Production process of anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function

Abstract

This invention belongs to the field of pharmaceutical excipient synthesis, specifically relating to a production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct compression capability. The production process includes the following steps: raw material pretreatment, segmented neutralization reaction, in-situ surface modification, and gradient drying in a fluidized bed. This invention optimizes the production process by employing a segmented neutralization reaction of the raw materials, controlling the reaction conditions of each segment to first form crystal nuclei, and then inducing crystal growth through different temperature gradients, effectively controlling the crystal growth direction and morphology. Simultaneously, in-situ surface modification reduces the surface charge of the particles, further improving particle sphericity and stability, and enhancing direct compression flowability. Gradient drying sequentially removes free water, shapes pores, and removes bound water, preventing cracking and improving stability. The resulting anhydrous dicalcium phosphate has a high specific surface area, porous spherical structure, narrow particle size distribution, small angle of repose, good flowability, and stability, and can be directly compressed into tablets.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical excipient synthesis, and specifically relates to a production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function. Background Technology

[0002] Anhydrous calcium phosphate plays a crucial role as an excipient in oral solid dosage forms. It is commonly used as an additive in pharmaceutical processes, exhibiting buffering properties, enhancing solubility, and improving stability. It is widely used in the preparation of tablets, capsules, granules, and other pharmaceutical formulations, helping to improve drug bioavailability and stability, as well as enhancing taste and solubility. Furthermore, anhydrous calcium phosphate can also be used as a pharmaceutical excipient in dental products and oral calcium supplements.

[0003] In recent years, with the increasing demands for efficiency and quality in solid dosage form production in the pharmaceutical industry, direct compression technology has become the preferred process for tablet production due to its advantages such as simplified process, low cost, and avoidance of degradation of active ingredients by wet granulation. As a core excipient in the direct compression process, anhydrous dicalcium phosphate (DCP anhydrous form) needs to possess high flowability, low hygroscopicity, uniform particle size distribution, and excellent compressibility. However, although existing preparation technologies have made some progress, significant shortcomings remain in process stability, particle morphology control, and optimization of direct compression performance. For example, traditional methods (such as direct neutralization and metathesis methods) often result in particles with many sharp edges, wide particle size distribution, and large angles of repose due to coarse reaction conditions. Direct compression easily leads to cracking and poor flowability, requiring the addition of lubricants or binders to meet the direct compression requirements. Neutralization and processing methods improve yield by adding magnesium oxide or adjusting pH, but still face problems such as difficulty in controlling the reaction endpoint and slow crystal growth rate, resulting in poor batch-to-batch particle uniformity and stability. Summary of the Invention

[0004] To address the above-mentioned deficiencies or improvement needs of existing technologies, this invention provides a production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct compression function. The anhydrous dicalcium phosphate prepared by this production process has a high specific surface area porous spherical structure with small particle size difference, narrow particle size distribution, small angle of repose, good flowability, and stability, and can be directly compressed into tablets.

[0005] To achieve the above objectives, the present invention provides a production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, comprising the following steps:

[0006] (1) Raw material pretreatment: Dilute phosphoric acid to a concentration of 20-30% to obtain a phosphoric acid solution for later use; mix calcium carbonate with water and ball mill for 20-30 min to obtain a calcium carbonate suspension for later use;

[0007] (2) Neutralization reaction: Phosphoric acid solution and calcium carbonate suspension are added to a reactor equipped with a gas-liquid co-stirring system and the neutralization reaction is carried out in stages;

[0008] (3) In-situ surface modification: After the reaction in step (2) is completed, a surface modifier is added, and after stirring for 10-20 minutes, a pH adjuster is added to adjust to neutral, and then solid-liquid separation is performed;

[0009] (4) Drying: The separated solids are placed in a fluidized bed for gradient drying to obtain anhydrous calcium hydrogen phosphate.

