Production process for preparing medicinal anhydrous calcium hydrogen phosphate by dry method

Abstract

The invention relates to the technical field of production of pharmaceutic adjuvants, and particularly discloses a production process for preparing pharmaceutical-grade anhydrous calcium hydrogen phosphate by a dry method. According to the process, calcium hydroxide and phosphoric acid are used as raw materials, and the problems of high water consumption, high energy consumption, low product purity and the like of a traditional water process are solved through integration of dry reaction, vacuum belt drying and special mixing equipment. The method comprises the steps of equipment preparation, feeding, neutralization reaction, vacuum belt type drying, mixing and sieving, packaging and warehousing and finished product inspection. According to the method, the water consumption is only one tenth of that of a water method process, the drying time and the energy consumption are greatly reduced, no wastewater is discharged, the product purity meets the medicinal grade standard, the process steps are simplified, the equipment investment is low, and the method is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to a dry process for preparing pharmaceutical-grade anhydrous dicalcium phosphate, belonging to the field of pharmaceutical excipient production technology. Background Technology

[0002] Anhydrous dicalcium phosphate is a key raw material in the field of pharmaceutical excipients, and its production process has long relied on the traditional water-based reaction route.

[0003] The conventional aqueous reaction process consists of eight steps: 1. Feeding; 2. Slurry preparation (using a large amount of water, more than twice the amount of raw materials); 3. Neutralization reaction; 4. Post-treatment; 5. Solid-liquid separation; 6. Drying and finished product; 7. Wastewater treatment.

[0004] This process uses an aqueous solution as the reaction medium and achieves product preparation through steps such as acid-base neutralization, solid-liquid separation, and high-temperature drying. However, its technical route has the following core problems:

[0005] I. High water consumption and environmental pollution problems

[0006] The water-based process, centered on "wet neutralization," consumes a large amount of deionized water to prepare the reaction slurry (3-6 tons of water per ton of product), with over 90% discharged as wastewater. This wastewater contains unreacted phosphate, calcium ions, and trace heavy metal ions, requiring complex treatment (such as lime slurry precipitation and membrane filtration) to meet discharge standards. Treatment costs account for 15-20% of production costs. Some small and medium-sized enterprises simplify treatment processes to reduce costs, leading to the risk of eutrophication in water bodies.

[0007] II. Energy-intensive and low drying efficiency

[0008] In traditional aqueous processes, the dicalcium phosphate slurry produced by the neutralization reaction has a water content as high as 60-80%. After centrifugation, the product needs to be dried by hot air or spray drying to remove the moisture. Taking hot air drying as an example, the inlet air temperature needs to be controlled at 120-150℃, the outlet air temperature at 75-90℃, and the drying time is as long as 2-4 hours, accounting for more than 60% of the total energy consumption of production. At the same time, high-temperature hot air is prone to local overheating, causing some dicalcium phosphate to dehydrate and generate byproducts such as dicalcium pyrophosphate (CaH2P2O7), affecting the purity of the product (the purity is usually only 98.5-99.0%).

[0009] III. Insufficient product purity and quality stability

[0010] In aqueous processes, the neutralization reaction between calcium salts and phosphoric acid is easily affected by localized concentration unevenness, resulting in the formation of dicalcium phosphate containing water of crystallization (such as CaHPO4·2H2O). This necessitates the addition of crystal-directing agents (such as citric acid or tartaric acid) to inhibit water of crystallization, leading to the risk of residual organic impurities. Furthermore, traditional processes use plate and frame filtration or centrifugation for solid-liquid separation, which easily traps mother liquor impurities in the filter cake, requiring multiple washings and further increasing water consumption and process complexity. The final product exhibits a large pH fluctuation range (typically 3.0-6.0), and the heavy metal content (such as Pb and As) is difficult to stably control below 10 ppm, with some indicators failing to meet the requirements of international pharmacopoeias such as USP and EP.

