A preparation method of a coated dicalcium phosphate-magnesium stearate composite medicinal adjuvant

Abstract

The application discloses a preparation method of a coated dicalcium phosphate-magnesium stearate composite medicinal auxiliary material. A wet-synthesized dicalcium phosphate aqueous slurry is used as a base, sodium stearate active solution is prepared by saponification of stearic acid, stearate ion is uniformly adsorbed on the surface of dicalcium phosphate particles by a spray feeding mode, and then a magnesium salt solution is introduced to generate an in-situ metathesis reaction on the particle surface, thereby generating a uniform, firm and low-free magnesium stearate thin layer coating structure on the surface of the dicalcium phosphate core, and an integrated composite auxiliary material is obtained. The application discards the traditional dry powder physical mixing mode, effectively eliminates the negative effects caused by excessive hydrophobicity of free magnesium stearate, significantly improves the powder flowability, bulk density and compressibility of the auxiliary material, reduces the tablet weight difference, greatly improves the compatibility stability of the auxiliary material and acidic and weakly acidic raw drugs, and ensures the stability of the tablet disintegration rate and drug dissolution.

Description

Technical Field

[0001] This invention discloses a method for preparing a coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient, belonging to the field of pharmaceutical excipient technology. Background Technology

[0002] dicalcium phosphate is a commonly used filler excipient in the pharmaceutical industry, possessing advantages such as high bulk density, cost-effectiveness, chemical stability, and wide compatibility. It is widely used in the production of oral solid dosage forms, effectively increasing tablet formability and improving formulation hardness, making it one of the core filler excipients for tablets, chewable tablets, and sustained-release formulations. However, dicalcium phosphate powder has a high coefficient of friction, poor flowability, and generally poor compressibility. When used alone, it is prone to production problems such as uneven material feeding, large differences in tablet weight, mold sticking, and tablet cracking under high-speed tableting processes, failing to meet the production requirements of modern high-speed pharmaceutical production lines. To address the insufficient lubrication performance of dicalcium phosphate, the industry's conventional technical approach is to physically mix dicalcium phosphate with magnesium stearate in dry powder form. This utilizes the excellent lubrication and anti-sticking properties of magnesium stearate to improve the overall flowability of the powder and its adaptability to the tableting process. However, this traditional mixing method has many inherent technical defects: First, the two are only simple physical doping, with limited mixing uniformity. Magnesium stearate is prone to local agglomeration and uneven distribution, resulting in large differences in lubrication effect in different parts of the tablet and poor batch stability. Second, the system contains a large amount of free magnesium stearate, whose strong hydrophobic properties can encapsulate drug particles and excipient pores, easily causing slow tablet disintegration and decreased drug dissolution, seriously affecting the efficacy of the formulation. Third, the weak alkalinity of free magnesium stearate can form a local high pH microenvironment on the surface of drug particles, which can react with acidic and weakly acidic raw materials in the formulation, causing drug degradation, reduced content, and increased impurities, significantly reducing the storage stability of the formulation. Fourth, the two excipients need to be added separately and mixed for a long time, which is cumbersome, inefficient, and results in a high total amount of excipients added, making it difficult to control production costs. Currently, there is no mature integrated composite modification technology in the industry that can combine the filling and molding advantages of dicalcium phosphate with the lubrication and anti-sticking advantages of magnesium stearate, while completely solving the disintegration, dissolution, and stability defects caused by free magnesium stearate. Existing composite excipients and preparation processes all have obvious technical shortcomings. Therefore, developing a structurally stable, free hydrophobic component-free, process-adaptable, and excellent filling and lubrication properties of dicalcium phosphate-magnesium stearate composite pharmaceutical excipient is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0003] To address the aforementioned technical problems, this invention provides a method for preparing a coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient, comprising the following steps: S1. Preparation of aqueous dicalcium phosphate slurry: Using calcium carbonate suspension as raw material, phosphoric acid solution is added dropwise under controlled temperature to adjust the pH of the system. After the reaction is complete, an aqueous dicalcium phosphate slurry is obtained. This step retains the original slurry from the wet synthesis and does not perform pre-filtration and drying, so that the particle surface has abundant active adsorption sites, providing a basis for the subsequent coating reaction.

