Production process of pharmaceutical adjuvant anhydrous calcium hydrogen phosphate with direct compression function

Abstract

The invention belongs to the field of pharmaceutical adjuvant synthesis, and particularly relates to a production process of pharmaceutical adjuvant anhydrous calcium hydrogen phosphate with a direct pressure function, and the production process comprises the following steps: raw material pretreatment, segmented neutralization reaction, in-situ surface modification, and gradient drying by a fluidized bed. According to the invention, the production process is optimized, the raw materials are subjected to segmented neutralization reaction, the reaction conditions of each segment are controlled, crystal nucleuses are firstly formed, and then crystal growth is induced through different temperature gradients, so that the growth direction and morphology of the crystal can be effectively controlled; meanwhile, through in-situ surface modification, surface charges of the particles are reduced, the sphericity and stability of the particles are further improved, and the direct-pressure fluidity is enhanced; through gradient drying, the purposes of sequentially removing free water, pore shaping, removing bound water and the like are achieved, cracking is prevented, the stability is improved, and the obtained anhydrous calcium hydrogen phosphate has a porous spherical structure with a high specific surface area, is narrow in particle size distribution, small in repose angle, good in fluidity and stable, and can be directly tableted.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of pharmaceutical excipients, and particularly relates to a production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with direct compression function. Background Art

[0002] Anhydrous calcium hydrogen phosphate plays an important role as an important excipient in oral solid preparations. Anhydrous calcium hydrogen phosphate is usually used as an additive in the pharmaceutical process, and has the characteristics of buffering, enhancing solubility and stability. It is widely used in the preparation of pharmaceutical preparations such as tablets, capsules, and granules, which helps to improve the bioavailability and stability of drugs, and improve the taste and dissolution properties of drugs. In addition, anhydrous calcium hydrogen phosphate can also be used as a pharmaceutical excipient in the fields of dental products, oral calcium supplements, etc.

[0003] In recent years, with the improvement of the requirements for the production efficiency and quality of solid preparations in the pharmaceutical industry, the direct compression technology (Direct Compression) has become the preferred process for tablet production due to its advantages such as simplified process, low cost, and avoiding the degradation of active ingredients by wet granulation. As the core excipient of the direct compression process, anhydrous calcium hydrogen phosphate (DCP anhydrous) needs to have high fluidity, low hygroscopicity, uniform particle size distribution and excellent compression molding properties. However, although certain progress has been made in the existing preparation technologies, there are still significant deficiencies in process stability, particle morphology control and direct compression performance optimization. For example, traditional methods (such as direct neutralization method, double decomposition method) often result in particles with many edges and corners, wide particle size distribution, and large angle of repose due to rough reaction conditions, and direct tableting is prone to cracking and poor fluidity, and additional lubricants or adhesives need to be added to meet the direct compression requirements; in the neutralization technology, the yield is increased by adding magnesium oxide or adjusting the pH, but still faces problems such as difficult control of the reaction end point and slow crystal growth rate, resulting in poor particle uniformity and stability between batches. Summary of the Invention

[0004] Aiming at the above defects or improvement requirements of the existing technology, the present invention provides a production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with direct compression function. The anhydrous calcium hydrogen phosphate prepared by this production process has a highly specific surface area porous spherical structure, with small particle size difference, narrow particle size distribution, small angle of repose, good fluidity, stability, and can be directly tableted.

[0005] To achieve the above object, the present invention provides a production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with direct compression function, including the following steps: (1) Raw material pretreatment: Dilute phosphoric acid to a concentration of 20 - 30% to obtain a phosphoric acid solution for standby; Mix calcium carbonate with water and then perform ball milling for 20 - 30 min to obtain a calcium carbonate suspension for standby; (2) Neutralization reaction: Add phosphoric acid solution and calcium carbonate suspension into a reaction kettle equipped with a gas-liquid synergistic stirring system, and carry out the neutralization reaction in stages; (3) In-situ surface modification: Add a surface modifier at the end of the reaction in step (2). After stirring for 10 - 20 min, add a pH regulator to adjust to neutral, and then carry out solid-liquid separation; (4) Drying: Put the separated solid into a fluidized bed for gradient drying to obtain anhydrous calcium hydrogen phosphate.