[0011] IV. Complex processes and lengthy production cycles

[0012] A typical water-based process includes: preparation of phosphoric acid solution → preparation of calcium carbonate slurry → staged neutralization → static heat preservation → solid-liquid separation → multiple washing → drying → pulverization and sieving. The entire process takes 8-12 hours. In terms of equipment, multiple sets of equipment such as reactors, filters, and dryers are required, resulting in high investment costs. Furthermore, frequent equipment cleaning and maintenance lead to downtime accounting for 15-20% of the production cycle, limiting the efficiency of large-scale production.

[0013] V. By-product disposal and resource waste issues

[0014] During the neutralization reaction, excessive lime slurry needs to be added to adjust the pH value, leading to an imbalance in the calcium-to-phosphorus ratio and the generation of byproducts such as calcium phosphate (Ca3(PO4)2), reducing the yield of the main product to 90-93%. These byproducts require hazardous waste treatment, further increasing environmental costs. Furthermore, the water and heat recovery rate in the process is less than 30%, which contradicts the trend of green manufacturing.

[0015] In summary, traditional water-based processes have significant drawbacks in terms of environmental protection, energy consumption, product quality, and economic efficiency. There is an urgent need to develop a new preparation process that is low in water consumption, highly efficient, and produces high-purity products to meet the pressing needs of the pharmaceutical excipient industry for high-quality and green production. Summary of the Invention

[0016] The technical problem to be solved by the present invention is to provide a dry production process for preparing pharmaceutical-grade anhydrous dicalcium phosphate, which aims to reduce water consumption, shorten the production cycle, reduce energy consumption, improve product purity, and achieve zero wastewater discharge.

[0017] The technical solution adopted in this invention is: a dry process for preparing pharmaceutical-grade anhydrous dicalcium phosphate, comprising the following steps:

[0018] S1. Equipment preparation: Start the high-shear horizontal twin-shaft reactor, check the operating status of the stirring system, heating device and sensor, and introduce condensate into the condenser tube;

[0019] S2. Feeding: Add a certain weight of food-grade calcium hydroxide powder (particle size ≤50μm, purity ≥99%) to the reactor in batches through a vacuum feeding system. Then, measure 85% food-grade phosphoric acid at 1.5-1.6 times the mass of calcium hydroxide and store it in a phosphoric acid feeding tank with stirring function. Stir evenly and set aside for later use.

[0020] S3, Neutralization reaction: Control the phosphoric acid to be added dropwise to the reactor within 30-40 minutes, with a stirring speed of 40-50 Hz. When the pH value stabilizes at 4.0-5.0 and the moisture content is 3-4%, proceed to the next step.

[0021] S4. Enhanced reaction: Add 0.5-0.6 times the amount of purified water to the reactor, heat with steam to 100°C, and maintain a saturated steam pressure of 0.2-0.25 MPa. Continue the reaction for 30-40 minutes until the moisture content of the sample is <4.5-5% and the material is in a loose granular form.

[0022] S5. Vacuum Belt Drying: Employs a vacuum heat pump belt dryer, using a combined process of "vacuum environment boiling point reduction + heat pump low-temperature heating + thin-layer dense spreading + segmented temperature control": Vacuum boiling point reduction: -0.09MPa vacuum degree (10kPa absolute pressure), reducing the boiling point of water to 45℃, avoiding high-temperature agglomeration of fine powder; Heat pump energy saving: air source heat pump (COP=3.5) + waste heat recovery, reducing heating energy consumption by more than 60%; Thin-layer dense spreading: 50mm material layer thickness (17% less than conventional), balancing the air permeability of fine powder and output; Segmented temperature control: preheating section (35℃) → main drying section (45℃) → deep drying section (40℃), adapting to the requirements of moisture gradient diffusion.

[0023] S6. Mixing and sieving: The dried material is directly fed into a horizontal ribbon mixer (effective volume 2000L, speed 30-40Hz) through a closed pipe and mixed evenly. Then it is sieved through a 100-110 mesh stainless steel screen to remove particles and impurities with a particle size >150μm, and obtain a powder with uniform particles.

[0024] S7. Packaging and Warehousing: After aseptic packaging, the products are stored in a temperature-controlled warehouse.

[0025] S8. Finished product inspection: Testing for content, pH, heavy metals and microbial indicators.