[0004] S2. Preparation of sodium stearate active soap solution: Stearic acid is heated and melted, and then fully saponified with sodium hydroxide solution to obtain sodium stearate soap solution, which is then cooled and kept warm for later use; This soap solution can achieve ion-level uniform dispersion, avoiding the problem of traditional powder mixing and agglomeration; S3. In-situ adsorption and surface coating modification: Sodium stearate soap solution is added to dicalcium phosphate slurry by spraying, and the mixture is stirred at a constant temperature to allow stearate ions to be fully adsorbed on the surface of dicalcium phosphate particles; then, magnesium salt solution is added dropwise under controlled temperature, and a thin layer of magnesium stearate coating is uniformly generated on the surface of dicalcium phosphate particles through in-situ metathesis reaction, thus obtaining a coated and modified composite slurry. S4. Post-processing and refining: The coated and modified composite slurry is washed with countercurrent pure water, dehydrated by pressure filtration, dried under low temperature vacuum, and pulverized and sieved to obtain an integrated coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient.

[0005] Preferably, the molar ratio of raw materials in S1 is calcium carbonate:phosphoric acid = 1:(1.01~1.06); preferably, calcium carbonate:phosphoric acid = 1:1.03; phosphoric acid is added dropwise at a controlled temperature of 40~55℃, with a phosphoric acid dropping rate of 15-30mL / min, and the pH of the system is adjusted to 6.2~6.5; after the addition is completed, the mixture is kept warm and stirred for 60~120 min at a stirring speed of 200~350 r / min.

[0006] Preferably, in S1, the calcium carbonate suspension has a mass fraction of 10%~20% and the calcium carbonate is 300~400 mesh; the phosphoric acid is prepared as follows: the dilute phosphoric acid has a mass fraction of 10%~18% and is made by diluting 85% phosphoric acid with pure water.

[0007] Preferably, after the S1 reaction is completed, the dry solids content of the calcium hydrogen phosphate slurry is 12%~20wt.%.

[0008] Preferably, the raw material molar ratio in S2 is stearic acid:NaOH = 1:1.10, and the mass fraction of sodium hydroxide aqueous solution is 10% to 15%. After the stearic acid is completely melted at 75 to 80 °C, the alkali solution is added dropwise at a uniform rate for 30 to 60 min. After the addition is completed, the solution is kept warm and stirred for 60 to 90 min until the solution is clear, transparent and free of floating oil.

[0009] Preferably, the sodium stearate soap solution in S2 has a mass fraction of 7%~9%, the saponification reaction temperature is 78~82 ℃, and the temperature is maintained at 70~75 ℃ after saponification.

[0010] Preferably, the in-situ adsorption and surface coating modification in S3 involves: maintaining the temperature of the dicalcium phosphate slurry system at 50-60°C, with a sodium stearate soap solution mass fraction of 7-9%, and the amount of sodium stearate added on a dry basis being 2.0%-3.0% of the dicalcium phosphate mass. After the soap solution is fed, the system is kept at a constant temperature and stirred for 30-35 minutes for adsorption. The system is then maintained at 50-60°C, and a magnesium salt solution is added dropwise. Through an in-situ metathesis reaction, a thin layer of magnesium stearate is uniformly formed on the surface of the dicalcium phosphate particles, resulting in a coated and modified composite slurry.

[0011] Preferably, in step S3, the spray feeding time is 70-75 min, the spray pressure is controlled at 0.28-0.32 MPa, the spray flow rate is 1-2.5 L / h, and the dicalcium phosphate slurry level is 2-5 cm.

[0012] Preferably, in step S3, a 12%~14% magnesium sulfate aqueous solution is added dropwise at a magnesium ion to sodium stearate molar ratio of (1.03~1.06):1, at a rate of 10-15 mL / min. After the addition is complete, the mixture is kept warm and stirred for 40-50 min to mature. Preferably, the post-processing refining in S4 involves the following steps: the modified composite slurry is subjected to three-stage countercurrent washing with purified water at 40-50 ℃, with the mass ratio of slurry to washing water controlled sequentially at 1:(2.5-2.8). The washing process is terminated after the chloride and sulfate levels in the filtrate meet the standards at the washing endpoint. The material is then filtered through a plate and frame filter press to obtain a filter cake with a moisture content of 20%-25%. The filter cake is placed in a vacuum drying oven and dried at a vacuum degree of -0.06 to -0.08 MPa and a drying temperature of 65-75 ℃ until the moisture content is ≤1.5%. The dried material is then pulverized and passed through a 100-mesh sieve. The coarse particles remaining on the sieve are re-pulverized, and the powder passing through the sieve is the integrated coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient.

