Synthetic method of medicinal-grade calcium hydrophosphate dihydrate

Abstract

The invention discloses a synthetic method of medicinal-grade calcium hydrophosphate dihydrate, and belongs to the field of pharmaceutical adjuvant synthesis. The preparation method comprises the following steps: firstly, adding calcite into dilute phosphoric acid to obtain mixed slurry; lime milk and sodium pyrophosphate are slowly added into the mixed slurry, nucleation is carried out under the assistance of ultrasonic waves, magnesium hydrogen phosphate is continuously added after the reaction is carried out to a certain degree, and calcium hydrogen phosphate dihydrate slurry is obtained through microwave heating treatment; and finally, carrying out centrifugal filtration, pneumatic drying and grading to obtain the medicinal-grade calcium hydrophosphate dihydrate. According to the technology, nucleation and growth of crystals are regulated and controlled through multi-means and multi-step neutralization reactions, and the finally prepared calcium hydrophosphate dihydrate is high in sphericity degree, uniform in size distribution, good in fluidity, high in main component content, low in impurity content and good in stability, meets the related standard of calcium hydrophosphate dihydrate in Chinese pharmacopoeia and has good application prospects. The method is suitable for preparing and forming high-quality solid preparations.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of pharmaceutical excipients, and particularly relates to a method for synthesizing pharmaceutical-grade calcium hydrogen phosphate dihydrate. Background Art

[0002] Calcium hydrogen phosphate dihydrate (CaHPO4·2H2O) is a white crystalline powder, which does not react with most drugs, has good biocompatibility, chemical stability and biological activity, and can be used as a diluent or adsorbent to improve the fluidity and compressibility of drugs. It is widely used in the pharmaceutical industry as a tablet, capsule filler, disintegrant or calcium supplement.

[0003] Research shows that the crystal morphology (such as flaky, needle-like, spherical or amorphous aggregates) and particle size (usually in the range of 20 - 200 μm) of calcium hydrogen phosphate dihydrate directly determine its bulk density, specific surface area and fluidity (usually evaluated by the angle of repose or Carr index). The current preparation methods of calcium hydrogen phosphate dihydrate mostly adopt wet precipitation, which is generated by neutralization crystallization of phosphoric acid and calcium salt. These traditional preparation processes generally do not control the physical properties of the product, and irregular crystals or wide-distribution particles are easily generated under the fluctuation of reaction conditions, etc., which will further lead to poor fluidity of the product and affect the tableting efficiency and quality uniformity of the preparation.

[0004] In view of this, how to optimize the crystallization kinetic parameters on the basis of traditional processes, accurately control crystal nucleation and growth, and obtain pharmaceutical-grade calcium hydrogen phosphate dihydrate with high fluidity, suitable morphology and size has become the key to improving the process performance of solid preparations. Summary of the Invention

[0005] Aiming at the problems mentioned in the background art, the purpose of the present invention is to provide a method for synthesizing pharmaceutical-grade calcium hydrogen phosphate dihydrate. The present invention realizes the preparation of high-quality pharmaceutical-grade calcium hydrogen phosphate dihydrate by regulating crystal nucleation and growth through multiple means and multi-step neutralization reactions. The obtained product has high sphericity, uniform size distribution and good fluidity.

[0006] To achieve the above purpose, the present invention specifically adopts the following technical solutions: The present invention provides a synthesis process of pharmaceutical-grade calcium hydrogen phosphate dihydrate, comprising the following steps: Step 1: Add calcite to dilute phosphoric acid, and continuously stir to obtain a mixed slurry for standby; Step 2: Slowly add lime milk and sodium pyrophosphate to the obtained mixed slurry, nucleate under ultrasonic assistance. When the reaction proceeds to a certain extent, continue to add magnesium hydrogen phosphate, and perform microwave heating treatment to obtain a calcium hydrogen phosphate dihydrate slurry; Step 3: Centrifugally filter the obtained calcium hydrogen phosphate dihydrate slurry, and the obtained filter cake is dried by air flow and classified to obtain pharmaceutical-grade calcium hydrogen phosphate dihydrate.