[0026] Preferably, in step S3, after the phosphoric acid is added, stirring continues for a period of time, and samples are taken every 5 minutes to test the pH value and moisture content.

[0027] Preferably, in step S7, the packaging process is as follows: In a clean area, the powder is packed into double-layer PE bags (sterile inner layer, anti-static outer layer), 25kg per bag; Storage: the production batch, date and quality inspection number are marked, and the powder is stored in a constant temperature warehouse (temperature 20±2℃, relative humidity ≤40%), with a shelf life of 24 months.

[0028] Preferably, in step S8, the physicochemical index tests include: content (anhydrous dicalcium phosphate 97.5-102.5%), pH (6.5-7.5), heavy metals (Pb≤10ppm, As≤2ppm); microbial limits: total aerobic bacteria ≤1000cfu / g, molds and yeasts ≤100cfu / g, and no Escherichia coli.

[0029] The beneficial effects of this invention are:

[0030] 1. This invention changes the fundamental process, changing the production process for preparing pharmaceutical-grade anhydrous dicalcium phosphate from an aqueous process to a dry process.

[0031] 2. Compared with existing technologies, the present invention has environmental advantages: the water consumption of the dry reaction is only 1 / 10 of that of the traditional water method, the wastewater discharge is almost zero, the steam condensate can be recycled and reused, achieving zero wastewater discharge and avoiding environmental pollution; the energy consumption of vacuum belt drying is reduced by 1 / 6 compared with flash drying, and the waste gas meets the emission standards after being adsorbed by activated carbon.

[0032] 3. Compared with the prior art, the product of this invention has high purity: no crystal-directing agent is needed, avoiding the introduction of organic impurities; vacuum belt drying reduces ash carryover (ash content ≤ 0.1%), and the purity is 0.5-1.0 percentage points higher than that of commercially available products.

[0033] 4. Compared with the existing technology, the present invention is highly efficient and low-consumption: the equipment is simple, the steps are few, it is energy-saving and efficient, and the time is significantly shortened compared with the traditional process. The total process cycle (including drying) is shortened to about 4.5 hours (the traditional process requires more than 12 hours), and the equipment footprint is reduced by 40%.

[0034] 5. Compared with the prior art, the present invention is safe and stable: In the prior art, taking Xidian as an example, a large amount of alcohol is used and the drying tower is used, which has a high risk factor. In this application, the entire process is carried out in a closed manner, with no risk of dust leakage; the product moisture content fluctuation is <0.3%, which meets the international pharmacopoeia standards such as USP and EP.

[0035] 6. Compared with the prior art, the present invention generates no by-products and has a high recovery and utilization rate of water resources (utilization rate > 90%) and heat energy (utilization rate > 60%) in the process. Attached Figure Description

[0036] Figure 1 This is a block diagram of the process flow in this invention. Detailed Implementation

[0037] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0038] Example 1:

[0039] A dry process for preparing pharmaceutical-grade anhydrous calcium hydrogen phosphate, such as Figure 1 As shown, it includes the following steps:

[0040] S1. Equipment preparation: Start the high-shear horizontal twin-shaft reactor, check the operating status of the stirring system, heating device and sensors, and introduce condensate into the condenser tube.

[0041] Equipment system configuration and parameter calibration:

[0042] Core reaction unit: A high-shear horizontal twin-shaft reactor (made of 316L stainless steel, with polished inner wall Ra≤0.8μm), with an effective volume of 800L and a rotation speed adjustment range of 5-50Hz (corresponding to a stirring linear velocity of 0.3-1.5m / s). The reactor integrates a PT100 platinum resistance temperature sensor (measurement accuracy ±0.5℃), an online pH meter, and a near-infrared moisture analyzer, with data transmitted to the DCS control system in real time.

[0043] Drying unit: Vacuum heat pump belt drying equipment is selected.

[0044] Equipment no-load verification:

[0045] Start the reactor stirring system, gradually increasing the frequency from 5Hz to 50Hz, and run for 30 minutes. Confirm that the bearing temperature rise is <30℃ and the noise is ≤75dB(A).

