Sodium phosphate compound and preparation method thereof

Abstract

The invention provides a preparation method of a sodium phosphate compound, which comprises the following steps: A) mixing a disodium hydrogen phosphate raw material and potassium chloride to obtain mixed powder; and B) mixing the dried sodium dihydrogen phosphate raw material with the mixed powder to obtain the sodium phosphate compound. The potassium chloride is added into the sodium phosphate compound, electrolyte balance of a patient can be better maintained, the problem of mixing uniformity of the potassium chloride in the product is solved through a specific production and preparation process, and the property stability of the product under high-temperature and normal-temperature conditions is guaranteed; the problem that products are gathered and clustered according to a conventional powder preparation process is solved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sodium phosphate salt complex and a preparation method thereof. BACKGROUND

[0002] Sodium phosphate salt is a high-quality bowel preparation drug, which is used for cleaning the intestines of patients before colon X-ray and endoscopy or surgery, and its safety, effectiveness, convenience and patient compliance have been widely proven.

[0003] There are relevant clinical literature reports on oral sodium phosphate salt solution. The oral sodium phosphate salt solution is the first efficient and safe bowel preparation preparation, and its effectiveness and safety have been fully verified in clinical practice. As the current first-line bowel preparation preparation, it has the advantages of reduced dosage, rapid onset, 1500 mL solution can achieve satisfactory enema effect, and simple operation, good taste and easy acceptance by patients. At the same time, the literature also mentions that mild hypokalemia and other mild electrolyte disorders may occasionally occur after taking the oral sodium phosphate salt solution, which can be effectively alleviated by taking a small amount of potassium chloride granules. Therefore, the raw material potassium chloride can be added in the prescription to better maintain the electrolyte balance of the patients.

[0004] However, the sodium phosphate dihydrate raw material is sodium phosphate dihydrate (NaH2PO4·H2O), and it is accidentally found that sodium phosphate dihydrate (NaH2PO4·H2O) will aggregate into lumps after being stored at high temperature for 5-10 days. It is found through research that the reason for the aggregation of sodium phosphate dihydrate (NaH2PO4·H2O) into lumps is that sodium phosphate dihydrate (NaH2PO4·H2O) contains a crystal water, which will quickly precipitate under high temperature conditions. It is also accidentally found during the research that the crystal water of sodium phosphate dihydrate (NaH2PO4·H2O) will slowly precipitate at room temperature (10℃-30℃), and will also aggregate into lumps after being stored for a period of time, thereby causing the solid preparation containing sodium phosphate dihydrate (NaH2PO4·H2O) to also aggregate into lumps. After subsequent research, only the high-temperature drying method can completely solve the aggregation of sodium phosphate dihydrate (NaH2PO4·H2O) and solid preparations containing sodium phosphate dihydrate (NaH2PO4·H2O) into lumps under high-temperature conditions and at room temperature for a long period of time.

[0005] However, potassium chloride is colorless long prismatic, cubic crystal or white crystalline powder, and its particle size is large, more than 95% of which is large particle (more than 50 mesh sieve), so it is usually needed to be crushed into powder before subsequent product preparation when it is prepared into solid preparation such as powder or granules, otherwise, the product quality (mainly the mixing uniformity) will be unqualified due to the large particle size of potassium chloride and / or the inconsistent particle size of other raw and auxiliary materials in the product, but due to the inherent physicochemical properties of potassium chloride, the potassium chloride will quickly gather into lumps even after being crushed into powder, which seriously affects the content uniformity and properties of the product.

[0006] Therefore, it is a problem to be solved to provide a sodium phosphate salt compound with uniform content and good properties. SUMMARY

[0007] Therefore, it is a problem to be solved to provide a sodium phosphate salt compound with uniform content and good properties.

[0008] The application provides a preparation method of a sodium phosphate salt compound, which comprises the following steps:

[0009] A) mixing sodium phosphate dibasic raw material and potassium chloride to obtain mixed powder;

[0010] B) mixing the dried sodium phosphate dibasic raw material and the mixed powder to obtain a sodium phosphate salt compound.

[0011] Preferably, the particle size of the sodium phosphate dibasic raw material, potassium chloride and the dried sodium phosphate dibasic raw material is ≤80 mesh.

[0012] Preferably, the sodium phosphate dibasic raw material is selected from sodium phosphate dibasic or sodium phosphate dibasic monohydrate.

[0013] Preferably, in step A), the mixing is performed in a wet granulation mixer.

[0014] The rotation speed of the mixing is 60-200 rpm, the rotation speed of the cutter is 1000-3000 rpm during the mixing, and the mixing time is 2-10 minutes.

[0015] Preferably, the mass ratio of the sodium phosphate dibasic raw material to potassium chloride is 3-6:0.5-3.

