Preparation method of macroporous silica with large pore volume for pharmaceutical adjuvant

Abstract

The present application belongs to the technical field of silica material preparation, and relates to a preparation method of macroporous volume silica for medical excipients, comprising the following steps: S1, dissolving solid high-purity water glass in a reaction kettle A under the condition of 200-500 DEG C and 1-2 Mpa, adding an inorganic treating agent to filter, and then adding water to dilute to obtain a water glass solution; S2, raising the temperature of a reaction kettle B to 120-200 DEG C and the pressure to 0.3-0.6 Mpa, adding the water glass solution and sulfuric acid into the reaction kettle B at the same time, stirring, adjusting the pH to be alkaline, stopping the stirring after the addition is completed, dispersing and emulsifying again to form a gel; S3, adding the gel into sulfuric acid to adjust the pH to be neutral, lowering the pressure and temperature of the reaction kettle B to age, adding sulfuric acid to adjust the pH to be acidic after the aging is completed, aging, then washing to obtain a silica slurry; S4, spray drying the slurry, and crushing to obtain the product. The silica synthesized by the present application has the advantages of large pore volume, low total number of aerobic bacteria, low sulfate content, few spots, and high silica content, and can be better applied in the medical field.

Description

Technical Field

[0001] This invention belongs to the technical field of silica material preparation, specifically relating to a method for preparing macroporous silica for pharmaceutical excipients. Background Technology

[0002] Organosilicon products include silane coupling agents, silicone oils, silicone rubbers, and silicone resins, which are widely used in construction, electronics, textile dyeing and finishing, automotive, machinery, leather, and papermaking industries. Inorganic silicon products include monocrystalline silicon, polycrystalline silicon, silicon tetrachloride, and pharmaceutical excipient silica (commonly known as micronized silica gel). Pharmaceutical excipient silica has the structural formula mSiO2:nH2O. It is a white powder with good flowability, high purity, and no pollution. It features small particle size, large specific surface area, and numerous pores. The silanol groups distributed on its surface also give it excellent adsorption properties. Adding silica can effectively improve the quality and performance of pharmaceutical preparations, especially tablets, significantly enhancing the market competitiveness of drugs. Its application in pharmaceutical preparations has received increasing attention.

[0003] The structure-activity relationship of silica used in pharmaceutical excipients is as follows: First, its particle size is very small, allowing silica particles to be fully accommodated between drug particles. This filling method reduces the interaction forces between drug particles, improving drug flowability and providing lubrication and flow-aiding effects. Silica also effectively prevents material from sticking to the punch surface during tableting, facilitating tablet ejection, preventing tablet breakage, and ensuring smooth tableting operations, thus acting as an anti-adhesion agent. Second, its specific surface area is typically greater than 100 m² / g. 2 With a surface activity of / g, it can produce significant adsorption and can be used as an adsorbent or oil absorbent; thirdly, the surface of pharmaceutical excipient silica is rich in hydroxyl groups, resulting in a very small contact angle, which gives it good hydrophilic properties. Therefore, silica is widely used in the field of pharmaceutical excipients.

[0004] Chinese patent CN201610172009 discloses a method for preparing silica for pharmaceutical excipients. The method involves adding sulfuric acid to sodium silicate as a raw material, controlling the amount of sulfuric acid added to control the porosity of the silica, and then proceeding through synthesis, washing, refining, and drying to obtain silica for pharmaceutical excipients. The resulting silica has a content of over 99.5% and a pore volume of 1.6–2.0 ml / g. However, the silica synthesized by this method has a small pore volume, resulting in poor flowability in pharmaceutical systems, low tablet forming rate, and poor taste, thus affecting the production efficiency and product quality of pharmaceutical companies. Furthermore, this method does not describe the application performance of the silica used as a pharmaceutical excipient. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for preparing macroporous silica for pharmaceutical excipients. The silica prepared by this invention has large pore volume, low total aerobic bacteria count, low sulfate content, and low spot count, exhibiting excellent adsorption and flowability in the field of pharmaceutical excipients, and has been successfully applied in the pharmaceutical excipient field.

[0006] The primary objective of this invention is to provide a method for preparing macroporous silica for pharmaceutical excipients. To achieve this objective, the technical solution adopted by this invention is as follows:

[0007] A method for preparing macroporous silica for pharmaceutical excipients includes the following steps:

[0008] S1. Under the conditions of temperature of 200℃~500℃ and pressure of 1Mpa~2Mpa, solid high-purity water glass is placed in reaction vessel A for dissolution, inorganic treatment agent is added for filtration, and then water is added for dilution to obtain water glass solution.

[0009] S2. Under the conditions of heating reactor B to 120℃~200℃ and pressure of 0.3Mpa~0.6Mpa, add the water glass solution obtained in step S1 and sulfuric acid to reactor B at the same time, stir in parallel flow, adjust the pH value to be alkaline, stop stirring after the parallel flow is completed, and then disperse and emulsify to form silica gel.