[0006] The present invention adopts 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, through in-situ surface modification, the surface charge of particles is reduced, and the direct compression fluidity is enhanced. Through gradient drying, the purposes of sequentially removing free water, pore shaping, and removing bound water are achieved, preventing cracking and improving stability. The obtained anhydrous calcium hydrogen phosphate has a narrow particle size distribution, a repose angle less than or equal to 26°, excellent flow performance, and can be directly compressed into tablets.

[0007] Further, 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 - 20 μm, and the solid-liquid ratio of the calcium carbonate to water is 1:3 - 4.

[0008] Further, in step (2) of the above technical solution, the volume ratio of the phosphoric acid solution to the calcium carbonate suspension is 1:1.5 - 2.

[0009] Further, in step (2) of the above technical solution, the gas-liquid synergistic stirring system has a three-layer structure of upper, middle, and lower layers. The upper layer is a turbine-type stirring paddle with a blade setting angle of 45°, the middle layer is a porous titanium alloy gas distributor, and the lower layer is a screw propeller-type stirring paddle with a blade setting angle of 30°.

[0010] In this technical solution, a gas-liquid synergistic stirring system is adopted. The upper layer is a 45° inclined blade for promoting dispersion, the lower layer is a 30° propeller blade for strengthening the bottom material circulation to avoid sedimentation and agglomeration, and the middle layer uses a gas distributor to continuously generate bubbles, which can create pores while dispersing, improving the porosity.

[0011] 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 kettle, heat it up to 40 - 50 °C, start the stirring paddle, and slowly dropwise add 40 - 50% of the total amount of the calcium carbonate suspension until the reaction is completed; then adjust the rotation speed of the stirring paddle and start the gas distributor at the same time, and dropwise add the remaining calcium carbonate suspension in three times, with an interval of 5 - 10 minutes each time, and the reaction temperatures are 50 ± 2 °C, 65 ± 2 °C, and 40 ± 2 °C in sequence. In this technical solution, the segmented neutralization reaction method is adopted. First, pre-react at a low temperature to generate calcium dihydrogen phosphate microcrystal nuclei, and then add the remaining calcium carbonate suspension in segments. At the same time, turn on the gas distributor to ventilate and control different temperatures (realize pore expansion and shaping through thermodynamic phase change), and utilize the synergistic effect of the temperature gradient to induce crystal growth directionality and gas expansion to form a microporous structure and a through-channel, improving the specific surface area and disintegration rate.

[0012] Further, in the above technical solution, the rotation speed of the stirring paddle when it is started for the first time is 200 - 300 rpm; the rotation speed of the stirring paddle is adjusted to 50 - 80 rpm for the second time. Different stirring speeds are adopted in the segmented reaction of this technical solution. A faster speed is beneficial for nucleation, while a slower speed is beneficial for directional growth and can avoid the collapse of rapid pores or channels.

[0013] Further, in the above technical solution, the gas is a mixed gas with a volume ratio of N2 to CO2 of 1:1 - 2, and the flow rate is 0.5 - 1 L / min. The gas in the gas distributor of this technical solution is mixed with carbon dioxide. Bubbles can adhere to the surface of the crystal nuclei and overflow with the reaction to form micropores. At the same time, using the fact that the solubility of carbon dioxide decreases with the increase of temperature, it expands to form through-channels during the rapid growth stage at a subsequent higher temperature (65 ± 2 °C).

[0014] Further, in step (3) of the above technical solution, the surface modifier is a mixture of polyethylene glycol and hydroxypropyl methylcellulose with a mass ratio of 0.2 - 0.3:1, and the dosage 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. Adding it at the end of the reaction can slow down the crystal growth rate, maintain the uniformity of particle size, and at the same time, the hydrophilic groups in its molecular chain can adsorb on the particle surface to form steric hindrance, reducing the electrostatic adsorption effect of particle bonds, preventing particle agglomeration, and improving fluidity; hydroxypropyl methylcellulose can form a viscoelastic network structure to coat the particle surface, form a uniform thin film layer and maintain a slightly wet state on the particle surface, improving the sphericity and stability of the particles. In this technical solution, the above two substances are added at the same time, and through their synergy, the surface characteristics of the particles can be optimized, and at the same time, the integrity of the particles can be maintained during the subsequent drying process.