[0016] Preferably, the preparation of the dried sodium phosphate dibasic raw material comprises the following steps:

[0017] The sodium phosphate dibasic raw material is placed in a fluidized bed for drying until the loss on drying of the sodium phosphate dibasic raw material is not higher than 1%.

[0018] The fluidized bed has an air inlet temperature of 50-100℃, an air inlet frequency of 8-25Hz, and a drying time of 60-120 minutes.

[0019] Preferably, in step B), the mixing is performed in a hopper mixer.

[0020] The mixing speed is 6-10rpm, and the mixing time is 15-60 minutes.

[0021] Preferably, in step A), a defoaming agent is also added during the mixing.

[0022] In step B), an auxiliary material is also added during the mixing.

[0023] The present application also provides a sodium phosphate salt compound prepared by the above preparation method, comprising:

[0024] 15-30 parts by weight of sodium dihydrogen phosphate raw material;

[0025] 3-6 parts by weight of disodium hydrogen phosphate raw material;

[0026] 0.5-3 parts by weight of potassium chloride;

[0027] 0-0.3 parts by weight of defoaming agent;

[0028] 0-0.25 parts by weight of sweetener;

[0029] 0-0.04 parts by weight of flavoring agent.

[0030] Preferably, the dosage form of the sodium phosphate salt compound is oral dosage;

[0031] The defoaming agent is selected from dimethicone or simethicone;

[0032] The sweetener is selected from one or more of acesulfame potassium, chloro sucrose or sodium saccharin;

[0033] The flavoring agent is selected from lemon flavor.

[0034] Compared with the prior art, the present application provides a preparation method of a sodium phosphate salt compound, comprising the following steps: A) mixing disodium hydrogen phosphate raw material and potassium chloride to obtain mixed powder; B) mixing dried sodium dihydrogen phosphate raw material and the mixed powder to obtain a sodium phosphate salt compound. The present application adds potassium chloride to the sodium phosphate salt compound, which not only better maintains the electrolyte balance of patients, but also solves the problem of uniformity of potassium chloride in the product and ensures the stability of the product under high-temperature and normal-temperature conditions through a specific production preparation process, and solves the problem of product aggregation into a group according to the conventional preparation process of a dispersible preparation. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 Sampling profile for hopper blender. DETAILED DESCRIPTION

[0036] The present application provides a preparation method of sodium phosphate salt complex, comprising the following steps:

[0037] A) mixing disodium hydrogen phosphate raw material and potassium chloride to obtain mixed powder;

[0038] B) mixing the dried sodium dihydrogen phosphate raw material and the mixed powder to obtain the sodium phosphate salt complex.

[0039] Before preparing the sodium phosphate salt complex, the present application first grinds the raw materials, and the particle size of the disodium hydrogen phosphate raw material, the potassium chloride, and the dried sodium dihydrogen phosphate raw material is ≤80 mesh.

[0040] Then, the disodium hydrogen phosphate raw material and the potassium chloride are mixed to obtain the mixed powder.

[0041] In the present application, the mixing is carried out in a wet granulation mixer. Among them, the rotation speed of the mixing is 60-200 rpm, which can be 60, 80, 100, 120, 140, 150, 160, 180, 200, or any value between 60-200 rpm, the cutter rotation speed is 1000-3000 rpm, which can be 1000, 1500, 2000, 2500, 3000, or any value between 1000-3000 rpm, and the mixing time is 2-10 minutes, which can be 2, 3, 4, 5, 6, 7, 8, 9, 10, or any value between 2-10 minutes.

[0042] In the present application, the mixing is carried out using a wet granulation mixer, and in the mixing process, the mixing rotation speed is 60-200 rpm, and the cutter rotation speed is 1000-3000 rpm. Under the above high-speed mixing parameters, the mixing time of 2-10 minutes can make the potassium chloride powder particles uniformly dispersed in the disodium hydrogen phosphate powder particles, and the powder particles of the two materials are firmly adsorbed together. Compared with other types or principles of mixers, the wet granulation mixer has strong mixing force in commonly used pharmaceutical mixing equipment and is commonly used for mixing between difficult-to-mix materials. Other mixing equipment cannot effectively mix the potassium chloride powder and the disodium hydrogen phosphate powder uniformly, and cannot make the powder particles of the two materials firmly adsorbed together due to insufficient mixing strength.

[0043] In the present application, the mass ratio of the sodium phosphate dibasic raw material and potassium chloride is 3-6:0.5-3. Among them, the amount of sodium phosphate dibasic raw material is greater than or equal to the amount of potassium chloride. In some embodiments of the present application, the mass ratio of the sodium phosphate dibasic raw material and potassium chloride is 4.3:0.5, 4.3:1, 4.3:2, 4.3:3, or any value between 3-6:0.5-3.

[0044] In some embodiments of the present application, a defoaming agent is added during the mixing process.