[0007] Further, the concentration of the dilute phosphoric acid in Step 1 is 35%-45%, and it is prepared with 85% food-grade thermal phosphoric acid; the pH of the mixed slurry is 4.0-5.0.

[0008] Further, the calcite in Step 1 needs to be prepared into a slurry and then added to the dilute phosphoric acid: Grind the calcite to 200-300 mesh, add 1-2 times the mass of deionized water, add ethylenediaminetetraacetic acid for impurity removal and heat preservation, then centrifuge and dehydrate to obtain the filter cake. Continue to add 4-5 times the mass of deionized water to the filter cake and stir well, and pass through a 200-mesh filter screen to obtain the calcite slurry.

[0009] Further, the mass ratio of the calcite slurry to the dilute phosphoric acid is (2-3):1.

[0010] Further, the addition amount of sodium pyrophosphate in Step 2 is 0.05%-0.25% of the mass of the mixed slurry.

[0011] Further, the concentration of the lime milk in Step 2 is 5%-10%. Under ultrasonic assistance, continuously and slowly add the lime milk until the pH reaches 5.5-6.0, and then add magnesium hydrogen phosphate.

[0012] Further, the frequency of the ultrasonic wave in Step 2 is 30-40 kHz, the power is 50-60 W, and the time is 8-10 min.

[0013] Further, the addition amount of magnesium hydrogen phosphate in Step 2 is 0.01%-0.04% of the mass of the mixed slurry. After adding magnesium hydrogen phosphate, continue to add lime milk until the pH reaches 6.5-7.0 for microwave heating treatment.

[0014] Further, the temperature of the microwave heating treatment in Step 2 is 70-80°C, and the time is 15-20 min.

[0015] Further, the air flow drying and classification in Step 3 are carried out at 60-90°C.

[0016] Aiming at the problem that the physical properties of calcium hydrogen phosphate dihydrate products cannot be controlled by the current traditional preparation process, the present invention regulates nucleation and growth through multi-step neutralization reactions: in the initial stage of the reaction (pH = 4.0 - 5.0), calcite reacts with an appropriate amount of dilute phosphoric acid to generate calcium dihydrogen phosphate. In the middle stage of the reaction, first, sodium pyrophosphate is added to the initial reaction system. On the one hand, sodium pyrophosphate can combine with calcium ions to regulate the crystal growth rate, and is conducive to the formation of more uniform crystal nuclei by slowing down crystal growth. On the other hand, it can adsorb on specific crystal planes to limit anisotropic growth, which is beneficial to improving the product morphology; while adding sodium pyrophosphate, lime milk is continuously and slowly added to adjust the pH, and calcium dihydrogen phosphate gradually reacts to form calcium hydrogen phosphate dihydrate. In the initial stage of nucleation, the present invention applies short-time ultrasonic treatment. Through ultrasonic cavitation, agglomerates are broken, the dispersibility is improved, and at the same time, the formation of fine crystal nuclei is promoted, providing a basis for subsequent uniform nucleation. In the middle and late stages of the reaction, when the system pH rises to 5.5 - 6.0, the present invention further adds a small amount of magnesium hydrogen phosphate. Through its doping effect, the crystal grains are further refined and the surface smoothness is improved, thereby enhancing the fluidity of the product. When lime milk is continuously added until the pH is 6.5 - 7.0, the present invention uses microwave heating treatment to accelerate the later reaction and end nucleation. Microwave heating has the characteristic of volumetric heating, with rapid and uniform temperature rise, which can reduce the temperature gradient, avoid local non-uniform nucleation, and promote the formation of regular morphology. After ripening, a calcium hydrogen phosphate dihydrate slurry is obtained.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The process of the present invention regulates crystal nucleation and growth through multiple means and multi-step neutralization reactions. Finally, the morphology of the prepared calcium hydrogen phosphate dihydrate is spherical (sphericity > 0.85), its size distribution is uniform (polydispersity index < 0.1), and it has good fluidity (angle of repose ≤ 30°), meeting the requirements of pharmaceutical excipients.