[0015] Further, in step (4) of the above technical solution, the steps of gradient drying are as follows: in the first stage, the temperature is set at 55 - 65 °C, the wind speed is 1.2 - 1.5 m / s, and drying is carried out for 15 - 25 min; in the second stage, the temperature is set at 80 - 90 °C, the wind speed is 1.6 - 2.0 m / s, and drying is carried out for 250 - 400 min; in the third stage, the temperature is 40 - 50 °C, the wind speed is 0.6 - 1.0 m / s, and drying is carried out for 10 - 20 min. In this technical solution, gradient drying is adopted. In the first stage, a lower temperature is used to remove free water and prevent cracking at the same time. In the second stage, a higher temperature is adopted to remove crystal water and make the hydroxypropyl methylcellulose film denser. In the third stage, a low temperature is used to release internal stress and improve stability.

[0016] Further, in the above technical solution, the particle size D of the anhydrous calcium hydrogen phosphate 50 is 80 - 120 μm, and the angle of repose ≤ 26°.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. By optimizing the production process, the present invention uses the pretreated raw materials for segmented reaction. By controlling the reaction temperature and stirring rate of each segment, crystal nuclei are first formed, and then crystal growth is induced by different temperature gradients, which can effectively control the crystal growth direction and morphology. At the same time, gas stirring is adopted; meanwhile, in-situ surface modification is carried out to reduce the surface charge of particles, further improve the sphericity and stability of particles, and enhance the direct compression fluidity; through gradient drying, the purposes of sequentially removing free water, pore shaping, and removing bound water are achieved, preventing cracking and improving stability.

[0018] 2. The production process of the present invention is simple in operation, high in efficiency, safe, environmentally friendly, and the obtained anhydrous calcium hydrogen phosphate has a narrow particle size distribution, an angle of repose less than or equal to 26°, excellent fluidity, a large specific surface area, can be directly tabletted, and has significant economic benefits as a pharmaceutical excipient. Specific Embodiments

[0019] The experimental methods in the following examples are all conventional methods unless otherwise specified. The raw materials involved in the following examples are all ordinary commercially available products unless otherwise specified, and can all be obtained through market purchase.

[0020] The above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions.

[0021] The reaction kettle used was customized from Hangzhou Yuanzheng Engineering Technology Equipment Company. A gas-liquid co-agitation system is provided in the reaction kettle. The upper layer is a turbine-type agitator paddle with a blade setting angle of 45°. The middle layer is a porous titanium alloy gas distributor with horizontal tube distribution. The lower layer is a screw propeller agitator paddle with a blade setting angle of 30°.

[0022] Example 1 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with direct compression function, comprising the following steps: (1) Raw material pretreatment: Dilute 85% food-grade phosphoric acid to a concentration of 20% to obtain a phosphoric acid solution for standby; Mix food-grade calcium carbonate (particle size 10 - 20 μm) with water at a solid-liquid ratio of 1:4 and then perform ball milling for 30 min to obtain a calcium carbonate suspension for standby; (2) Neutralization reaction: Add the phosphoric acid solution and the calcium carbonate suspension into a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:1.5, and perform the neutralization reaction in stages. Specifically: First, add all the phosphoric acid solution into the reaction kettle, heat up to 40 °C, start the stirring paddle (200 rpm), and slowly drip 40% of the total amount of the calcium carbonate suspension solution until the reaction is completed; Then adjust the stirring paddle speed (60 rpm) and at the same time start the gas distributor (introduce a mixed gas with a flow rate of 0.5 L / min and a volume ratio of N2 / CO2 of 1:1), and drip the remaining calcium carbonate suspension solution in three times, with an interval of 5 min each time, and the reaction temperatures are 50 ± 2 °C, 65 ± 2 °C, and 40 ± 2 °C in sequence; (3) In-situ surface modification: Add a mixture of 1% of the total amount of the reaction liquid of polyethylene glycol and hydroxypropyl methylcellulose with a mass ratio of 0.3:1 as a surface modifier at the end of the reaction in step (2). After stirring for 10 min, add calcium hydroxide to adjust to neutrality, and then perform solid-liquid separation; (4) Drying: Put the separated solid into a fluidized bed for gradient drying. The specific steps are as follows: Divide it into three stages. The first stage is set at a temperature of 55 °C, a wind speed of 1.5 m / s, and drying for 25 min; The second stage is set at a temperature of 80 °C, a wind speed of 2.0 m / s, and drying for 400 min; The third stage is at a temperature of 40 °C, a wind speed of 1.0 m / s, and drying for 20 min, thus obtaining anhydrous calcium hydrogen phosphate.