[0045] After obtaining the mixed powder, the dried sodium phosphate dibasic raw material and the mixed powder are mixed to obtain a sodium phosphate salt complex.

[0046] The preparation of the dried sodium phosphate dibasic raw material includes the following steps:

[0047] The sodium phosphate dibasic raw material is placed in a fluidized bed for drying until the dried loss on drying of the sodium phosphate dibasic raw material is not higher than 1%.

[0048] The inlet air temperature of the fluidized bed is 50-100°C, which can be 50, 60, 70, 80, 90, 100, or any value between 50-100°C; the inlet air frequency is 8-25Hz, which can be 8, 10, 15, 20, 25, or any value between 8-25Hz; and the drying time is 60-120 minutes, which can be 60, 70, 80, 90, 100, 110, 120, or any value between 60-120 minutes.

[0049] The drying is performed until the dried loss on drying of the sodium phosphate dibasic raw material is not higher than 1%, removing the crystal water in the sodium phosphate dibasic raw material. Before drying, the sodium phosphate dibasic raw material is sieved to control the particle size of the raw material, preferably sieved through an 80-mesh sieve to make the particle size of the raw material below 80 mesh.

[0050] After drying the sodium phosphate dibasic raw material, the dried sodium phosphate dibasic raw material and the mixed powder are mixed to obtain a sodium phosphate salt complex.

[0051] The mixing is performed in a hopper mixer. The rotation speed of the mixing is 6-10 revolutions per minute, which can be 6, 7, 8, 9, 10, or any value between 6-10 revolutions per minute; and the mixing time is 15-60 minutes, which can be 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or any value between 15-60 minutes.

[0052] In some embodiments of the present application, an auxiliary material is added during the mixing. The auxiliary material is selected from sweeteners and fragrances.

[0053] The obtained dry powder is preferably sieved before mixing, preferably through a 50-80 mesh sieve, more preferably through a 50 mesh sieve. The mixed powder is preferably sieved before mixing, preferably through a 50-80 mesh sieve, more preferably through a 50 mesh sieve. The sweetener powder and the flavoring agent are preferably sieved before mixing, preferably through an 80 mesh sieve, so that the particle size of the sweetener and the flavoring agent is less than 80 mesh. After obtaining the final sodium phosphate salt complex powder, it is packaged.

[0054] The sodium phosphate salt complex provided by the application adds potassium chloride raw materials in the prescription, so that it not only has significant clinical effect when cleaning the intestinal tract, good intestinal cleaning degree, good patient tolerance, high safety, and can better maintain the electrolyte balance of the patient, but also can solve the problem that the product is affected in quality due to the precipitation of the crystal water of sodium dihydrogen phosphate (NaH2PO4·H2O) under high temperature or long-term storage conditions at room temperature. The potassium chloride which is easily aggregated into a block after being crushed and sieved is uniformly dispersed in the disodium hydrogen phosphate by the principle of high-efficiency stirring and uniform mixing of the wet mixing machine, which can effectively delay the aggregation and blocking of potassium chloride. Finally, the disodium hydrogen phosphate, potassium chloride and defoaming agent mixture are sieved again before total mixing, which successfully solves the problem of potassium chloride aggregation and blocking during product preparation, thereby achieving the effect of quality stability of the product under high temperature conditions and long-term storage conditions at room temperature.

[0055] The applicant found in the research process that the sieved potassium chloride is sieved again before premixing, so that the aggregated potassium chloride is dispersed again to have a particle size of ≤80 mesh, and then the sieved potassium chloride is added to the disodium hydrogen phosphate. The mixture of disodium hydrogen phosphate and potassium chloride obtained after mixing by the wet granulator can greatly delay the aggregation and blocking of potassium chloride. Through in-depth research, it is found that the principle may be related to the physicochemical properties and / or crystal form of potassium chloride and disodium hydrogen phosphate. When disodium hydrogen phosphate is mixed with potassium chloride, the disodium hydrogen phosphate powder particles and the potassium chloride powder particles will mutually adsorb, so that the potassium chloride powder particles are firmly adsorbed on the disodium hydrogen phosphate powder particles, forming a condition similar to mixed crystals, thereby achieving the effect of uniformly dispersing the potassium chloride powder in the disodium hydrogen phosphate powder. Ultimately, not only is the aggregation and blocking of potassium chloride solved, but also a product with uniform content and other quality standards is obtained. Moreover, the product prepared by this process has good stability and will not aggregate and block under high temperature or long-term storage conditions.

[0056] The application also provides a sodium phosphate salt complex prepared by the above preparation method, comprising:

[0057] 15-30 parts by weight of sodium dihydrogen phosphate raw material;

[0058] 3-6 parts by weight of sodium phosphate dibasic raw material;

[0059] 0.5-3 parts by weight of potassium chloride;

[0060] 0-0.3 parts by weight of antifoaming agent;

[0061] 0-0.25 parts by weight of sweetener;

[0062] 0-0.04 parts by weight of fragrance.