[0010] This invention employs a segmented reaction method. By controlling the reaction temperature and stirring method, the crystal growth direction and morphology can be effectively controlled. At the same time, in-situ surface modification is performed to reduce the surface charge of the particles and enhance direct pressure flowability. Gradient drying is used to remove free water, fix pores, and remove bound water in sequence, preventing cracking and improving stability. The resulting anhydrous calcium hydrogen phosphate has a narrow particle size distribution, an angle of repose of less than or equal to 26°, and excellent flowability, and can be directly compressed into tablets.

[0011] Furthermore, in step (1) of the above technical solution, the phosphoric acid is 85% food-grade phosphoric acid; the calcium carbonate is food-grade calcium carbonate with a particle size of 10-20μm, and the solid-liquid ratio of the calcium carbonate to water is 1:3-4.

[0012] Furthermore, in step (2) of the above technical solution, the volume ratio of the phosphoric acid solution and the calcium carbonate suspension is 1:1.5-2.

[0013] Furthermore, in step (2) of the above technical solution, the gas-liquid synergistic stirring system is divided into three layers: upper, middle and lower. The upper layer is a turbine-type stirring blade with a blade angle of 45°, the middle layer is a porous titanium alloy gas distributor, and the lower layer is a spiral propulsion stirring blade with a blade angle of 30°.

[0014] This technical solution employs a gas-liquid co-mixing system. The upper layer consists of 45° inclined blades to promote dispersion, while the lower layer consists of 30° propulsion blades to enhance bottom material circulation and prevent sedimentation and agglomeration. The middle layer uses a gas distributor to continuously generate bubbles, which can create pores while dispersing, thereby increasing porosity.

[0015] Further, in step (2) of the above technical solution, the steps of the segmented neutralization reaction are as follows: First, add the phosphoric acid solution to the reaction vessel, heat it to 40-50℃, start the stirrer, and slowly add 40-50% of the total calcium carbonate suspension solution until the reaction is complete; then adjust the speed of the stirrer and start the gas distributor, and add the remaining calcium carbonate suspension solution in three batches, with an interval of 5-10 minutes each time. The reaction temperatures are 50±2℃, 65±2℃, and 40±2℃ respectively. In this technical solution, a segmented neutralization reaction is adopted. First, a pre-reaction is carried out at low temperature to generate calcium dihydrogen phosphate microcrystal nuclei. Then, the remaining calcium carbonate suspension solution is added in stages, and the gas distributor is turned on to ventilate and control different temperatures (achieving pore expansion and shaping through thermodynamic phase change). The temperature gradient induces the directionality of crystal growth and the gas expansion synergistic effect to form a microporous structure and interconnected channels, thereby increasing the specific surface area and disintegration rate.

[0016] Furthermore, in the above technical solution, the initial stirring speed of the agitator is 200-300 rpm; the second adjustment of the stirring speed is 50-80 rpm. This technical solution employs different stirring speeds for segmented reactions; a faster speed is beneficial for nucleation, while a slower speed is beneficial for directional growth and can prevent the collapse of rapid pores or channels.

[0017] Furthermore, in the above technical solution, the gas is a mixture of N2 and CO2 with a volume ratio of 1:1-2, and the flow rate is 0.5-1 L / min. In this technical solution, the gas in the gas distributor contains carbon dioxide, which can be used to attach bubbles to the surface of the crystal nucleus and overflow with the reaction to form micropores. At the same time, the solubility of carbon dioxide decreases with increasing temperature, and it expands to form through channels during the subsequent rapid growth stage at a higher temperature (65±2℃).

[0018] Further, in step (3) of the above technical solution, the surface modifier is a mixture of polyethylene glycol and hydroxypropyl methylcellulose in a mass ratio of 0.2-0.3:1, and the amount of the surface modifier is 1-1.5% of the total amount of the reaction solution. The polyethylene glycol is food grade and can be PEG-6000. Its addition at the end of the reaction can slow down the crystal growth rate, maintain particle size uniformity, and utilize the hydrophilic groups in its molecular chain to adsorb onto the particle surface, forming steric hindrance to reduce electrostatic adsorption of particle bonds, preventing particle agglomeration and improving flowability. Hydroxypropyl methylcellulose can form a viscoelastic network structure to coat the particle surface, forming a uniform thin film layer and maintaining a slightly moist state on the particle surface, improving particle sphericity and stability. In this technical solution, both substances are added simultaneously; through their synergy, the particle surface characteristics can be optimized, and the integrity of the particles can be maintained during the subsequent drying process.

