total amount of excipients).

[0084] (3) Premixing: Add weighed amounts of sodium dihydrogen phosphate and disodium hydrogen phosphate into a wet granulator for premixing to obtain a premix.

[0085] (4) Granulation: Hydroxypropyl cellulose is dissolved in an ethanol solution and sprayed into the granules in the form of a liquid spray. Stirring and cutting are started to perform wet granulation.

[0086] (5) Drying: Dry the wet granules and then perform dry granulation after drying.

[0087] (6) Dry granulation: The dry granules are dry granulated using a portal granulator.

[0088] (7) Blending: Add magnesium stearate to the above dry granules and blend them.

[0089] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0090] The prescription is 68.75% of sodium dihydrogen phosphate, 24.79% of disodium hydrogen phosphate, 5.46% of hydroxypropyl cellulose, and 1.0% of magnesium stearate. The compound phosphate granules are prepared by process flow 4, wherein in step (1), sodium dihydrogen phosphate and disodium hydrogen phosphate are sieved as shown in Table 4.

[0091] Table 4

[0092]

[0093] The results of key quality attributes are shown in Table 5, and the results of mixing uniformity are shown in Table 6. The results show that as the mesh size of the sieve decreases, the proportion of fine powder increases, the adsorption between fine powders is more obvious, and the proportion of fine powder that can pass through the 100-mesh sieve decreases. The proportion of fine powder affects the fluidity of the material. An increase in the proportion will clog the sieve, and the mixing uniformity of the particles will also deteriorate.

[0094] Table 5

[0095]

[0096]

[0097] Table 6

[0098]

[0099] Embodiment 23:

[0100] Prescription: Sodium dihydrogen phosphate 68.75%, disodium hydrogen phosphate 24.79%, hydroxypropyl cellulose 5.96%, magnesium stearate 0.5%.

[0101] Process 5:

[0102] (1) Pretreatment: Sodium dihydrogen phosphate is sieved through 20 mesh, and disodium hydrogen phosphate is sieved through 40 mesh.

[0103] (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate, and wetting agent ethanol, wherein the amount of ethanol is 2% of the total amount of the excipients.

[0104] (3) Premixing: Add the weighed sodium dihydrogen phosphate and disodium hydrogen phosphate into a wet granulator for premixing at a premixing speed of 3 r / s for the stirring paddle and 40 r / s for the cutting blade for 5 min to obtain a premix.

[0105] (4) Granulation: Hydroxypropyl cellulose was dissolved in ethanol solution and sprayed into granules in the form of a liquid spray. Stirring and cutting were started with a stirring paddle speed of 3 r / s and a cutting blade speed of 40 r / s for wet granulation. The granulation time was 1 min.

[0106] (5) Drying: The wet granules are dried using a multifunctional fluidized bed at a drying temperature of 60°C. After drying, dry granulation is performed.

[0107] (6) Dry granulation: A gantry granulator is used for dry granulation, and a 20-mesh iron sieve is used as the sieve.

[0108] (7) Blending: Add magnesium stearate to the above dry granules and blend them for 10 min.

[0109] (8) Granule Packaging: The total mixed granules are packaged into granules.

[0110] The sample of Example 23 was compared with the commercially available reference preparation. The solubility results are as follows: Figure 4 The quality attribute comparison is shown in Table 7. The sample preparation process of Example 23 was smooth, and no abnormalities occurred in each process. From the particle size distribution data, the proportion of coarse particles above 60 mesh and fine powder below 100 mesh in Example 23 was less than that of the reference preparation, and the particle size was relatively more concentrated, which was more conducive to the control of the particle filling amount; the solubility test results of the sample of Example 23 showed that the sample dissolved quickly, without flocs and precipitation, and met the solubility quality standards.

[0111] Table 7

[0112]

[0113] 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 compound phosphate granules, characterized in that: The prescription is 68.75% of sodium dihydrogen phosphate, 24.79% of disodium hydrogen phosphate, 5.46% to 5.96% of hydroxypropyl cellulose, and 0.5% to 1.0% of magnesium stearate. The preparation process includes the following steps: (1) Pretreatment: Sodium dihydrogen phosphate is sieved through 20-40 mesh, and disodium hydrogen phosphate is sieved through 40-60 mesh; (2) Ingredients: Weigh sodium dihydrogen phosphate, disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate and a wetting agent; wherein the wetting agent is ethanol, and the amount used is 2% of the total amount of the excipients; (3) Premixing: adding weighed amounts of sodium dihydrogen phosphate and disodium hydrogen phosphate into a wet granulator for premixing to obtain a premix; (4) Granulation: Dissolve hydroxypropyl cellulose in a wetting agent, add to a wet granulator, and start stirring and cutting; wherein the hydroxypropyl cellulose and the wetting agent are added by spraying; (5) Drying: The wet granules are dried using a multifunctional fluidized bed, and then dry granulation is performed after the drying is completed; (6) Dry granulation: Use a portal granulator for dry granulation; (7) Blending: adding magnesium stearate to the dry granules for blending; (8) Granule Packaging: The total mixed granules are packaged into granules.

2. The method for preparing the composite phosphate granules according to claim 1, characterized in that: In the step (1), sodium dihydrogen phosphate is sieved through 20 meshes, and disodium hydrogen phosphate is sieved through 40 meshes.

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