[0018] 2. The process of the present invention precisely controls the reaction progress at each stage and optimizes the dosage ratio of raw materials, making the prepared calcium hydrogen phosphate dihydrate have a high main component content, low impurities, and good stability, meeting the relevant standards of calcium hydrogen phosphate dihydrate in the Chinese Pharmacopoeia (2020), and being suitable for the preparation and molding of high-quality solid preparations. Specific Embodiments

[0019] To make the objectives, technical solutions, and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments. Those not specified in the embodiments are carried out according to the conventional conditions or the conditions recommended by the manufacturer. Those reagents or instruments not specified in the manufacturer are all conventional products that can be obtained through commercial purchase.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field of the present invention. The terms used in the description of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0021] Example 1 A method for synthesizing pharmaceutical grade calcium hydrogen phosphate dihydrate, comprising the following steps: 1. Prepare a dilute phosphoric acid solution with a concentration of 40% using 85% food-grade thermal phosphoric acid; grind calcite to 200 - 300 mesh, add 1.5 times the mass of deionized water and mix evenly, then add 0.5% of ethylenediaminetetraacetic acid based on the mass of calcite for impurity removal, keep warm at 40 °C for 0.5 h, then centrifuge to dehydrate and take the filter cake. Continue to add 4.5 times the mass of deionized water to the filter cake and stir well, and pass through a 200-mesh filter screen to obtain calcite slurry. Pour the prepared calcite slurry into the dilute phosphoric acid solution (the mass ratio of calcite slurry to dilute phosphoric acid solution is 2.5:1), and continuously stir to obtain a mixed slurry (pH = 4.4).

[0022] 2. Add 0.15% of sodium pyrophosphate based on the mass of the mixed slurry to the mixed slurry, and at the same time continuously and slowly add 8% lime milk (the addition flow rate of lime milk is controlled at 2 - 3 L / min). Ultrasonic treatment (frequency 35 kHz, power 60 W) is also applied within 10 min after the reaction starts. When the pH of the slurry reaches 5.8, continue to add 0.03% of magnesium hydrogen phosphate based on the mass of the mixed slurry to the slurry, and continue to slowly add lime milk for reaction. When the pH of the slurry reaches 6.8, stop introducing lime milk, and microwave heat (75 °C) the reaction mixture for 20 min, and finally age for 1 h to obtain a calcium hydrogen phosphate dihydrate slurry.

[0023] 3. Centrifuge and filter the calcium hydrogen phosphate dihydrate slurry, wash it alternately with deionized water and ethanol, and then dry and classify it by air drying at 80 °C to obtain the finished product of pharmaceutical grade calcium hydrogen phosphate dihydrate.

[0024] Example 2 A method for synthesizing pharmaceutical grade calcium hydrogen phosphate dihydrate, comprising the following steps: 1. Prepare a dilute phosphoric acid solution with a concentration of 35% using 85% food-grade thermal phosphoric acid; grind calcite to 200 - 300 mesh, add 1.5 times the mass of deionized water and mix evenly, then add 0.5% of ethylenediaminetetraacetic acid based on the mass of calcite for impurity removal, keep it at 40 °C for 0.5 h, then centrifuge to dehydrate and take the filter cake. Continue to add 4 times the mass of deionized water to the filter cake and stir evenly, and pass through a 200-mesh filter screen to obtain calcite slurry. Pour the calcite slurry into the prepared dilute phosphoric acid solution (the mass ratio of calcite slurry to dilute phosphoric acid solution is 2.8:1), and continuously stir to obtain a mixed slurry (pH = 4.7).