[0013] Compared with the prior art, the present invention has the following significant advantages: First, this invention abandons the traditional dry powder physical blending mode and adopts a slurry in-situ adsorption-surface metathesis coating process, so that magnesium stearate is uniformly and firmly bonded to the surface of calcium hydrogen phosphate particles. This controls the deviation between the actual amount of magnesium stearate and the theoretical amount within ±3%, fundamentally eliminating the problem of magnesium stearate agglomeration and uneven dispersion, completely eliminating the strong hydrophobic side effects of free magnesium stearate, effectively avoiding the defects of slow tablet disintegration and decreased drug dissolution, and significantly improving the efficacy stability of the formulation and the finished product qualification rate. Secondly, the integrated composite excipient prepared by this invention has significantly improved powder flowability and bulk density, and greatly reduced angle of repose. It can effectively improve production problems such as uneven feeding, large differences in tablet weight, sticking, and cracking during tableting. It is perfectly adapted to modern high-speed tableting production lines and significantly improves formulation production efficiency and batch stability.

[0014] Third, this invention achieves the integration of the microstructures of dicalcium phosphate and magnesium stearate, avoiding the side reactions between the weak acidity of dicalcium phosphate and free magnesium stearate, significantly improving the compatibility stability of excipients with acidic and weakly acidic raw materials, reducing drug degradation and impurity generation, and significantly extending the shelf life of the formulation. Fourth, the composite excipient of this invention can replace the traditional dicalcium phosphate + magnesium stearate dual excipient system with a single component, simplifying the formulation feeding and mixing process, reducing the total amount of excipients added, and lowering production energy consumption and material costs; at the same time, the process can be realized by modifying existing dicalcium phosphate wet production equipment without the need for new large-scale equipment, making mass production highly feasible and economically beneficial. Detailed Implementation The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0015] Unless otherwise specified, all reagents and raw materials used in the following examples and experimental cases are commercially available products.

[0016] Example 1 A method for preparing a coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient includes the following steps: Step 1: Select 300-mesh calcium carbonate and prepare a 15% (w / w) calcium carbonate suspension using pure water. Stir well and set aside. Dilute 85% phosphoric acid with pure water to prepare a 15% (w / w) dilute phosphoric acid solution. Set the material feeding ratio according to a calcium carbonate to phosphoric acid molar ratio of 1:1.03 (with a trace excess of 3% phosphoric acid). Place the prepared calcium carbonate suspension in a reaction vessel, control the system temperature at 45℃, maintain the stirring speed at 250 r / min, and slowly and uniformly add the dilute phosphoric acid solution while continuously stirring. The total addition time of phosphoric acid is controlled to be 90 min. After the addition is completed, continue to keep the system at the temperature and stir for 60 min to mature. The pH value of the system is controlled to be stable at 6.2 at the end of the reaction. After the reaction is fully completed, a uniform and stable hydrated calcium hydrogen phosphate dihydrate slurry with a dry basis solids content of 12 wt.% is obtained. This step retains the original slurry system of the wet synthesis without pre-filtration and drying to ensure that the particle surface has abundant active adsorption sites, providing a basis for the subsequent coating reaction.

[0017] Step 2: Prepare materials according to a stearic acid to sodium hydroxide molar ratio of 1:1.10. Prepare a 10% sodium hydroxide aqueous solution using purified water. Take stearic acid, heat it to 75℃ to completely melt it, maintain the system temperature at 78℃, and add the prepared sodium hydroxide aqueous solution dropwise at a uniform rate for 30 minutes while stirring. After the alkali solution is added, continue to stir and maintain the temperature for 90 minutes to saponify until the solution is clear and transparent, without floating oil or layering, ensuring complete saponification of stearic acid. After the reaction is complete, cool the system to 75℃ and maintain the temperature for later use. Finally, a clear sodium stearate active soap solution with a mass fraction of 9% and uniform dispersion is obtained. This soap solution can achieve ion-level uniform dispersion, avoiding the problem of traditional powder mixing and agglomeration, and providing a guarantee for subsequent uniform coating.