[0019] Furthermore, in step (4) of the above technical solution, the gradient drying process is as follows: the first stage is set at a temperature of 55-65℃ and a wind speed of 1.2-1.5m / s, drying for 15-25min; the second stage is set at a temperature of 80-90℃ and a wind speed of 1.6-2.0m / s, drying for 250-400min; the third stage is set at a temperature of 40-50℃ and a wind speed of 0.6-1.0m / s, drying for 10-20min. This technical solution employs gradient drying. The first stage uses a lower temperature to remove free water and prevent cracking. The second stage uses a higher temperature to remove crystal water and promote a denser hydroxypropyl methylcellulose membrane. The third stage uses a lower temperature to release internal stress and improve stability.

[0020] Furthermore, in the above technical solution, the particle size D of the anhydrous calcium hydrogen phosphate is... 50 The value is 80-120μm, and the angle of repose is ≤26°.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] 1. This invention optimizes the production process by using a segmented reaction of pretreated raw materials. By controlling the reaction temperature and stirring rate of each segment, crystal nuclei are first formed, and then crystal growth is induced through different temperature gradients. This effectively controls the crystal growth direction and morphology. Gas stirring is also employed. Simultaneously, in-situ surface modification is performed to reduce the surface charge of the particles, further improving the sphericity and stability of the particles and enhancing direct pressure flowability. Gradient drying is used to sequentially remove free water, solidify pores, and remove bound water, preventing cracking and improving stability.

[0023] 2. The production process of this invention is simple to operate, highly efficient, safe and environmentally friendly. The resulting anhydrous calcium hydrogen phosphate has a narrow particle size distribution, an angle of repose of less than or equal to 26°, excellent flow properties, and a large specific surface area. It can be directly compressed into tablets and has significant economic benefits as a pharmaceutical excipient. Detailed Implementation

[0024] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the raw materials used in the following examples are all commercially available products and can be purchased from the market.

[0025] The above-described technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions.

[0026] The reactor used was custom-made by Hangzhou Yuanzheng Engineering Technology Equipment Co., Ltd. The reactor is equipped with a gas-liquid co-stirring system, in which the upper layer is a turbine-type stirring blade with a blade angle of 45°, the middle layer is a porous titanium alloy gas distributor with horizontal pipe distribution, and the lower layer is a spiral propulsion stirring blade with a blade angle of 30°.

[0027] Example 1

[0028] A production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, includes the following steps:

[0029] (1) Raw material pretreatment: Dilute 85% food grade phosphoric acid to a concentration of 20% to obtain a phosphoric acid solution for later use; mix food grade calcium carbonate (particle size 10-20μm) with water at a solid-liquid ratio of 1:4 and then ball mill for 30 min to obtain a calcium carbonate suspension for later use.

[0030] (2) Neutralization reaction: Phosphoric acid solution and calcium carbonate suspension were added to a reactor equipped with a gas-liquid co-stirring system at a volume ratio of 1:1.5. The neutralization reaction was carried out in stages. Specifically, all phosphoric acid solution was added to the reactor first, the temperature was raised to 40°C, the stirring paddle was started (200 rpm), and 40% of the total calcium carbonate suspension was slowly added dropwise until the reaction was completed. Then the stirring paddle speed was adjusted (60 rpm) and the gas distributor was started at the same time (a mixed gas of N2 / CO2 with a volume ratio of 1:1 was introduced at a flow rate of 0.5 L / min). The remaining calcium carbonate suspension was added dropwise in three batches at 5 min intervals. The reaction temperatures were 50±2°C, 65±2°C, and 40±2°C, respectively.

[0031] (3) In-situ surface modification: At the end of the reaction in step (2), a mixture of polyethylene glycol and hydroxypropyl methylcellulose with a mass ratio of 0.3:1, accounting for 1% of the total reaction liquid, is added as a surface modifier. After stirring for 10 minutes, calcium hydroxide is added to adjust to neutrality, and then solid-liquid separation is performed.