[0023] Example 2 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with direct compression function, comprising the following steps: (1) Raw material pretreatment: Dilute 85% food-grade phosphoric acid to a concentration of 30% to obtain a phosphoric acid solution for standby; Mix food-grade calcium carbonate (particle size 10 - 20 μm) with water at a solid-liquid ratio of 1:3 and then perform ball milling for 25 min to obtain a calcium carbonate suspension for standby; (2) Neutralization reaction: Add phosphoric acid solution and calcium carbonate suspension into a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:1.8, and carry out the neutralization reaction in stages. Specifically: First, add all the phosphoric acid solution into the reaction kettle, heat it up to 45°C, start the stirring paddle (250 rpm), and slowly dropwise add 45% of the total amount of the calcium carbonate suspension solution until the reaction is completed; then adjust the stirring paddle speed (60 rpm) and start the gas distributor at the same time (introduce a mixed gas with a flow rate of 0.8 L / min and a volume ratio of N2 / CO2 of 1:1.5), and dropwise add the remaining calcium carbonate suspension solution in three times, with an interval of 8 minutes each time, and the reaction temperatures are 50±2°C, 65±2°C, and 40±2°C in sequence; (3) In-situ surface modification: Add a mixture of polyethylene glycol accounting for 1.2% of the total amount of the reaction solution and hydroxypropyl methylcellulose with a mass ratio of 0.2:1 as a surface modifier at the end of the reaction in step (2). After stirring for 15 minutes, add calcium hydroxide to adjust to neutral, and then carry out solid-liquid separation; (4) Drying: Put the separated solid into a fluidized bed for gradient drying. The specific steps are as follows: Divide it into three stages. In the first stage, set the temperature at 60°C, the wind speed at 1.3 m / s, and dry for 20 minutes; in the second stage, set the temperature at 85°C, the wind speed at 1.8 m / s, and dry for 300 minutes; in the third stage, the temperature is 45°C, the wind speed is 0.8 m / s, and dry for 15 minutes to obtain anhydrous calcium hydrogen phosphate.

[0024] Example 3 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with direct compression function, comprising the following steps: (1) Raw material pretreatment: Dilute 85% food-grade phosphoric acid to a concentration of 30% to obtain a phosphoric acid solution for standby; Mix food-grade calcium carbonate (particle size 10 - 20 μm) and water according to a solid-liquid ratio of 1:3 - 4, and carry out ball milling treatment for 20 minutes to obtain a calcium carbonate suspension for standby; (2) Neutralization reaction: Add phosphoric acid solution and calcium carbonate suspension into a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:2, and carry out the neutralization reaction in stages. Specifically: First, add all the phosphoric acid solution into the reaction kettle, heat it up to 50°C, start the stirring paddle (300 rpm), and slowly dropwise add 50% of the total amount of the calcium carbonate suspension solution until the reaction is completed; then adjust the stirring paddle speed (80 rpm) and start the gas distributor at the same time (introduce a mixed gas with a flow rate of 0.5 - 1 L / min and a volume ratio of N2 / CO2 of 1:2), and dropwise add the remaining calcium carbonate suspension solution in three times, with an interval of 10 minutes each time, and the reaction temperatures are 50±2°C, 65±2°C, and 40±2°C in sequence; (3) In-situ surface modification: At the end of the reaction in step (2), a mixture of 1.5% of the total reaction solution volume of polyethylene glycol and hydroxypropyl methylcellulose with a mass ratio of 0.3:1 was added as a surface modifier. After stirring for 20 min, calcium hydroxide was added to adjust to neutrality, and then solid-liquid separation was carried out. (4) Drying: The separated solid was placed in a fluidized bed for gradient drying. The specific steps were as follows: It was divided into three stages. In the first stage, the temperature was set at 65 °C, the wind speed was 1.2 m / s, and drying was carried out for 15 min. In the second stage, the temperature was set at 90 °C, the wind speed was 1.6 m / s, and drying was carried out for 250 min. In the third stage, the temperature was 50 °C, the wind speed was 0.6 m / s, and drying was carried out for 10 min, thus obtaining anhydrous calcium hydrogen phosphate.