[0018] Step 3: Maintain a constant temperature of 50℃ for the dicalcium phosphate slurry system. Under continuous stirring, feed 9% (w / w) sodium stearate soap solution using a low-pressure spray method at a uniform rate. The spray pressure is controlled at 0.28 MPa, and the spray flow rate is 1.5 L / h. Based on the dry weight of dicalcium phosphate, the amount of sodium stearate added is 2.0% of the dicalcium phosphate mass, corresponding to a theoretical magnesium stearate production of 2.05% of the dry weight of dicalcium phosphate. In actual production, the final magnesium stearate loading is controlled at 2.0% of the dicalcium phosphate mass. The total spray feeding time is controlled at 70 min. After the soap solution is fed, continue to maintain the temperature and stir for 30 min to allow stearate ions to be fully and uniformly adsorbed on the outer surface of the dicalcium phosphate particles. The system was maintained at a constant temperature of 50 °C throughout the process. A 12% (w / w) magnesium sulfate aqueous solution was slowly added dropwise at a magnesium ion to sodium stearate molar ratio of 1.03:1. The flow rate of the magnesium sulfate solution was controlled at 1.0 L / h, and the addition time was controlled at 60 min. The free magnesium stearate content (the percentage of magnesium stearate in the total system) was 0.05%. After the addition was complete, the system was kept at the same temperature and stirred for another 40 min to mature. Through in-situ metathesis reaction, a dense, thin layer of magnesium stearate without free components was uniformly formed on the surface of the dicalcium phosphate particles (the dicalcium phosphate slurry surface height was 3 cm), ultimately obtaining a structurally stable coated modified composite slurry.

[0019] Step 4: The modified composite slurry is subjected to a three-stage countercurrent washing process using purified water at 40℃. The mass ratio of slurry to purified water in each stage is strictly controlled at 1:2.5. Washing continues with real-time monitoring of the washing filtrate until the residual chloride and sulfate levels in the filtrate meet the pharmacopoeia limits for dicalcium phosphate. The washing process is then terminated. After washing, the material is dewatered by plate and frame filter press to obtain a wet filter cake with a moisture content of 20%. The wet filter cake is placed in a vacuum dryer and dried under low-temperature vacuum conditions of -0.06MPa and 65℃ until the moisture content of the material drops to 1.0%. The dried material is then pulverized and passed through a 100-mesh pharmacopoeia standard sieve. The coarse particles remaining on the sieve are re-pulverized and sieved to obtain a pre-treated uniform powder, which is then fed into a fluidized bed for further processing.

[0020] Example 2 A method for preparing a coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient includes the following steps: Step 1: Select 400-mesh calcium carbonate and prepare a 20% (w / w) calcium carbonate suspension using pure water. Stir well and set aside. Dilute 85% phosphoric acid with pure water to prepare a 20% (w / w) dilute phosphoric acid solution. Set the material feeding ratio according to a calcium carbonate to phosphoric acid molar ratio of 1:1.03 (with a trace excess of 3% phosphoric acid). Place the prepared calcium carbonate suspension in a reaction vessel, control the system temperature at 50℃, maintain the stirring speed at 350 r / min, and slowly and uniformly add the dilute phosphoric acid solution while continuously stirring. The total addition time of phosphoric acid is controlled to be 150 min. After the addition is completed, continue to keep the system at the temperature and stir for 65 min. Throughout the process, the pH value of the system is controlled to be stable at 6.5 at the final reaction point. After sufficient reaction, a uniform and stable hydrated calcium hydrogen phosphate dihydrate slurry with a dry basis solids content of 15 wt.% is obtained. This step retains the original slurry system from the wet synthesis and does not perform pre-filtration and drying to ensure that the particle surface has abundant active adsorption sites, providing a basis for subsequent coating reactions.

[0021] Step 2: Prepare materials according to a stearic acid to sodium hydroxide molar ratio of 1:1.10. Prepare a 15% (w / w) sodium hydroxide aqueous solution using purified water. Take stearic acid, heat it to 80℃ to completely melt it, and maintain the system at a constant temperature of 80℃. While stirring, add the prepared sodium hydroxide aqueous solution dropwise at a uniform rate for 40 minutes. After the alkali solution is completely added, continue stirring and maintaining the temperature for 90 minutes to saponify until the solution is clear and transparent, without floating oil or layering, ensuring complete saponification of the stearic acid. After the reaction is complete, cool the system to 80℃ and maintain the temperature for later use. Finally, a clear, uniformly dispersed sodium stearate active soap solution with a 12% (w / w) mass fraction is obtained. This soap solution achieves ion-level uniform dispersion, avoiding the problems of traditional powder mixing and agglomeration, and ensuring uniform coating in subsequent processes.