[0046] Calibrate the pH meter (using 4.0, 6.86, and 10.0 standard buffer solutions, with an error ≤ ±0.02).

[0047] Vacuum belt dryer no-load test run: Vacuum system and heat pump preheating (40 minutes before start-up) and vacuum gradient establishment:

[0048] Start the two-stage Roots vacuum pump unit (main pump power 37kW, backing pump 7.5kW) and evacuate in three stages:

[0049] Phase 1 (0-10 minutes): Pump from atmospheric pressure to -0.05 MPa (removing most of the air); Phase 2 (10-25 minutes): Pump to -0.08 MPa (stabilizing the vacuum environment);

[0050] Phase 3 (25-30 minutes): Evacuate to the target vacuum level of -0.09MPa (absolute pressure 10kPa), the boiling point of water drops to 45℃, and maintain the pressure for 5 minutes to confirm that the leakage rate is ≤0.005MPa / h.

[0051] Heat pump and heating plate preheating: Start the air source heat pump unit (heating capacity 120kW, COP=3.5), and control the heating medium (heat transfer oil) in three stages:

[0052] Preheating section (top layer): 35℃ (slow heating to avoid crusting of fine powder).

[0053] Main drying section (middle layer): 45℃ (core dehydration, matching the boiling point of 45℃);

[0054] Deep drying section (bottom layer): 40℃ (low gradient drying to prevent over-drying and agglomeration).

[0055] The temperature uniformity of the heating plate is controlled by a circulating pump (flow rate 50 m³ / h), with a deviation of ≤ ±1℃.

[0056] S2. Feeding: Add 160kg of powder to the reactor in 6 batches using a vacuum feeder (90 seconds between each batch) to avoid local accumulation. Start the mixer (stirring frequency 25Hz), turn on the dust removal device on the top of the reactor (negative pressure -0.02MPa), and mix for 5 minutes until the powder is loose and fluid. Then, measure 85% food-grade phosphoric acid at 1.52 times the mass of calcium hydroxide (i.e., 243.2kg), store it in a phosphoric acid feeding tank with stirring function, stir evenly, and set aside.

[0057] S3, Neutralization Reaction: Add phosphoric acid dropwise to the reactor over 30 minutes, stirring at 40 Hz. When the pH stabilizes at 4.0-5.0 and the moisture content is 3-4%, proceed to the next step. Key points for the neutralization reaction are as follows:

[0058] Phase 1: Gradient Dropping Reaction. Turn on the phosphoric acid metering pump and use a "slow at first, fast later" gradient flow rate control: 10 L / min for the first 10 minutes, 15 L / min for the middle 10 minutes, and 12 L / min for the last 10 minutes. Simultaneously increase the stirring speed to 40 Hz, turn on the cooling water in the vessel jacket (inlet water temperature 25℃, flow rate 5 m³ / h), and control the reaction temperature ≤ 60℃.

[0059] Phase Two: Dynamic Monitoring and Adjustment. After the phosphoric acid is added, continue stirring for 20 minutes, and take a sample every 5 minutes (using an automatic sampler, with a sample size of 100g / time).

[0060] Moisture content test: Use a moisture meter to dry at a constant temperature of 105℃ until constant weight.

[0061] pH determination: Add water to the dried sample at a ratio of 1:10 and stir to form a suspension for testing. When the pH is stable at 4.5±0.2 and the moisture content is 3.5±0.3% for three consecutive tests, the enhanced reaction stage is entered.

[0062] S4. Enhanced reaction: Add 80kg of purified water or steam condensate recycled water to the reactor, heat the steam to 100℃, 0.2MPa saturated steam, and continue the reaction for 30 minutes until the sample moisture content is <5% and the material is loose granular; the heating process adopts programmed temperature rise: rise from 60℃ to 100℃ within 30 minutes and hold for 30 minutes.