[0025] Comparative Example 1 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that in (2) neutralization reaction: the phosphoric acid solution and calcium carbonate suspension were added to a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:1.8. Specifically: First, all the phosphoric acid solution was added to the reaction kettle, heated to 45 °C, the stirring paddle was started (250 rpm), and all the calcium carbonate suspension solution was slowly added dropwise until the reaction was completed.

[0026] Comparative Example 2 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that in (2) neutralization reaction: the phosphoric acid solution and calcium carbonate suspension were added to a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:1.8, and the neutralization reaction was carried out in stages. Specifically: First, all the phosphoric acid solution was added to the reaction kettle, heated to 45 °C, the stirring paddle was started (250 rpm), and 45% of the total calcium carbonate suspension solution was slowly added dropwise until the reaction was completed; then the stirring paddle speed was adjusted (60 rpm) and at the same time the gas distributor was started (a mixed gas of N2 / CO2 with a volume ratio of 1:1.5 and a flow rate of 0.8 L / min was introduced), and the remaining calcium carbonate suspension solution was added dropwise in three times, with an interval of 8 min each time, and the reaction temperature was 65 ± 2 °C.

[0027] Comparative Example 3 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that: (2) Neutralization reaction: The phosphoric acid solution and the calcium carbonate suspension are added to a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages. Specifically: First, all the phosphoric acid solution is added to the reaction kettle, heated to 45°C, the stirring paddle is started (250 rpm), and a suspension of 45% of the total amount of the calcium carbonate suspension solution is slowly added dropwise until the reaction is completed; then the stirring paddle speed is adjusted (250 rpm) and at the same time the gas distributor is started (a mixed gas of N2 / CO2 with a volume ratio of 1:1.5 and a flow rate of 0.8 L / min is introduced), and the remaining calcium carbonate suspension solution is added dropwise in three times, with an interval of 8 minutes each time, and the reaction temperatures are 50±2°C, 65±2°C, and 40±2°C in sequence.

[0028] Comparative Example 4 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that: (2) Neutralization reaction: The phosphoric acid solution and the calcium carbonate suspension are added to a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages. Specifically: First, all the phosphoric acid solution is added to the reaction kettle, heated to 45°C, the stirring paddle is started (250 rpm), and a suspension of 45% of the total amount of the calcium carbonate suspension solution 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 solution is added dropwise in three times, with an interval of 8 minutes each time, and the reaction temperatures are 50±2°C, 65±2°C, and 40±2°C in sequence.

[0029] Comparative Example 5 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that: (2) Neutralization reaction: The phosphoric acid solution and the calcium carbonate suspension are added to a reaction kettle equipped with a gas-liquid synergistic stirring system according to a volume ratio of 1:1.8, and the neutralization reaction is carried out in stages. Specifically: First, all the phosphoric acid solution is added to the reaction kettle, heated to 45°C, the stirring paddle is started (250 rpm), and a suspension of 45% of the total amount of the calcium carbonate suspension solution is slowly added dropwise until the reaction is completed; then the stirring paddle speed is adjusted (60 rpm) and at the same time the gas distributor is started (N2 with a flow rate of 0.8 L / min is introduced), and the remaining calcium carbonate suspension solution is added dropwise in three times, with an interval of 8 minutes each time, and the reaction temperatures are 50±2°C, 65±2°C, and 40±2°C in sequence.