[0022] Step 3: Maintain a constant temperature of 60℃ for the dicalcium phosphate slurry system. While continuously stirring, feed a 12% (w / w) sodium stearate soap solution using a low-pressure spray method at a uniform rate. The spray pressure is controlled at 0.30 MPa, and the spray flow rate is 2.3 L / h. Based on the dry weight of dicalcium phosphate, the amount of sodium stearate added is 4.0% of the dicalcium phosphate mass, corresponding to a theoretical magnesium stearate production of 4.1% of the dry weight of dicalcium phosphate. In actual production, the final magnesium stearate loading is controlled at 4.0% of the dicalcium phosphate mass. The total spray feeding time is controlled at 60 min. After the soap solution is fed, continue to maintain the temperature and stir for 35 min to allow stearate ions to be fully and uniformly adsorbed onto the surface of the dicalcium phosphate particles. The system was maintained at a constant temperature of 60 °C throughout the process. A 12% magnesium sulfate aqueous solution was slowly added dropwise at a magnesium ion to sodium stearate molar ratio of 1.03:1. The flow rate of the magnesium sulfate solution was controlled at 1.2 L / h, and the addition time was controlled at 65 min. The free magnesium stearate content was 0.1%. After the addition was complete, the system was kept at the same temperature and stirred for 40 min to mature. Through in-situ metathesis reaction, a dense, thin layer of magnesium stearate without free components was uniformly formed on the surface of the dicalcium phosphate particles (the dicalcium phosphate slurry surface height was 4.1 cm), ultimately obtaining a structurally stable coated modified composite slurry. Precise control of the magnesium sulfate solution's drop rate and stirring rate ensured that no free magnesium stearate components remained.

[0023] Step 4: The modified composite slurry is subjected to a three-stage countercurrent washing process using purified water at 40 ℃. The mass ratio of slurry to purified water in each stage is strictly controlled at 1:2.5. Washing continues with real-time monitoring of the washing filtrate until the residual chloride and sulfate levels in the filtrate meet the pharmacopoeia limits for dicalcium phosphate. The washing process is then terminated. After washing, the material is dewatered by plate and frame filter press to obtain a wet filter cake with a moisture content of 20%. The wet filter cake is placed in a vacuum dryer and dried under low-temperature vacuum conditions of -0.06 MPa and 65 ℃ until the moisture content of the material drops to 1.0%. The dried material is then pulverized and passed through a 100-mesh pharmacopoeia standard sieve. The coarse particles remaining on the sieve are re-pulverized and sieved to obtain a pre-treated uniform powder, which is then fed into a fluidized bed for further processing to optimize product performance.

[0024] Example 3 S1 slurry concentration settings: calcium carbonate suspension mass fraction 15%, dilute phosphoric acid mass fraction 18%; the reaction endpoint is to prepare a raw slurry of dicalcium phosphate dihydrate with a dry basis solids content of 20 wt.%. The rest is the same as in Example 1.

[0025] Example 4 S3 spray flow rate is 2.5 L / h. The rest is the same as in Example 1.

[0026] Example 5 S1 slurry was synthesized in the same way as in Example 1, with 12 wt.% dry solids in the aqueous dicalcium phosphate slurry.

[0027] S3 spray flow rate is 1.0 L / h, with extended spray feeding time. The rest is the same as in Example 1.

[0028] Comparative Example 1: Traditional Dry Powder Physical Blending Process Pure calcium hydrogen phosphate dihydrate dry powder, which was synthesized by wet process and pre-pressed and dried, was mixed with commercially available magnesium stearate dry powder in the same molar ratio as in Example 1 in a three-dimensional mixer for 30 minutes to obtain a physical blend mixture without any liquid phase coating modification.

[0029] Comparative Example 2 Modify step S1: Filter and wash the aqueous slurry of dicalcium phosphate dihydrate obtained in step S1 with pure water, collect the filter cake, and dry it in a drying oven (drying temperature should not exceed 80 ℃). After drying, pulverize and sieve to obtain dry powder of dicalcium phosphate dihydrate. Redisperse the obtained dry powder in a pure water system according to the required solid content, stir evenly, and obtain a uniform and stable aqueous slurry of dicalcium phosphate dihydrate with a solid content of 15 wt.%. Subsequent processes S2-S4 are completely consistent with those in Example 1.