[0025] 2. Add 0.15% of sodium pyrophosphate based on the mass of the mixed slurry to the mixed slurry, and at the same time continuously and slowly add lime milk with a concentration of 8% (the addition flow rate of lime milk is controlled at 2 - 3 L / min). Ultrasonic treatment (frequency 35 kHz, power 60 W) is also applied within 9 min after the reaction starts. When the pH of the slurry reaches 5.5, continue to add 0.02% of magnesium hydrogen phosphate based on the mass of the mixed slurry to the slurry, and continue to slowly add lime milk for reaction. When the pH of the slurry reaches 6.5, stop feeding lime milk, heat the reaction mixture by microwave (80 °C) for 15 min, and finally age for 1 h to obtain calcium hydrogen phosphate dihydrate slurry.

[0026] 3. Centrifuge and filter the calcium hydrogen phosphate dihydrate slurry, wash it alternately with deionized water and ethanol, and then dry it by air flow at 80 °C and classify it to obtain the finished product of pharmaceutical-grade calcium hydrogen phosphate dihydrate.

[0027] Example 3 A method for synthesizing pharmaceutical-grade calcium hydrogen phosphate dihydrate, comprising the following steps: 1. Prepare a dilute phosphoric acid solution with a concentration of 45% using 85% food-grade thermal phosphoric acid; grind calcite to 200 - 300 mesh, add 1.5 times the mass of deionized water and mix evenly, then add 0.5% of ethylenediaminetetraacetic acid based on the mass of calcite for impurity removal, keep it at 40 °C for 0.5 h, then centrifuge to dehydrate and take the filter cake. Continue to add 5 times the mass of deionized water to the filter cake and stir evenly, and pass through a 200-mesh filter screen to obtain calcite slurry. Pour the calcite slurry into the prepared dilute phosphoric acid solution (the mass ratio of calcite slurry to dilute phosphoric acid solution is 2:1), and continuously stir to obtain a mixed slurry (pH = 4.2).

[0028] 2. Add sodium pyrophosphate at 0.05% of the mass of the mixed slurry to the mixed slurry. At the same time, continuously and slowly add lime milk with a concentration of 8% (the addition flow rate of lime milk is controlled at 2 - 3 L / min). Ultrasonic treatment (frequency 40 kHz, power 50 W) is also applied within 8 min after the start of the reaction. When the pH of the slurry reaches 5.9, continue to add magnesium hydrogen phosphate at 0.04% of the mass of the mixed slurry to the slurry, and continue to slowly add lime milk for reaction. When the pH of the slurry reaches 6.9, stop introducing lime milk, and subject the reaction mixture to microwave heating (70 °C) for 20 min, and finally age for 1 h to obtain the calcium hydrogen phosphate dihydrate slurry.

[0029] 3. Centrifuge and filter the calcium hydrogen phosphate dihydrate slurry, wash it alternately with deionized water and ethanol, and then dry it by air flow at 80 °C and classify it to obtain the finished product of pharmaceutical-grade calcium hydrogen phosphate dihydrate.

[0030] Example 4 A method for synthesizing pharmaceutical-grade calcium hydrogen phosphate dihydrate, comprising the following steps: 1. Prepare a dilute phosphoric acid solution with a concentration of 40% using 85% food-grade thermal phosphoric acid; grind calcite to 200 - 300 mesh, add 1.5 times the mass of deionized water and mix evenly, then add ethylenediaminetetraacetic acid at 0.5% of the mass of calcite for impurity removal, keep it at 40 °C for 0.5 h, then centrifuge and dehydrate to obtain the filter cake. Continue to add 4.5 times the mass of deionized water to the filter cake and stir evenly, and pass through a 200-mesh filter screen to obtain the calcite slurry. Pour the calcite slurry (the mass ratio of calcite slurry to dilute phosphoric acid solution is 2.4:1) into the prepared dilute phosphoric acid solution, and continuously stir to obtain a mixed slurry (pH = 4.6).