[0030] Comparative Example 6 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that: (2) Neutralization reaction: The phosphoric acid solution and the calcium carbonate suspension are added to a reaction kettle equipped with a turbine-type stirring paddle (the blade setting angle is 45°), and the neutralization reaction is carried out in stages.

[0031] Comparative Example 7 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that there is no in-situ surface modification step. After directly adding calcium hydroxide and adjusting to neutrality, solid-liquid separation is carried out.

[0032] Comparative Example 8 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that (3) in-situ surface modification: 1.2% of the total amount of the reaction solution of polyethylene glycol is added as a surface modifier at the end of the reaction in step (2). After stirring for 15 min, calcium hydroxide is added and adjusted to neutrality, and then solid-liquid separation is carried out.

[0033] Comparative Example 9 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that (3) in-situ surface modification: 1.2% of the total amount of the reaction solution of hydroxypropyl methylcellulose is added as a surface modifier at the end of the reaction in step (2). After stirring for 15 min, calcium hydroxide is added and adjusted to neutrality, and then solid-liquid separation is carried out.

[0034] Comparative Example 10 A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient, which is different from Example 2 in that (4) drying: The separated solid is put into a fluidized bed for drying. The specific steps are as follows: The temperature is set at 85 °C, the wind speed is 1.8 m / s, and drying is carried out for 335 min to obtain anhydrous calcium hydrogen phosphate.

[0035] Test Example 1. The morphology, particle size distribution, angle of repose, Carr index, specific surface area, and porosity of the final product anhydrous calcium hydrogen phosphate in Examples 1-3 and Comparative Examples 1-10 were detected and tested. The results are shown in Table 1. Among them, the morphology was observed under an electron microscope, the particle size distribution was measured by a laser particle size analyzer, the specific surface area was measured by the nitrogen adsorption-desorption method, and the porosity was calculated by the mercury intrusion method.

[0036] Table 1 Product Performance Indexes

[0037] From the results in Table 1, it can be seen that 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°, Carr index less than or equal to 11%, excellent flowability, large specific surface area, high porosity, and can be directly tableted. In Comparative Example 1, the neutralization reaction is reacted by adding raw materials at one time, and there is no nucleation-first-and-then-growth process. The particle size growth is uneven, the distribution is wide, and the sphericity, flowability, porosity and other properties are poor; in Comparative Example 2, the neutralization reaction growth stage adopts the same high temperature reaction. Although the porosity is high, the growth is also affected, the particle size distribution becomes wide, and the flowability is slightly poor; in Comparative Example 3, the neutralization reaction adopts a faster speed to react, which is not conducive to directional growth, and also affects the particle size distribution and flowability to a certain extent; in Comparative Example 4, the neutralization reaction adopts gas stirring, although it has little effect on sphericity and flowability, but because there is no gas pore formation, the specific surface area and porosity are low; In Comparative Example 5, only nitrogen stirring is used for the neutralization reaction. Although some pores can be generated, its effect is worse than that of carbon dioxide, and it is impossible to perform secondary foaming to form through channels in the subsequent process; in Comparative Example 6, an ordinary stirring device is used, and its dispersibility and anti-agglomeration performance are poor, which directly affects the uniform directional growth, the particle size distribution is wider, the fluidity is poor, and there is no gas pore formation, and the specific surface area and porosity are low; in Comparative Examples 7-9, no in-situ modification is performed after the neutralization reaction, or only a single modifier is used, and its sphericity and fluidity are affected to a certain extent; in Comparative Example 10, the subsequent drying is directly high-temperature drying, and due to excessive water loss, particle cracking and pore collapse will occur, affecting its performance.

[0038] 2. The anhydrous calcium hydrogen phosphate obtained in Examples 1-3 and Comparative Examples 1-10 was mixed with 50% aspirin raw material and directly tableted, and the disintegration performance and tableting performance were tested. The results are shown in Table 2. The disintegration performance was tested according to the disintegration time limit test of the pharmacopoeia, and the tableting performance was tested using a tablet strength tester and a friability tester.