[0032] (4) Drying: The separated solids are placed in a fluidized bed for gradient drying. The specific steps are as follows: the first stage is set at a temperature of 55℃ and a wind speed of 1.5m / s for 25min; the second stage is set at a temperature of 80℃ and a wind speed of 2.0m / s for 400min; the third stage is set at a temperature of 40℃ and a wind speed of 1.0m / s for 20min, and anhydrous calcium hydrogen phosphate is obtained.

[0033] Example 2

[0034] A production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, includes the following steps:

[0035] (1) Raw material pretreatment: Dilute 85% food grade phosphoric acid to a concentration of 30% to obtain a phosphoric acid solution for later use; mix food grade calcium carbonate (particle size 10-20μm) with water at a solid-liquid ratio of 1:3 and then ball mill for 25 min to obtain a calcium carbonate suspension for later use.

[0036] (2) Neutralization reaction: Phosphoric acid solution and calcium carbonate suspension were added to a reactor equipped with a gas-liquid co-stirring system at a volume ratio of 1:1.8. The neutralization reaction was carried out in stages. Specifically, all phosphoric acid solution was added to the reactor first, the temperature was raised to 45°C, the stirring paddle was started (250 rpm), and 45% of the total calcium carbonate suspension was slowly added dropwise until the reaction was completed. Then the stirring paddle speed was adjusted (60 rpm) and the gas distributor was started at the same time (a mixed gas of N2 / CO2 with a volume ratio of 1:1.5 was introduced at a flow rate of 0.8 L / min). The remaining calcium carbonate suspension was added dropwise in three batches at an interval of 8 min. The reaction temperatures were 50±2°C, 65±2°C, and 40±2°C, respectively.

[0037] (3) In-situ surface modification: At the end of the reaction in step (2), a mixture of polyethylene glycol and hydroxypropyl methylcellulose with a mass ratio of 0.2:1, which is 1.2% of the total reaction solution, is added as a surface modifier. After stirring for 15 minutes, calcium hydroxide is added to adjust to neutrality, and then solid-liquid separation is performed.

[0038] (4) Drying: The separated solids are placed in a fluidized bed for gradient drying. The specific steps are as follows: the first stage is set at a temperature of 60℃ and a wind speed of 1.3m / s for 20min; the second stage is set at a temperature of 85℃ and a wind speed of 1.8m / s for 300min; the third stage is set at a temperature of 45℃ and a wind speed of 0.8m / s for 15min, and anhydrous dicalcium phosphate is obtained.

[0039] Example 3

[0040] A production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, includes the following steps:

[0041] (1) Raw material pretreatment: Dilute 85% food grade phosphoric acid to a concentration of 30% to obtain a phosphoric acid solution for later use; mix food grade calcium carbonate (particle size 10-20μm) with water at a solid-liquid ratio of 1:3-4 and then ball mill for 20 min to obtain a calcium carbonate suspension for later use.

[0042] (2) Neutralization reaction: Phosphoric acid solution and calcium carbonate suspension were added to a reactor equipped with a gas-liquid co-stirring system at a volume ratio of 1:2. The neutralization reaction was carried out in stages. Specifically, all phosphoric acid solution was added to the reactor first, the temperature was raised to 50°C, the stirring paddle was started (300 rpm), and 50% of the total calcium carbonate suspension was slowly added dropwise until the reaction was completed. Then the stirring paddle speed was adjusted (80 rpm) and the gas distributor was started at the same time (a mixed gas of N2 / CO2 with a volume ratio of 1:2 was introduced at a flow rate of 0.5-1 L / min). The remaining calcium carbonate suspension was added dropwise in three batches at 10 min intervals. The reaction temperatures were 50±2°C, 65±2°C, and 40±2°C, respectively.