[0063] The sodium phosphate salt complex provided by the application comprises 15-30 parts by weight of sodium phosphate dibasic raw material, which can be 15, 17, 20, 22, 25, 27, 30, or any value between 15 and 30 parts by weight. The sodium phosphate dibasic raw material is selected from sodium phosphate dibasic or sodium phosphate dibasic monohydrate.

[0064] The sodium phosphate salt complex provided by the application further comprises 3-6 parts by weight of sodium phosphate dibasic raw material, which can be 3, 3.5, 4, 4.5, 5, 5.5, 6, or any value between 3 and 6 parts by weight.

[0065] The sodium phosphate salt complex provided by the application further comprises 0.5-3 parts by weight of potassium chloride, which can be 0.5, 1, 1.5, 2, 2.5, 3, or any value between 0.5 and 3 parts by weight.

[0066] The sodium phosphate salt complex provided by the application further comprises 0-0.3 parts by weight of antifoaming agent, which can be 0, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, or any value between 0 and 0.3 parts by weight. The antifoaming agent is selected from dimethicone or simethicone.

[0067] The sodium phosphate salt complex provided by the application further comprises 0-0.25 parts by weight of sweetener, which can be 0, 0.05, 0.1, 0.15, 0.2, 0.25, or any value between 0 and 0.25 parts by weight. The sweetener is selected from one or more of acesulfame, sucralose, or sodium saccharin.

[0068] The sodium phosphate salt complex provided by the application further comprises 0-0.04 parts by weight of fragrance, which can be 0, 0.01, 0.02, 0.03, 0.04, or any value between 0 and 0.04 parts by weight. The fragrance is selected from lemon essence.

[0069] In some specific implementations, the sodium phosphate salt complex provided by the application comprises:

[0070] 20-25 parts by weight of sodium phosphate dibasic or monohydrate thereof;

[0071] 4-5 parts by weight of sodium phosphate dibasic;

[0072] 0.5-2 parts by weight of potassium chloride;

[0073] 0-0.25 parts by weight of an antifoaming agent;

[0074] 0.05-0.25 parts by weight of a sweetener and

[0075] 0.015-0.04 parts by weight of a flavoring agent.

[0076] In the present application, the dosage form of the sodium phosphate salt complex is an oral dosage, specifically an oral powder.

[0077] The present application adds potassium chloride to the sodium phosphate salt complex, which not only better maintains the electrolyte balance of patients, but also solves the problem of uniform mixing of potassium chloride in the product and ensures the stability of the product under high-temperature and normal-temperature conditions, solving the problem of product aggregation into groups according to the conventional preparation process of powders.

[0078] In order to further understand the present application, the sodium phosphate salt complex and the preparation method thereof provided by the present application will be described below in conjunction with examples, and the protection scope of the present application is not limited by the following examples.

[0079] Example 1

[0080] 1. Prescription:

[0081] Sodium phosphate, dibasic (anhydrous) 21.6 kg Sodium phosphate, dibasic 4.3 kg Potassium chloride 0.5 kg Simethicone 0.15 kg Sodium saccharin 0.1 kg Lemon flavor 0.015 kg Make 1000 bags

[0082] 2. Preparation process steps:

[0083] (1) Pretreatment

[0084] Screen the sodium dihydrogen phosphate (monohydrate), disodium hydrogen phosphate and lemon essence through an 80-mesh sieve for standby;

[0085] Crush the sodium saccharin powder through an 80-mesh sieve for standby;

[0086] Crush the potassium chloride powder through an 80-mesh sieve for standby;

[0087] (2) Drying: add the sodium dihydrogen phosphate (monohydrate) into the fluidized bed for drying, set the inlet air temperature to 60℃, the inlet air frequency to 18Hz, and the drying time to 115 minutes, and then detect the product, and detect that the loss on drying of the product is not higher than 1%;

[0088] (3) Premixing: weigh the simethicone, potassium chloride and disodium hydrogen phosphate screened in step (1) according to the prescription amount, and add them into the wet granulator, set the mixing speed to 150 revolutions / minute, the cutter speed to 3000 revolutions / minute, and the mixing time to 3 minutes, mix and stir to make them uniformly mixed, to obtain a mixture of disodium hydrogen phosphate, potassium chloride and simethicone;

[0089] (4) Total mixing: the sodium phosphate dibasic dry powder of step (2) was sieved through a 50 mesh sieve, the mixture of sodium phosphate dibasic, potassium chloride and simethicone of step (3) was sieved through a 50 mesh sieve, and the lemon flavor and the crushed sodium saccharin of step (1) were added to the hopper mixer, which was set to a mixing speed of 7 revolutions per minute and a mixing time of 45 minutes, and mixed until uniform;

[0090] (5) Sub-packing: the mixed material was sub-packed with an aluminum plastic composite film to obtain the sodium phosphate salt powder.