[0010] S3. Add sulfuric acid to the silica gel obtained in step S2 to adjust the pH value to neutral. Reduce the pressure and temperature of reaction vessel B and age it. After aging, add sulfuric acid to adjust the pH value to acidic and age it. Then wash it to obtain silica slurry.

[0011] S4. Spray dry and pulverize the silica slurry described in step S3 to obtain macroporous silica for pharmaceutical excipients.

[0012] In step S1, the high-purity water glass silica modulus is 3.00 to 3.30, the Fe element content is ≤15ppm, the Al element content is ≤1ppm, the Ca element content is ≤1ppm, the Mg element content is ≤1ppm, and the solid water glass solubility is ≥99.8%.

[0013] Preferably, the inorganic treatment agent in step S1 is one of diatomaceous earth, precipitated silica, fumed silica, and silica gel, and the amount used is 2wt%-5wt% of the water glass silica content.

[0014] Preferably, the silica concentration of the water glass solution in step S2 is 10wt% to 20wt%, and the sulfuric acid concentration is 5wt% to 15wt%.

[0015] Preferably, the reactor B in step S2 is a pressure-controlled reactor with an emulsification pump.

[0016] Preferably, the pH value in step S2 is 10 to 12.

[0017] Preferably, the stirring frequency in step S2 is 40-50 Hz, and the co-current time is controlled between 90 min and 120 min.

[0018] Preferably, the emulsification speed in step S2 is 10,000 rpm to 20,000 rpm, and the emulsification time is 10 min to 30 min.

[0019] Preferably, step S3 involves adjusting the pH to a neutral value of 6.8–7.2 and an acidic value of 3.0–5.0.

[0020] Preferably, the pressure reduction in step S3 is 101 kPa to 105 kPa, the cooling temperature is 80°C to 100°C, the aging time is 90 min to 120 min, and the maturation time is 30 min to 60 min.

[0021] Preferably, the washing process in step S3 uses pure water at a temperature of 50℃~80℃ and an edible alkali solution with a concentration of 0.01wt%~0.05wt%, and the washing time is controlled at 5h~8h. The washing is carried out in the order of pure water, edible alkali solution, and pure water, with a time interval ratio of 3:1:6. The edible alkali is either sodium carbonate or sodium bicarbonate. The washing is carried out until the conductivity is below 50us / cm.

[0022] Preferably, the pulverization method in step S4 is airflow pulverization.

[0023] Preferably, the silica content in step S4 is greater than 99.5%, and the porosity is 2.00–2.30 cm⁻¹. 3 / g, pH 6.0–8.0, total aerobic bacteria count less than 200 cfu / g, sulfate content less than 0.5%, spots less than 5 / dm³ 2 .

[0024] The silica particles synthesized in this application have large pore volume and high purity, and exhibit good flowability and adsorption properties in pharmaceutical excipients.

[0025] Compared with the prior art, the beneficial effects of the present invention are:

[0026] (1) Before preparing high-purity water glass, the water glass needs to be purified. The inorganic treatment agent for high-purity water glass is one of diatomaceous earth, precipitated silica, fumed silica, and silica gel. Diatomaceous earth, precipitated silica, fumed silica, and silica gel all have large pore volumes, which can adsorb insoluble impurities and trace elements in high-purity water glass. The main component of the inorganic treatment agent used is also silica, which can reduce the introduction of impurities.

[0027] (2) The reaction is carried out under the conditions of pressure of 0.3 to 0.6 MPa, temperature of 120 to 200 °C and pH of 10.0 to 12.0. High temperature and pressure and high pH can increase the rate of silica formation, and the generated silica particles are larger in size and have larger pore volume.

[0028] (3) The emulsification speed of the emulsification pump in reactor B of this application is 10,000 to 20,000 rpm. The emulsification pump can emulsify the generated primary silica particles uniformly, prevent secondary agglomeration of primary silica particles, and further ensure that the synthesized silica particles are uniform in size, which helps the flow-aiding effect of pharmaceutical silica.

[0029] (4) The edible alkali solution washing of this application can increase the pH of pharmaceutical silica. The edible alkali solution washing ensures that the pH of silica reaches near neutral and does not introduce other impurities. The washing sequence of pure water, edible alkali solution and pure water with time intervals of 3:1:6 not only saves water washing amount, but also increases the pore volume of silica particles to a certain extent. Detailed Implementation

[0030] The technical solution of the present invention will be clearly and completely described below with reference to embodiments and comparative examples. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0031] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; the materials and reagents used are commercially available unless otherwise specified.