[0043] (3) In-situ surface modification: At the end of the reaction in step (2), a mixture of polyethylene glycol and hydroxypropyl methylcellulose with a mass ratio of 0.3:1, which is 1.5% of the total reaction solution, is added as a surface modifier. After stirring for 20 minutes, calcium hydroxide is added to adjust to neutrality, and then solid-liquid separation is performed.

[0044] (4) Drying: The separated solids are placed in a fluidized bed for gradient drying. The specific steps are as follows: the first stage is set at a temperature of 65℃ and a wind speed of 1.2m / s for 15min; the second stage is set at a temperature of 90℃ and a wind speed of 1.6m / s for 250min; the third stage is set at a temperature of 50℃ and a wind speed of 0.6m / s for 10min to obtain anhydrous calcium hydrogen phosphate.

[0045] Comparative Example 1

[0046] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that (2) neutralization reaction: phosphoric acid solution and calcium carbonate suspension are added to a reaction vessel equipped with a gas-liquid co-stirring system at a volume ratio of 1:1.8. Specifically, all phosphoric acid solution is added to the reaction vessel first, the temperature is raised to 45°C, the stirring paddle is started (250 rpm), and all calcium carbonate suspension is slowly added dropwise until the reaction is completed.

[0047] Comparative Example 2

[0048] A process for producing anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from Example 2 in that (2) neutralization reaction: Phosphoric acid solution and calcium carbonate suspension are added to a reactor equipped with a gas-liquid co-stirring system at a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages. Specifically, all phosphoric acid solution is added to the reactor first, the temperature is raised to 45°C, the stirring paddle is started (250 rpm), and 45% of the total amount of calcium carbonate suspension is slowly added dropwise until the reaction is completed; then the stirring paddle speed is adjusted (60 rpm) and the gas distributor is started at the same time (a mixed gas with a flow rate of 0.8 L / min and a volume ratio of N2 / CO2 of 1:1.5 is introduced), and the remaining calcium carbonate suspension is added dropwise in three batches at 8 min intervals, with a reaction temperature of 65±2°C.

[0049] Comparative Example 3

[0050] A process for producing anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from Example 2 in that (2) neutralization reaction: Phosphoric acid solution and calcium carbonate suspension are added to a reactor equipped with a gas-liquid co-stirring system at a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages. Specifically, all phosphoric acid solution is added to the reactor first, the temperature is raised to 45°C, the stirring paddle is started (250 rpm), and 45% of the total amount of calcium carbonate suspension is slowly added dropwise until the reaction is completed; then the stirring paddle speed is adjusted (250 rpm) and the gas distributor is started at the same time (a mixed gas with a flow rate of 0.8 L / min and a volume ratio of N2 / CO2 of 1:1.5 is introduced), and the remaining calcium carbonate suspension is added dropwise in three batches at 8 min intervals, with the reaction temperatures being 50±2°C, 65±2°C, and 40±2°C respectively.

[0051] Comparative Example 4

[0052] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that (2) neutralization reaction: Phosphoric acid solution and calcium carbonate suspension are added to a reactor equipped with a gas-liquid co-stirring system at a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages. Specifically, all phosphoric acid solution is added to the reactor first, the temperature is raised to 45°C, the stirring paddle is started (250 rpm), and 45% of the total amount of calcium carbonate suspension is slowly added dropwise until the reaction is completed; then the stirring paddle speed is adjusted (60 rpm) and the gas distributor is not started, and the remaining calcium carbonate suspension is added dropwise in three batches, with an interval of 8 minutes each time. The reaction temperatures are 50±2°C, 65±2°C, and 40±2°C respectively.

[0053] Comparative Example 5

[0054] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that (2) neutralization reaction: Phosphoric acid solution and calcium carbonate suspension are added to a reactor equipped with a gas-liquid co-stirring system at a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages. Specifically, all phosphoric acid solution is added to the reactor first, the temperature is raised to 45°C, the stirring paddle is started (250 rpm), and 45% of the total amount of calcium carbonate suspension is slowly added dropwise until the reaction is completed; then the stirring paddle speed is adjusted (60 rpm) and the gas distributor is started at the same time (N2 with a flow rate of 0.8 L / min is introduced), and the remaining calcium carbonate suspension is added dropwise in three batches at 8 min intervals, with the reaction temperatures being 50±2°C, 65±2°C, and 40±2°C respectively.