[0031] 2. Add sodium pyrophosphate at 0.25% of the mass of the mixed slurry to the mixed slurry. At the same time, continuously and slowly add lime milk with a concentration of 8% (the addition flow rate of lime milk is controlled at 2 - 3 L / min). Ultrasonic treatment (frequency 35 kHz, power 60 W) is also applied within 10 min after the start of the reaction. When the pH of the slurry reaches 5.6, continue to add magnesium hydrogen phosphate at 0.01% of the mass of the mixed slurry to the slurry, and continue to slowly add lime milk for reaction. When the pH of the slurry reaches 6.6, stop introducing lime milk, and subject the reaction mixture to microwave heating (75 °C) for 15 min, and finally age for 1 h to obtain the calcium hydrogen phosphate dihydrate slurry.

[0032] 3. Centrifuge and filter the calcium hydrogen phosphate dihydrate slurry, wash it alternately with deionized water and ethanol, and then dry it by air flow at 80 °C and classify it to obtain the finished product of pharmaceutical-grade calcium hydrogen phosphate dihydrate.

[0033] Comparative Example 1 Refer to the step parameters of Example 1, the difference is that sodium pyrophosphate is not added in step 2.

[0034] Comparative Example 2 Referring to the step parameters of Example 1, the difference is that after adding sodium pyrophosphate and lime milk in Step 2, ultrasonic treatment is not applied within 10 minutes after the reaction starts.

[0035] Comparative Example 3 Referring to the step parameters of Example 1, the difference is that magnesium hydrogen phosphate is not added in Step 2, that is, after adding sodium pyrophosphate and ultrasonic treatment, lime milk is continuously added until the pH of the slurry reaches 6.8, and then microwave heating treatment is directly carried out.

[0036] Comparative Example 4 Referring to the step parameters of Example 1, the difference is that microwave heating treatment is not carried out in the later stage of the reaction in Step 2.

[0037] Test Example The calcium hydrogen phosphate dihydrate products prepared in the above Examples 1-4 and Comparative Examples 1-4 were subjected to component detection using the calcium hydrogen phosphate dihydrate standard in the Chinese Pharmacopoeia (2020), and the results are shown in Table 1.

[0038] Table 1 Detection Results of Components of Calcium Hydrogen Phosphate Dihydrate Products

[0039] The morphology, angle of repose, and particle size distribution of the calcium hydrogen phosphate dihydrate products prepared in the above Examples 1-4 and Comparative Examples 1-4 were tested, and the results are shown in Table 2. Among them, the morphology was observed under an electron microscope, the angle of repose was measured according to the pharmacopoeia standard, and the particle size distribution was measured using a laser particle size analyzer and a dynamic light scattering instrument.

[0040] Table 2 Detection Results of Morphology, Fluidity, and Particle Size Distribution of Calcium Hydrogen Phosphate Dihydrate Products

[0041] According to the component detection results in Table 1, the component contents of the calcium hydrogen phosphate dihydrate finished products prepared in Examples 1-4 of the present invention all meet the relevant pharmacopoeia standards, while the main component contents of the calcium hydrogen phosphate dihydrate finished products prepared in Comparative Examples 1, 3, and 4 all exceed the pharmacopoeia standard range. According to the detection results of morphology, fluidity, and particle size distribution in Table 2, the morphology of the calcium hydrogen phosphate dihydrate finished products prepared in Examples 1-4 of the present invention is regular spherical with high sphericity; their average angle of repose does not exceed 30°, indicating that the calcium hydrogen phosphate dihydrate prepared by the present invention has excellent fluidity and meets the requirements of the pharmacopoeia for tableting excipients; in addition, from the particle size analysis, it can be seen that the particle size of the calcium hydrogen phosphate dihydrate prepared in the examples of the present invention is close to a normal distribution and has high uniformity (PDI does not exceed 1). By comparing the detection results of the samples in Comparative Examples 1-4, it can be seen that sodium pyrophosphate, ultrasonic treatment, magnesium hydrogen phosphate, and microwave heating treatment all affect the morphology, fluidity, and particle size distribution of the prepared calcium hydrogen phosphate dihydrate to varying degrees, and the sphericity and fluidity of the prepared products are significantly reduced. In particular, the particle size shows a polydisperse distribution. From the width of its particle size distribution (Span exceeds 1.5), it can be seen that the particle diameter distribution of the calcium hydrogen phosphate dihydrate prepared in Comparative Examples 1-4 shows a large skew. In summary, the synthesis process of the present invention regulates crystal nucleation and growth through multiple means and multi-step neutralization reactions, and prepares calcium hydrogen phosphate dihydrate with high sphericity, uniform size distribution, and good fluidity, providing a better choice for high-quality solid pharmaceutical excipients.