[0091] Example 2

[0092] 1. Prescription:

[0093] Sodium phosphate, dibasic (anhydrous) 21.6 kg Sodium phosphate, dibasic 4.3 kg Potassium chloride 3.0 kg Simethicone 0.30 kg Acesulfame potassium 0.15 kg Lemon flavor 0.03 kg Make 1000 bags

[0094] 2. Preparation process steps:

[0095] (1) Pretreatment

[0096] Sodium phosphate dibasic (monohydrate), sodium phosphate dibasic and lemon flavor were sieved through an 80 mesh sieve and prepared for use;

[0097] Acesulfame-K was crushed and sieved through an 80 mesh sieve and prepared for use;

[0098] Potassium chloride was crushed and sieved through an 80 mesh sieve and prepared for use;

[0099] (2) Drying: sodium phosphate dibasic (monohydrate) was added to the fluidized bed for drying, which was set to an inlet air temperature of 90°C and an inlet air frequency of 15 Hz, and the drying time was 60 minutes. The product was detected and the loss on drying was not higher than 1%;

[0100] (3) Premixing: simethicone, potassium chloride and sieved sodium phosphate dibasic of step (1) were weighed according to the prescription and added to the wet granulator, which was set to a mixing speed of 150 revolutions per minute and a cutter speed of 3000 revolutions per minute, and mixed for 3 minutes to obtain a mixture of sodium phosphate dibasic, potassium chloride and simethicone;

[0101] (4) Total mixing: the sieved sodium phosphate dibasic dry powder of step (2) was sieved through a 50 mesh sieve, the mixture of sodium phosphate dibasic and simethicone of step (3) was sieved through a 50 mesh sieve, and the lemon flavor and the crushed sodium saccharin of step (1) were added to the hopper mixer, which was set to a mixing speed of 8 revolutions per minute and a mixing time of 30 minutes, and mixed until uniform;

[0102] (5) Sub-packing: the mixed material was sub-packed with an aluminum plastic composite film to obtain the sodium phosphate salt powder.

[0103] Example 3

[0104] 1. Prescription:

[0105] Sodium phosphate, dibasic (anhydrous) 21.6 kg Sodium phosphate, dibasic 4.3 kg Potassium chloride 1.0 kg Simethicone 0.05 kg Sucralose 0.05 kg Lemon flavor 0.04 kg Make 1000 bags

[0106] 2、Process steps:

[0107] (1) Pretreatment

[0108] Sodium phosphate dibasic (monohydrate), sodium phosphate dibasic and lemon flavor were sieved through an 80-mesh screen and prepared for use;

[0109] Sucralose was crushed through an 80-mesh screen and prepared for use;

[0110] Potassium chloride was crushed through an 80-mesh screen and prepared for use;

[0111] (2) Drying: Sodium phosphate dibasic (monohydrate) was added to the fluidized bed for drying, with an inlet air temperature of 80°C, an inlet air frequency of 20 Hz, and a drying time of 75 minutes. The product was inspected, and the loss on drying was not higher than 1%;

[0112] (3) Premixing: According to the prescription, simethicone, potassium chloride, and sodium phosphate dibasic sieved in step (1) were weighed and added to a wet granulator, with a mixing speed of 150 rpm and a cutter speed of 3000 rpm. The mixture was mixed for 3 minutes to ensure uniformity. The mixture of sodium phosphate dibasic, potassium chloride, and simethicone was obtained;

[0113] (4) Total mixing: The sodium phosphate dibasic dry powder sieved through a 50-mesh screen in step (2) was weighed according to the prescription. The mixture of sodium phosphate dibasic and simethicone in step (3) was sieved through a 50-mesh screen. Lemon flavor and sodium saccharin crushed in step (1) were added to the hopper mixer, with a mixing speed of 6 rpm and a mixing time of 60 minutes. The mixture was mixed uniformly;

[0114] (5) Subpackaging: The mixed material was subpackaged with aluminum plastic composite film to obtain sodium phosphate salt powder.

[0115] Example 4

[0116] 1 Prescription:

[0117]

[0118]

[0119] 2、Process steps:

[0120] (1) Pretreatment

[0121] Sodium phosphate dibasic (monohydrate), sodium phosphate dibasic, and lemon flavor were sieved through an 80-mesh screen and prepared for use;

[0122] Acesulfame-K was crushed through an 80-mesh screen and prepared for use;

[0123] Potassium chloride was crushed through an 80-mesh screen and reserved;

[0124] (2) Drying: Sodium phosphate monobasic (monohydrate) was added to the fluid bed for drying, with an inlet air temperature of 70°C, an inlet air frequency of 10 Hz, and a drying time of 90 minutes. The product was tested, and the loss on drying was not higher than 1%.