[0055] Comparative Example 6

[0056] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that (2) neutralization reaction: phosphoric acid solution and calcium carbonate suspension are added to a reactor equipped with a turbine-type stirring paddle (the paddle angle is 45°) at a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages.

[0057] Comparative Example 7

[0058] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that it does not involve an in-situ surface modification step. Instead, calcium hydroxide is directly added to adjust the pH to neutral, followed by solid-liquid separation.

[0059] Comparative Example 8

[0060] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that (3) in-situ surface modification: at the end of step (2) reaction, 1.2% of the total amount of polyethylene glycol in the reaction solution is added as a surface modifier. After stirring for 15 minutes, calcium hydroxide is added to adjust to neutrality, and then solid-liquid separation is performed.

[0061] Comparative Example 9

[0062] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that (3) in-situ surface modification: 1.2% of the total amount of hydroxypropyl methylcellulose in the reaction solution is added as a surface modifier at the end of step (2). After stirring for 15 minutes, calcium hydroxide is added to adjust to neutrality, and then solid-liquid separation is performed.

[0063] Comparative Example 10

[0064] The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient, differs from that of Example 2 in that (4) drying: the separated solid is placed in a fluidized bed for drying. The specific steps are: set the temperature to 85°C, the wind speed to 1.8 m / s, and dry for 335 min to obtain anhydrous dicalcium phosphate.

[0065] Test case

[0066] 1. The morphology, particle size distribution, angle of repose, Karl Fischer index, specific surface area, and porosity of the final product anhydrous calcium phosphate in Examples 1-3 and Comparative Examples 1-10 were tested, and the results are shown in Table 1. Morphology was observed under an electron microscope, particle size distribution was measured using a laser particle size analyzer, specific surface area was determined using nitrogen adsorption-desorption, and porosity was calculated using mercury intrusion porosimetry.

[0067] Table 1 Product Performance Indicators

[0068]

[0069] As can be seen from the results in Table 1, the anhydrous calcium hydrogen phosphate prepared by the present invention has high sphericity, narrow particle size distribution, angle of repose less than or equal to 26°, Karl Fischer index less than or equal to 11%, excellent flowability, large specific surface area, and high porosity, and can be directly compressed into tablets. In contrast, in Comparative Example 1, the neutralization reaction was carried out by adding the raw materials at one time without a nucleation and growth process, resulting in uneven particle size growth, wide distribution, and poor sphericity, flowability, and porosity. In Comparative Example 2, the neutralization reaction and growth stages were carried out at the same high temperature. Although the porosity was high, the growth was also affected, the particle size distribution became wider, and the flowability was slightly worse. In Comparative Example 3, the neutralization reaction was carried out at a relatively fast rotation speed, which was not conducive to directional growth and also affected the particle size distribution and flowability to a certain extent. In Comparative Example 4, the neutralization reaction was carried out by gas stirring. Although it had little effect on sphericity and flowability, the specific surface area and porosity were low due to the lack of gas pore formation. In Comparative Example 5, the neutralization reaction was stirred only with nitrogen. Although it could produce some pores, its effect was worse than that of carbon dioxide, and it could not form interconnected channels through secondary foaming in the subsequent process. In Comparative Example 6, a common stirring device was used, which had poor dispersibility and anti-agglomeration performance, directly affecting the uniform directional growth, resulting in a wider particle size distribution and poor flowability. At the same time, there was no gas to create pores, resulting in low specific surface area and porosity. In Comparative Examples 7-9, no in-situ modification was carried out after the neutralization reaction, or only a single modifier was used, which affected the sphericity and flowability to a certain extent. In Comparative Example 10, the subsequent drying was carried out directly at high temperature. Due to the rapid loss of water, particle cracking and pore collapse occurred, affecting its performance.