[0042] The embodiments described above only represent several preferred embodiments of the present invention. The description is relatively specific and detailed, but it is not intended to limit the present invention. It should be pointed out that for those skilled in the art, the present invention can also have various changes and modifications. Any modifications, equivalent replacements, improvements, etc. made within the concept and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing pharmaceutical-grade calcium hydrogen phosphate dihydrate, characterized in that, It includes the following steps: Step 1: Add calcite into dilute phosphoric acid, continuously stir, and reserve the obtained mixed slurry; Step 2: Continuously and slowly add lime milk and sodium pyrophosphate into the obtained mixed slurry, nucleate under ultrasonic assistance. When the reaction proceeds to a certain extent, continue to add magnesium hydrogen phosphate, and obtain calcium hydrogen phosphate dihydrate slurry through microwave heating treatment; Step 3: Centrifugally filter the obtained calcium hydrogen phosphate dihydrate slurry, and the obtained filter cake is dried by air flow and classified to obtain pharmaceutical-grade calcium hydrogen phosphate dihydrate.

2. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, characterized in that, The concentration of the dilute phosphoric acid described in Step 1 is 35%-45%, and it is prepared with 85% food-grade thermal phosphoric acid; the pH of the mixed slurry is 4.0-5.

0.

3. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, characterized in that, The calcite described in Step 1 needs to be prepared into a slurry and then added into dilute phosphoric acid: Grind calcite to 200-300 mesh, add 1-2 times the mass of deionized water, add ethylenediaminetetraacetic acid for impurity removal and heat preservation, then centrifuge and dehydrate to obtain the filter cake. Continue to add 4-5 times the mass of deionized water to the filter cake and stir evenly, and pass through a 200-mesh filter screen to obtain calcite slurry.

4. The synthetic method of dibasic calcium phosphate dihydrate for pharmaceutical use according to claim 3, characterized in that, The mass ratio of the calcite slurry to the dilute phosphoric acid is (2-3):

1.

5. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, characterized in that, The addition amount of sodium pyrophosphate described in Step 2 is 0.05%-0.25% of the mass of the mixed slurry.

6. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, characterized in that, The concentration of the lime milk described in Step 2 is 5%-10%. Under ultrasonic assistance, continuously and slowly add lime milk until the pH reaches 5.5-6.0, and then add magnesium hydrogen phosphate.

7. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, wherein The frequency of the ultrasonic wave described in Step 2 is 30-40 kHz, the power is 50-60 W, and the time is 8-10 min.

8. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, characterized in that, The addition amount of magnesium hydrogen phosphate described in Step 2 is 0.01%-0.04% of the mass of the mixed slurry. After adding magnesium hydrogen phosphate, continue to add lime milk until the pH reaches 6.5-7.0 for microwave heating treatment.

9. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, wherein The temperature of the microwave heating treatment described in Step 2 is 70-80°C, and the time is 15-20 min.

10. The synthesis method of pharmaceutical grade calcium hydrogen phosphate dihydrate according to claim 1, characterized in that, The air flow drying and classification in Step 3 are carried out at 60-90°C.

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