[0125] (3) Premixing: Potassium chloride and sodium phosphate dibasic that had been sieved in step (1) were weighed according to the prescription and added to a wet granulator, with a mixing speed of 150 rpm and a cutter speed of 3000 rpm. The mixture was mixed for 3 minutes, and the sodium phosphate dibasic and potassium chloride were mixed uniformly.

[0126] (4) Total mixing: The sodium phosphate monobasic dry powder of step (2) was sieved through a 50-mesh screen, and the prescription amount of the sodium phosphate dibasic and potassium chloride mixture, lemon flavor, and sodium saccharin that had been crushed in step (1) were added to a hopper mixer, with a mixing speed of 9 rpm and a mixing time of 15 minutes. The mixture was mixed uniformly.

[0127] (5) Dispensing: The mixed material was dispensed using an aluminum-plastic composite film to obtain sodium phosphate salt powder.

[0128] Comparative Example 1

[0129] 1. Prescription:

[0130] Sodium phosphate, dibasic (anhydrous) 21.6 kg Sodium phosphate, dibasic 4.3 kg Potassium chloride 2.0 kg Acesulfame potassium 0.25 kg Lemon flavor 0.02 kg Make 1000 bags

[0131] 2. Preparation process steps:

[0132] (1) Pretreatment

[0133] Sodium phosphate monobasic (monohydrate), sodium phosphate dibasic, and lemon flavor were sieved through an 80-mesh screen and reserved.

[0134] Acesulfame-K was crushed through an 80-mesh screen and reserved.

[0135] Potassium chloride was crushed through an 80-mesh screen and reserved.

[0136] (2) Total mixing: The above-mentioned sodium phosphate monobasic (monohydrate), sodium phosphate dibasic, lemon flavor, acesulfame-K, and potassium chloride that had been sieved and treated were weighed according to the prescription and added to a hopper mixer, with a mixing speed of 9 rpm and a mixing time of 15 minutes. The mixture was mixed uniformly.

[0137] (3) Dispensing: The mixed material was dispensed using an aluminum-plastic composite film to obtain sodium phosphate salt powder.

[0138] Comparative Example 2

[0139] 1. Prescription:

[0140] Sodium phosphate, dibasic (anhydrous) 21.6 kg Sodium phosphate, dibasic 4.3 kg Potassium chloride 2.0 kg Acesulfame potassium 0.25 kg Lemon flavor 0.02 kg Make 1000 bags

[0141] 2. Preparation process steps:

[0142] (1) Pretreatment

[0143] Sodium dihydrogen phosphate (monohydrate), disodium hydrogen phosphate and lemon flavor were sieved through an 80-mesh screen and prepared for use;

[0144] Acesulfame-K was crushed through an 80-mesh screen and prepared for use;

[0145] Potassium chloride was crushed through an 80-mesh screen and prepared for use;

[0146] (2) Drying: Sodium dihydrogen phosphate (monohydrate) was added to a fluidized bed for drying, with an inlet air temperature of 70°C, an inlet air frequency of 10 Hz, and a drying time of 90 minutes. The product was inspected, and the loss on drying was not higher than 1%;

[0147] (3) Premixing:

[0148] The dried sodium dihydrogen phosphate 4.3 kg and the prescribed amount of potassium chloride were weighed and added to a wet granulator, with a mixing speed of 150 rpm and a cutter speed of 3000 rpm, for 3 minutes of mixing. The mixture was stirred until uniform, obtaining a sodium dihydrogen phosphate and potassium chloride mixture;

[0149] (4) Total mixing:

[0150] The remaining amount of sodium dihydrogen phosphate dry powder, the sodium dihydrogen phosphate and potassium chloride mixture, and the prescribed amount of disodium hydrogen phosphate, lemon flavor, and saccharin sodium crushed in step (1) were sieved through a 50-mesh screen and added to a hopper mixer, with a mixing speed of 9 rpm and a mixing time of 15 minutes. The mixture was mixed until uniform;

[0151] (5) Packaging: The mixed material was packaged with aluminum plastic composite film, obtaining sodium phosphate salt powder.