[0070] 2. The anhydrous dicalcium phosphate obtained in Examples 1-3 and Comparative Examples 1-10 was mixed with 50% aspirin raw material and directly compressed into tablets. The disintegration performance and tableting performance were tested, and the results are shown in Table 2. The disintegration performance was determined according to the pharmacopoeia disintegration time test, and the tableting performance was tested using a tablet strength tester and a friability tester.

[0071] Table 2. Testing of disintegration performance and tableting performance

[0072]

[0073] As can be seen from the data in Table 2, the anhydrous dicalcium phosphate prepared in this invention can be directly used for tableting after mixing with medicinal materials. The resulting tablets have short disintegration time, stable long-term storage performance, tensile strength that meets the requirements of direct compression processing, and friability that meets the pharmacopoeia requirements. The obtained anhydrous dicalcium phosphate is suitable as a pharmaceutical excipient for direct compression. However, due to defects in the anhydrous dicalcium phosphate prepared in Comparative Examples 1-10, the tablets produced after direct mixing with medicinal materials and tableting do not meet the requirements for pharmaceutical excipients.

[0074] Finally, it should be emphasized that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A production process for anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, characterized in that, Includes the following steps: (1) Raw material pretreatment: Dilute phosphoric acid to a concentration of 20-30% to obtain a phosphoric acid solution for later use; mix calcium carbonate with water and ball mill for 20-30 min to obtain a calcium carbonate suspension for later use; (2) Neutralization reaction: Phosphoric acid solution and calcium carbonate suspension are added to a reactor equipped with a gas-liquid co-stirring system for staged neutralization reaction; the gas-liquid co-stirring system consists of three layers: the upper layer is a turbine-type stirring impeller with a blade angle of 45°, the middle layer is a porous titanium alloy gas distributor, and the lower layer is a helical propulsion stirring impeller with a blade angle of 30°; the steps of the staged neutralization reaction are as follows: first, add phosphoric acid solution to the reactor, heat to 40-50°C, start the stirring impeller, and slowly add calcium carbonate suspension. A suspension of 40-50% of the total volume of the solution is added until the reaction is complete. Then, the stirring speed is adjusted while the gas distributor is started, and the remaining calcium carbonate suspension is added dropwise in three batches, with an interval of 5-10 minutes between each addition. The reaction temperatures are 50±2℃, 65±2℃, and 40±2℃ respectively. The stirring speed is 200-300 rpm for the first addition and 50-80 rpm for the second addition. The gas is a mixture of N2 and CO2 with a volume ratio of 1:1-2 and a flow rate of 0.5-1 L / min. (3) In-situ surface modification: After the reaction in step (2) is completed, a surface modifier is added and stirred for 10-20 min. Then, a pH adjuster is added to adjust the pH to neutral, and the solid and liquid are separated. The surface modifier is a mixture of polyethylene glycol and hydroxypropyl methylcellulose in a mass ratio of 0.2-0.3:1, and the amount of the surface modifier is 1-1.5% of the total amount of the reaction solution. (4) Drying: The separated solids are placed in a fluidized bed for gradient drying to obtain anhydrous dicalcium phosphate. The gradient drying steps are as follows: the first stage is set at a temperature of 55-65℃ and a wind speed of 1.2-1.5m / s for 15-25min; the second stage is set at a temperature of 80-90℃ and a wind speed of 1.6-2.0m / s for 250-400min; the third stage is set at a temperature of 40-50℃ and a wind speed of 0.6-1.0m / s for 10-20min.

2. The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, according to claim 1, is characterized in that, In step (1), the phosphoric acid is 85% food-grade phosphoric acid; the calcium carbonate is food-grade calcium carbonate with a particle size of 10-20 μm, and the solid-liquid ratio of the calcium carbonate to water is 1:3-4.

3. The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, according to claim 1, is characterized in that... In step (2), the volume ratio of the phosphoric acid solution to the calcium carbonate suspension is 1:1.5-2.

4. The production process of anhydrous dicalcium phosphate, a pharmaceutical excipient with direct pressure function, according to claim 1, is characterized in that... The particle size D of the anhydrous calcium hydrogen phosphate 50 The value is 80-120μm, and the angle of repose is ≤26°.

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