[0039] Table 2 Disintegration and tableting properties

[0040] From the data in Table 2, it can be seen that the anhydrous calcium hydrogen phosphate prepared by the present invention can be directly used for tableting after being mixed with medicinal materials, and the obtained tablets have a short disintegration time, stable long-term storage performance, tensile strength that meets the direct compression process requirements, and friability that meets the pharmacopoeia requirements, and the obtained anhydrous calcium hydrogen phosphate is suitable as a direct compression pharmaceutical excipient. However, in Comparative Examples 1-10, due to the defects of the prepared anhydrous calcium hydrogen phosphate, it is directly mixed with medicinal materials and then tableted, and the tablet performance cannot meet the requirements of pharmaceutical excipients.

[0041] Finally, it should be emphasized that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with a direct compression function, characterized in that, It includes the following steps: (1) Raw material pretreatment: Dilute phosphoric acid to a concentration of 20 - 30% to obtain a phosphoric acid solution for standby; Mix calcium carbonate with water and then perform ball milling for 20 - 30 min to obtain a calcium carbonate suspension for standby; (2) Neutralization reaction: Add the phosphoric acid solution and the calcium carbonate suspension to a reaction kettle equipped with a gas - liquid synergistic stirring system and carry out the neutralization reaction in stages; (3) In - situ surface modification: Add a surface modifier at the end of the reaction in step (2), stir for 10 - 20 min, then add a pH regulator to adjust to neutrality, and then perform solid - liquid separation; (4) Drying: Put the separated solid into a fluidized bed for gradient drying to obtain anhydrous calcium hydrogen phosphate.

2. The production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with a direct pressing function according to claim 1, 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 calcium hydrogen phosphate as a pharmaceutical excipient with a direct pressing function according to claim 1, 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 calcium hydrogen phosphate as a pharmaceutical excipient with a direct pressing function according to claim 1, characterized in that, In step (2), the gas - liquid synergistic stirring system has a three - layer structure of upper, middle and lower layers. The upper layer is a turbine - type stirring paddle with the blade setting angle of 45°, the middle layer is a porous titanium alloy gas distributor, and the lower layer is a spiral - propelling type stirring paddle with the blade setting angle of 30°.

5. The production process of anhydrous calcium hydrogen phosphate for pharmaceutical excipients with a direct pressing function according to claim 4, characterized in that, In step (2), the steps of the staged neutralization reaction are as follows: First, add the phosphoric acid solution to the reaction kettle, heat up to 40 - 50 °C, start the stirring paddle, and slowly drip 40 - 50% of the total amount of the calcium carbonate suspension solution until the reaction is completed; Then adjust the stirring paddle speed and start the gas distributor at the same time, and drip the remaining calcium carbonate suspension solution in three times, with an interval of 5 - 10 min each time, and the reaction temperatures are 50 ± 2 °C, 65 ± 2 °C, and 40 ± 2 °C in sequence.

6. The production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with a direct pressing function according to claim 5, characterized in that, The rotation speed of the stirring paddle when starting for the first time is 200 - 300 rpm; The rotation speed of the stirring paddle when adjusted for the second time is 50 - 80 rpm.

7. The production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with a direct pressing function according to claim 4 or 5, characterized in that, The gas is a mixed gas with a volume ratio of N2 and CO2 of 1:1 - 2, and the flow rate is 0.5 - 1 L / min.

8. The production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with a direct pressing function according to claim 1, characterized in that, In step (3), the surface modifier is a mixture of polyethylene glycol and hydroxypropyl methylcellulose with a mass ratio of 0.2 - 0.3:1, and the dosage of the surface modifier is 1 - 1.5% of the total amount of the reaction solution.

9. The production process of anhydrous calcium hydrogen phosphate as a pharmaceutical excipient with a direct pressing function according to claim 1, characterized in that, In step (4), the steps of gradient drying are: In the first stage, set the temperature to 55 - 65 °C, the wind speed to 1.2 - 1.5 m / s, and dry for 15 - 25 min; In the second stage, set the temperature to 80 - 90 °C, the wind speed to 1.6 - 2.0 m / s, and dry for 250 - 400 min; In the third stage, the temperature is 40 - 50 °C, the wind speed is 0.6 - 1.0 m / s, and dry for 10 - 20 min.

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

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