[0152] Comparative Example 3

[0153] 1. Prescription:

[0154] Sodium phosphate, dibasic (anhydrous) 21.6 kg Sodium phosphate, dibasic 4.3 kg Potassium chloride 2.0 kg Acesulfame potassium 0.25 kg Lemon flavor 0.02 kg Make 1000 bags

[0155] 2. Preparation process steps:

[0156] (1) Pretreatment

[0157] Sodium dihydrogen phosphate (monohydrate), disodium hydrogen phosphate and lemon flavor were sieved through an 80-mesh screen and prepared for use;

[0158] Acesulfame-K was crushed through an 80-mesh screen and prepared for use;

[0159] Potassium chloride was crushed through an 80-mesh screen and used as needed;

[0160] (2) Drying: Sodium phosphate monobasic (monohydrate) was added to the fluidized bed for drying, with an inlet air temperature of 70°C, an inlet air frequency of 10 Hz, a drying time of 90 minutes, and the product was sent for inspection, with a loss on drying of no more than 1%;

[0161] (3) Premixing:

[0162] The dried sodium phosphate monobasic and potassium chloride were weighed according to the prescription amount, respectively, and added to the wet granulator, with a mixing speed of 150 rpm, a cutter speed of 3000 rpm, and a mixing time of 3 minutes, and the mixture was stirred until it was uniformly mixed to obtain a mixture of sodium phosphate monobasic and potassium chloride;

[0163] (4) Total mixing

[0164] The mixture of sodium phosphate monobasic and potassium chloride was passed through a 50-mesh screen, and sodium phosphate dibasic, citric essence, and acesulfame were added to the hopper mixer, with a mixing speed of 9 rpm and a mixing time of 15 minutes, and the mixture was mixed until it was uniformly mixed.

[0165] (5) Subpackaging: The mixed material was subpackaged with an aluminum-plastic composite film to obtain sodium phosphate salt powder.

[0166] Test Example

[0167] 1. Total mixing content uniformity test: After the total mixing of the product was completed, 11 samples were taken at different positions in the hopper mixer, and the sampling positions are shown in Figure 1 , Figure 1 The sampling distribution diagram of the hopper mixer. The content uniformity of the product was detected.

[0168] 2. Stability investigation

[0169] Test conditions: Inverted storage in a pharmaceutical stability test box at a temperature of 60°C ± 2°C and a humidity of 75% ± 5%, and sampling for inspection at the 5th day, 15th day, and 30th day, respectively;

[0170] Test conditions: Inverted storage in a pharmaceutical stability test box at a temperature of 40°C ± 2°C and a humidity of 75% ± 5%, and sampling for inspection at the 1st month, 2nd month, 3rd month, and 6th month, respectively;

[0171] Test conditions: Inverted storage in a pharmaceutical stability test box at a temperature of 25°C ± 2°C and a humidity of 60% ± 10%, and sampling for inspection at the 1st month, 2nd month, 3rd month, and 6th month, respectively;

[0172] Test index:

[0173] (1) Refer to the detection method of sodium phosphate salt powder quality standard content, and calculate the RSD of 11 samples.

[0174] (2) Refer to the detection method of sodium phosphate salt powder quality standard registration standard YBH13542021 and potassium chloride, the detection index (method) and limit are shown in Table 1, Table 1 is the stability detection index and limit of sodium phosphate salt powder;

[0175] Table 1 Stability detection index and limit of sodium phosphate salt powder

[0176]

[0177] Take the sodium phosphate salt powder provided by examples 1-4 and control examples 1-3 respectively, and detect the total mixing uniformity according to the above detection conditions, and the detection results are shown in Table 2; and the investigation results are shown in Tables 3-15 according to the above stability experiment conditions.

[0178] Table 2: Summary of detection results of sodium dihydrogen phosphate total mixing uniformity confirmation of examples and control examples

[0179]

[0180] Note: The total mixing uniformity of sodium dihydrogen phosphate is qualified data within 95%-105%.

[0181] From Table 2, it can be seen that the total mixing uniformity of sodium phosphate salt powder prepared in control examples 1-3 does not meet the quality requirements, and the total mixing uniformity of examples 1-4 meets the quality requirements, which shows that the product prepared according to the examples can solve the mixing uniformity problem of the product.

[0182] Table 3 Investigation results of sodium phosphate salt powder provided by example 1 at high temperature (60℃)

[0183]

[0184] Table 4 Investigation results of sodium phosphate salt powder provided by example 2 at high temperature (60℃)

[0185]

[0186]

[0187] Table 5 Investigation results of sodium phosphate salt powder provided by example 3 at high temperature (60℃)

[0188]

[0189] Table 6 Investigation results of sodium phosphate salt powder provided by example 4 at high temperature (60℃)

[0190]

[0191]

[0192] Table 7 High temperature (60°C) investigation results of sodium phosphate salt powders provided by Comparative Examples 1 to 3

[0193]

[0194] Note: Since the content uniformity of the comparative examples was not qualified, only the properties were investigated.

[0195] Table 8 High temperature (40°C) investigation results of sodium phosphate salt powders provided by Example 1

[0196]

[0197]

[0198] Table 9 High temperature (40°C) investigation results of sodium phosphate salt powders provided by Example 2

[0199]

[0200]

[0201] Table 10 High temperature (40°C) investigation results of sodium phosphate salt powders provided by Example 3

[0202]

[0203]

[0204] Table 11 High temperature (40°C) investigation results of sodium phosphate salt powders provided by Example 4

[0205]

[0206] Table 12 High temperature (40°C) investigation results of sodium phosphate salt powders provided by Comparative Examples 1 to 3

[0207]

[0208]

[0209] Note: Since the content uniformity of the comparative examples was not qualified, only the properties were investigated.