[0063] S5. Vacuum Belt Drying: A vacuum heat pump belt dryer is used to ensure that the moisture content is reduced to below 0.5%; after drying, the material is subjected to a magnetic separator to remove iron impurities. Key control points for vacuum belt drying are as follows:

[0064] Material feeding control: Turn on the twin-screw discharge machine at the bottom of the reactor, and use the vibrating distributor to evenly distribute the material onto the vacuum belt drying conveyor belt (50mm thick).

[0065] Process control: Employing a combination of technologies including "vacuum environment boiling point reduction + heat pump low-temperature heating + thin-layer close-laying + segmented temperature control," with a belt speed of 0.32 m / min.

[0066] Vacuum boiling point reduction: -0.09MPa vacuum (10kPa absolute pressure) lowers the boiling point of water to 45℃, preventing high-temperature agglomeration of 60-micron fine powder;

[0067] Heat pump energy saving: Air source heat pump (COP=3.5) + waste heat recovery reduces heating energy consumption by more than 60%;

[0068] Thin-layer dense application: 50mm material layer thickness, balancing the air permeability of fine powder with output;

[0069] Segmented temperature control: preheating section (35℃) → main drying section (45℃) → deep drying section (40℃), adapting to the needs of gradient moisture diffusion.

[0070] S6. Mixing and sieving: The dried material is directly fed into a horizontal ribbon mixer (effective volume 2000L, speed 30Hz) through a closed pipe and mixed evenly. Then it is sieved through a 100-mesh stainless steel screen to remove particles and impurities with a particle size >50μm, and obtain a powder with uniform particles.

[0071] S7. Packaging and Warehousing: In a clean area, pack the powder into double-layered PE bags (sterile inner layer, anti-static outer layer), 25kg per bag. Storage: Label with production batch, date, and quality inspection certificate number, and store in a temperature-controlled warehouse (temperature 20±2℃, relative humidity ≤40%), with a shelf life of 18 months.

[0072] S8. Finished product inspection: content (anhydrous dicalcium phosphate 97.5-102.5%), pH (6.5-7.5), heavy metals (Pb≤10ppm, As≤2ppm); microbial limits: total aerobic bacteria ≤1000cfu / g, molds and yeasts ≤100cfu / g, no Escherichia coli.

[0073] Table 1 shows a comparison of key data between this embodiment and the traditional water-based process.

[0074] The complete quality inspection report for the product in this embodiment is shown in Table 2.

[0075] Comparative Example 1

[0076] The difference between Comparative Example 1 and Example 1 is that S4 is removed and the reaction steps are enhanced.

[0077] Key process data for this embodiment are shown in Table 1.

[0078] The complete quality inspection report for the product in this embodiment is shown in Table 2.

[0079] The difference between Comparative Example 1 and Example 1 is that the core parameters were changed to set the neutralization reaction endpoint to pH 5.53 and moisture content to 3.6%. The results are shown in Tables 1 and 2.

[0080] As shown in Tables 1 and 2, compared with Example 1, Comparative Example 1 showed uneven reaction in the finished product without the hydrothermal strengthening step.

[0081] Comparative Example 2

[0082] The difference between Comparative Example 2 and Example 1 is that the core parameters were changed: the reaction endpoint pH was set to 5.53, and the moisture content was 3.6%.

[0083] Key process data for this embodiment are shown in Table 1.

[0084] The complete quality inspection report for the product in this embodiment is shown in Table 2.

[0085] As shown in Tables 1 and 2, compared with Example 1, the purity of the product in Comparative Example 2 decreased from 99.92% to 96.9%. After changing the reaction endpoint, the proportion of calcium hydroxide was too high, resulting in too many impurities and too low content in the finished product.

[0086] Comparative Example 3

[0087] The difference between Comparative Example 3 and Example 1 is that the core drying parameters are changed as follows:

[0088] Process control: Employing a combination of technologies including "vacuum environment boiling point reduction + heat pump low-temperature heating + thin-layer dense laying + segmented temperature control," with a belt speed of 0.5 m / min.

[0089] Heat pump: Air source heat pump (COP=4.0);

[0090] Segmented temperature control: preheating section (35℃) → main drying section (55℃) → deep drying section (40℃), adapting to the needs of gradient moisture diffusion.