[0030] The parameters of the above embodiments and comparative examples were compared, and the results are shown in Table 1 below. Free magnesium stearate content: refers to magnesium stearate in the composite system that is not bound to the surface of calcium dicalcium phosphate particles and exists as independent particles, as opposed to the coated and bound state, expressed as a percentage of the total mass of the composite additives. In other words, unbound magnesium stearate.

[0031] Table 1

[0032] Summary of the above coating effect comparison: A spray pressure of 0.28 MPa, a flow rate of 1.5 L / h, and a slurry solids content of 12 wt.% (Example 1) resulted in a continuous and uniform coating layer on the surface of dicalcium phosphate with very little free magnesium stearate. A flow rate reduced to 1.0 L / h (Example 5) resulted in better coating quality. A flow rate increased to 2.5 L / h (Example 4) easily led to homogeneous nucleation in the liquid phase, generating free particles. An increase in slurry solids content to 20 wt.% (Example 3) resulted in complete coating, but with trace amounts of free fragments. Increased slurry concentration increased the probability of particle collisions, causing trace amounts of magnesium stearate to detach from the particle surface, forming free fragments; therefore, the free content was slightly higher than in Example 1. Increasing the soap solution dosage, spray pressure, and flow rate (Example 2) yielded a thicker, more complete coating layer. If spraying was canceled and soap solution was added only once (Comparative Example 1), the coating was uneven and a large amount of free magnesium stearate was generated. It is evident that appropriate low-pressure spray flow rate and slurry solid content are key conditions for achieving uniform coating and reducing free magnesium stearate. Coating without retaining the wet-process virgin slurry and drying it prematurely (Comparative Example 2) yields poor results, as it destroys the active adsorption sites of the virgin particles. A slurry level that is too low (1.5 cm in Example 4, <1 cm in Comparative Example 1 / 2) leads to insufficient dispersion space for the soap solution spray, easily resulting in localized supersaturation and the formation of free magnesium stearate; a slurry level between 2 and 5 cm ensures sufficient dispersion and uniform adsorption of the spray droplets.

[0033] Control group 1 Quality standards for dicalcium phosphate in the Chinese Pharmacopoeia.

[0034] Control group 2 The quality standard for magnesium stearate in the Chinese Pharmacopoeia. Table 2 Physical parameters of traditional pharmaceutical excipients and compound pharmaceutical excipients (subject to quality standards)

[0035] The compound pharmaceutical excipients were used in the drug amlodipine besylate, and the resulting drug parameters are shown in Table 3.

[0036] Table 3 shows the actual amount of composite excipients required to be incorporated into the drugs in Examples 1 and 2 (the control group is a traditional medicine formula).

[0037] As shown in Table 3, the composite excipient of the present invention has both filling and lubricating functions through integrated coating, without the need for additional magnesium stearate, and the particle formability is improved, reducing the total amount of excipient used.

[0038] The disintegration and drug dissolution of the tablets in the control group, Example 1, and Example 2 were monitored, and the results are shown in Table 4. Table 4. Disintegration time and mean drug dissolution rate in the control group, Examples 1 and 2

[0039] As can be seen from the above embodiments and experimental examples, the composite excipient of the present invention can replace the traditional dicalcium phosphate + magnesium stearate dual excipient system with a single component. It can reduce the total amount of excipients added, reduce production energy consumption and material costs, effectively avoid the defects of slow tablet disintegration and decreased drug dissolution, significantly improve powder flowability and bulk density, reduce the angle of repose, greatly improve the efficacy stability of the formulation and the finished product qualification rate, reduce drug degradation and impurity generation, and significantly extend the shelf life of the formulation. It has a very good development prospect in the future field of excipients.