[0210] Table 13 Long-term (25°C) investigation results of sodium phosphate salt powders provided by Example 1

[0211]

[0212]

[0213] Table 14 Long-term (25°C) investigation results of the sodium phosphate salt powder provided by Example 2

[0214]

[0215] Table 15 Long-term (25°C) investigation results of the sodium phosphate salt powder provided by Example 3

[0216]

[0217]

[0218] Table 16 Long-term (25°C) investigation results of the sodium phosphate salt powder provided by Example 4

[0219]

[0220]

[0221] Table 17 Long-term (25°C) investigation results of the sodium phosphate salt powder provided by Comparative Examples 1-3

[0222]

[0223] Note: Since the content uniformity of the comparative examples is unqualified, only the properties are investigated.

[0224] As shown in Tables 3-17, the sodium phosphate salt powders provided by Comparative Examples 1-3 began to agglomerate after 5 days of storage at high temperature (60°C), and seriously agglomerated or caked after 10-30 days. The sodium phosphate salt complexes provided by Examples 1-4 were stable and did not agglomerate or cake. The sodium phosphate salt powders provided by Comparative Examples 1-3 began to agglomerate after 1-2 months of storage at high temperature (40°C), and seriously agglomerated or caked after 3-6 months. The sodium phosphate salt complexes provided by Examples 1-4 were stable and did not agglomerate or cake. After 6 months of storage at room temperature (25°C), the sodium phosphate salt powders provided by Comparative Examples 1-3 began to agglomerate after 3 months, and seriously agglomerated after 6 months. The sodium phosphate salt complexes provided by Examples 1-4 were stable and did not change in properties, and other qualities met the quality standards and did not change significantly, and were stable and reliable.

[0225] The above only describes preferred embodiments of the present application, and it should be noted that those of ordinary skill in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should be considered within the protection scope of the present application.

Claims

1. A method for preparing a sodium phosphate salt complex, characterized by, The method comprises the following steps: A) mixing sodium phosphate dibasic raw material and potassium chloride to obtain mixed powder; B) mixing the dried sodium phosphate dibasic raw material and the mixed powder to obtain a sodium phosphate salt complex.

2. The production method according to claim 1, characterized by, The particle size of the sodium phosphate dibasic raw material, the potassium chloride, and the dried sodium phosphate dibasic raw material is less than or equal to 80 mesh.

3. The preparation method according to claim 1, characterized in that, The sodium phosphate dibasic raw material is selected from sodium phosphate dibasic or sodium phosphate dibasic monohydrate.

4. The production method according to claim 1, characterized by, In step A), the mixing is performed in a wet granulation mixer; The rotation speed of the mixing is 60-200 rpm, the rotation speed of the cutter during the mixing is 1000-3000 rpm, and the mixing time is 2-10 minutes.

5. The preparation method according to claim 1, characterized in that, The mass ratio of the sodium phosphate dibasic raw material to the potassium chloride is 3-6:0.5-3.

6. The method of claim 1, wherein, The preparation of the dried sodium phosphate dibasic raw material comprises the following steps: The sodium phosphate dibasic raw material is placed in a fluidized bed for drying until the loss on drying of the sodium phosphate dibasic raw material is not higher than 1%; The inlet air temperature of the fluidized bed is 50-100°C, the inlet air frequency is 8-25 Hz, and the drying time is 60-120 minutes.

7. The preparation method according to claim 1, characterized in that, In step B), the mixing is performed in a hopper mixer; The rotation speed of the mixing is 6-10 rpm, and the mixing time is 15-60 minutes.

8. The method of claim 1, wherein, In step A), a defoaming agent is also added during the mixing; In step B), an excipient is also added during the mixing.

9. The sodium phosphate salt complex prepared by the production method according to any one of claims 1 to 8, characterized in that, It comprises: 15-30 parts by weight of sodium phosphate dibasic raw material; 3-6 parts by weight of sodium phosphate dibasic raw material; 0.5-3 parts by weight of potassium chloride; 0-0.3 parts by weight of defoaming agent; 0-0.25 parts by weight of sweetener; 0-0.04 parts by weight of flavoring agent.

10. The sodium phosphate salt complex of claim 9, wherein, The dosage form of the sodium phosphate salt complex is oral dosage; The defoaming agent is selected from dimethicone or simethicone; The sweetener is selected from one or more of acesulfame potassium, chloro sucrose, or sodium saccharin; The flavoring agent is selected from lemon flavoring.

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