[0091] Key process data for this embodiment are shown in Table 1.

[0092] The complete quality inspection report for the product in this embodiment is shown in Table 2.

[0093] As shown in Tables 1 and 2, compared with Example 1, Comparative Example 3 showed the following: Energy consumption increased: Drying energy consumption increased from 35-45 kWh / ton to about 120 kWh / ton. Other test results were not significantly different, but the moisture content fluctuated greatly: The results of the three experiments were 0.7%, 1.2%, and 1.9%, respectively.

[0094] Table 1. Comparison of key data between Example 1 and Comparative Examples 1-3 and traditional water-based processes.

[0095]

[0096] Table 2. Full Quality Inspection Reports for Examples 1 and Comparative Examples 1-3

[0097]

[0098] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of protection of the claims.

Claims

1. A process for the production of pharmaceutical grade anhydrous dibasic calcium phosphate prepared by dry process, characterized by: It comprises the following steps: S1, equipment preparation: start the high shear horizontal double shaft reaction kettle, check the operation state of the stirring system, heating device and sensor, and pass cold water into the condenser tube; S2, feeding: a certain weight of food grade calcium hydroxide powder (particle size ≤50 μm, purity ≥99%) is added into the reaction kettle in batches through the vacuum feeding system, then 85% food grade phosphoric acid is measured at 1.5-1.6 times the mass of calcium hydroxide, stored in a phosphoric acid feeding bucket with stirring function, stirred uniformly, and standby; S3, neutralization reaction: control the drop of phosphoric acid into the reaction kettle within 30-40 minutes, the stirring speed is 40-50 Hz, when the pH value is stable at 4.0-5.0 and the moisture content is 3-4%, the next step is entered; S4, strengthening reaction: add 0.5-0.6 times the amount of purified water to the reaction kettle, steam heating to 100℃, saturated steam pressure is 0.2-0.25 MPa, continue to react for 30-40 minutes, until the moisture content of the sample is <4.5-5%, and the material is loose granular; S5, vacuum belt drying: vacuum heat pump belt dryer is used, and the combined process of "vacuum environment boiling point reduction + heat pump low temperature heating + thin layer dense packing + segmented temperature control" is adopted: vacuum boiling point reduction: vacuum degree is-0.09 MPa, which reduces the boiling point of water to 45℃; heat pump energy saving: air source heat pump (COP=3.5) + waste heat recovery; thin layer dense packing: 50 mm layer thickness; segmented temperature control: preheating section 35℃→main drying section 45℃→deep drying section 40℃; S6, mixing and sieving: the dried material is directly mixed in a horizontal screw belt mixer through airtight pipeline, then sieved through a 100-110 mesh stainless steel screen to remove particles with a particle size >150 μm and impurities, and a powder with uniform particles is obtained; S7, packaging and storage: after sterile packaging, store in a constant temperature warehouse; S8, finished product inspection: detect content, pH, heavy metal and microbial indicators.

2. A process for the dry preparation of pharmaceutical grade anhydrous dibasic calcium phosphate as claimed in claim 1, wherein: In step S3, after the phosphoric acid feeding is completed, continue to stir for a period of time, and detect the pH value and moisture every 5 minutes.

3. A process for the dry process production of pharmaceutical grade anhydrous dibasic calcium phosphate as claimed in claim 1, wherein: In step S7, the packaging process is as follows: in the clean area, fill the powder into double-layer PE bags (inner layer sterile, outer layer anti-static), 25 kg per bag; storage: mark the production batch, date and quality inspection number, and store in a constant temperature warehouse (temperature 20±2℃, relative humidity ≤40%), shelf life 24 months.

4. A process for the dry process production of pharmaceutical grade anhydrous dibasic calcium phosphate as claimed in claim 1, wherein: In step S8, the physical and chemical index inspection includes: content (anhydrous calcium hydrogen phosphate 97.5-102.5%), pH (6.5-7.5), heavy metal (Pb ≤10 ppm, As ≤2 ppm); microbial limit: total number of aerobic bacteria ≤1000 cfu / g, mold and yeast ≤100 cfu / g, no E. coli.

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