Claims

1. A method for preparing a coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient, characterized in that: S1. Preparation of aqueous dicalcium phosphate slurry: Using calcium carbonate suspension as raw material, phosphoric acid solution is added dropwise under controlled temperature, the pH of the system is adjusted, and after full reaction, aqueous dicalcium phosphate slurry is obtained. S2. Preparation of sodium stearate active soap solution: Stearic acid is heated and melted, and then fully saponified with sodium hydroxide solution to obtain sodium stearate soap solution, which is then cooled and kept warm for later use. S3. In-situ adsorption and surface coating modification: Sodium stearate soap solution is added to dicalcium phosphate slurry by spraying, and the mixture is stirred at a constant temperature to allow stearate ions to be fully adsorbed on the surface of dicalcium phosphate particles; then, magnesium salt solution is added dropwise under controlled temperature, and a thin layer of magnesium stearate coating is uniformly generated on the surface of dicalcium phosphate particles through in-situ metathesis reaction, thus obtaining a coated and modified composite slurry. S4. Post-processing and refining: The coated and modified composite slurry is washed with countercurrent pure water, dehydrated by pressure filtration, dried under low temperature vacuum, and pulverized and sieved to obtain an integrated coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient.

2. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: The molar ratio of raw materials in S1 is calcium carbonate:phosphoric acid = 1:(1.01~1.06); preferably, calcium carbonate:phosphoric acid = 1:1.

03. Add phosphoric acid dropwise at a temperature of 40-55℃, with a dropping rate of 15-30 mL / min, and adjust the pH of the system to 6.2-6.

5. After the addition is complete, keep the temperature warm and stir for 60-120 min at a stirring speed of 200-350 r / min.

3. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: In step S1, the calcium carbonate suspension has a mass fraction of 10%~20% and the calcium carbonate is 300~400 mesh; the phosphoric acid is prepared as follows: the dilute phosphoric acid has a mass fraction of 10%~18% and is made by diluting 85% phosphoric acid with pure water.

4. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: After the reaction in step S1 is completed, the dry solids content of the calcium dicalcium phosphate slurry is 12%~20wt.%.

5. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: In step S2, the raw material molar ratio is stearic acid:NaOH = 1:1.10, and the mass fraction of sodium hydroxide aqueous solution is 10% to 15%. After the stearic acid is completely melted at 75 to 80 °C, the alkali solution is added dropwise at a uniform rate for 30 to 60 minutes. After the addition is completed, the solution is kept warm and stirred for 60 to 90 minutes until the solution is clear, transparent and free of floating oil.

6. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: In step S2, the sodium stearate soap solution has a mass fraction of 5% to 12%, the saponification reaction temperature is 78 to 82 ℃, and the temperature is maintained at 70 to 75 ℃ after saponification.

7. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: In-situ adsorption and surface coating modification in S3: The temperature of the dicalcium phosphate slurry system is maintained at 50~60℃, the mass fraction of sodium stearate soap solution is 5~12%, and the amount of sodium stearate added is 2.0%~4.0% of the mass of dicalcium phosphate on a dry basis. After the soap solution is fed, the system is kept warm and stirred for 30~35 min for adsorption. The system is maintained at 50~60℃, and magnesium salt solution is added dropwise.

8. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: In S3, the spray feeding time is 50~75 min, the spray pressure is controlled at 0.28~0.32 MPa, the spray flow rate is 1~2.5 L / h, and the height of the dicalcium phosphate slurry is 2~5 cm.

9. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: In step S3, a 12% to 14% magnesium sulfate aqueous solution is added dropwise at a magnesium ion to sodium stearate molar ratio of (1.03 to 1.06):1, at a rate of 10 to 15 mL / min. After the addition is complete, the mixture is kept warm and stirred for 40 to 50 min.

10. The preparation method of the coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient according to claim 1, characterized in that: The post-processing and refining in S4 involves the following steps: the modified composite slurry is washed in three stages of countercurrent washing with purified water at 40-50 ℃. The mass ratio of slurry to washing water is controlled sequentially at 1:(2.5-2.8). The washing process is terminated after the chloride and sulfate levels in the filtrate meet the standards at the end of the washing process. The material is then filtered through a plate and frame filter press to obtain a filter cake with a moisture content of 20%-25%. The filter cake is placed in a vacuum drying oven and dried at a vacuum degree of -0.06 to -0.08 MPa and a drying temperature of 65-75 ℃ until the moisture content is ≤1.5%. The dried material is then pulverized and passed through a 100-mesh sieve. The coarse particles remaining on the sieve are re-pulverized, and the powder remaining on the sieve is the integrated coated calcium hydrogen phosphate-magnesium stearate composite pharmaceutical excipient.

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