[0032] Example 1

[0033] A method for preparing macroporous silica for pharmaceutical excipients includes the following steps:

[0034] Maintaining a temperature of 200℃ and a pressure of 2 MPa, solid high-purity sodium silicate (high-purity water glass with a silica modulus of 3.00–3.30, Fe content ≤15 ppm, Al content ≤1 ppm, Ca content ≤1 ppm, Mg content ≤1 ppm, and solid water glass solubility ≥99.8%) was simultaneously added to reactor A for dissolution. After dissolution, the water glass was filtered through a plate filter with 5 wt% diatomaceous earth (containing the silica content of the high-purity water glass) to remove impurities. The filtered high-purity water glass was diluted to 20 wt%. After dilution, under conditions of 200℃ and 0.3 MPa, high-purity water glass with a silica concentration of 20 wt% and sulfuric acid with a concentration of 15 wt% were simultaneously added to reactor B. The mixture was stirred and flowed concurrently for 90 minutes, with the pH maintained at 12. The stirring was stopped after the flow was completed at a speed of 50 Hz. The emulsification pump was then turned on, and the emulsification speed was adjusted to 10,000 RPM. Emulsification was carried out for 30 minutes. After dispersion and emulsification, 15 wt% sulfuric acid was added to adjust the pH to 7.0, the pressure was reduced to 101 kPa, and the temperature was reduced to 80℃. The mixture was then aged for 90 minutes. After aging, 15 wt% sulfuric acid was added at the same temperature to adjust the pH to 3.0 and the mixture was aged for 60 minutes. After aging, the mixture was pumped into a filter press frame for washing. The washing sequence of the filter cake was 80℃ pure water, 0.05 wt% sodium carbonate solution, and 80℃ pure water, with a time interval ratio of 3:1:6. The washing time was 5 hours. The silica slurry was washed until the conductivity was 48 μS / cm. After washing, the resulting slurry was spray-dried and air-jet pulverized to obtain macroporous silica for pharmaceutical excipients.

[0035] Test methods and standards for the physicochemical properties of products:

[0036] (1) Porosity test: TriStar II 3020 fully automatic specific surface area and porosity analyzer;

[0037] (2) Silicon dioxide content: Silicon dioxide was dissolved using hydrofluoric acid and then calculated using the difference method;

[0038] (3) Number of spots: The sample is laid flat on a clean white paper, and the number of obvious black spots is visually counted using a flat glass plate;

[0039] (4) pH test: Take 1g of sample, add 20ml of water, shake, filter, and then test with Leici PHS-3C.

[0040] (5) Total aerobic bacteria count: Take 1g of sample and culture it on tryptic soy peptone agar medium for 72 hours to determine the total aerobic bacteria count;

[0041] (6) Sulfate: Take 10 ml of the filtrate from the chloride section and place it in a 50 ml Nessler tube for colorimetric comparison; the physicochemical properties of the seven parallel products are shown in Table 1.

[0042] Table 1

[0043]

[0044] Note: The total aerobic bacteria count is tested using a method provided internally by the pharmaceutical auxiliary company.

[0045] Example 2

[0046] A method for preparing macroporous silica for pharmaceutical excipients includes the following steps:

[0047] Maintaining a temperature of 300℃ and a pressure of 1.5 MPa, solid high-purity sodium silicate was simultaneously added to reactor A for dissolution. After dissolution, the water glass was filtered through a plate filter with 4 wt% silica gel (containing high-purity water glass) to remove impurities. The filtered high-purity water glass was diluted to 15 wt%. After dilution, at a temperature of 180℃ and a pressure of 0.5 MPa, high-purity water glass with a silica concentration of 15 wt% and sulfuric acid with a concentration of 10 wt% were simultaneously added to reactor B. The co-flow time was 100 minutes, the co-flow pH was maintained at 12, and the stirring speed was 40 Hz. After the co-flow was completed, stirring was stopped, and the emulsification pump was turned on, adjusting the emulsification speed to 15000 RPM for emulsification. After 30 minutes of dispersion and emulsification, 10wt% sulfuric acid was added to adjust the pH to 6.9, the pressure was reduced to 102 kPa, and the temperature was reduced to 80℃. The mixture was then aged for 90 minutes. After aging, 10wt% sulfuric acid was added at the same temperature to adjust the pH to 3.0, and the mixture was aged for 45 minutes. After aging, the mixture was pumped into a filter press frame for washing. The filter cake was washed in the following order: 80℃ pure water, 0.04wt% sodium carbonate solution, and 80℃ pure water. The time interval ratio was 3:1:6, and the washing time was 6 hours. The silica slurry was washed until the conductivity was 37 μS / cm. After washing, the resulting slurry was spray-dried and air-jet pulverized to obtain macroporous silica for pharmaceutical excipients.

[0048] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 2.

[0049] Table 2

[0050]

[0051] Example 3

[0052] A method for preparing macroporous silica for pharmaceutical excipients includes the following steps:

[0053] Maintaining a temperature of 380℃ and a pressure of 1.7 MPa, solid high-purity sodium silicate was simultaneously added to reactor A for dissolution. After dissolution, the water glass was filtered through a plate filter to remove impurities by adding 5 wt% high-purity water glass containing silica precipitate. The filtered high-purity water glass was diluted to 18 wt%. After dilution, at a temperature of 150℃ and a pressure of 0.4 MPa, high-purity water glass with a silica concentration of 18 wt% and sulfuric acid with a concentration of 12 wt% were simultaneously added to reactor B. The co-flow time was 110 minutes, the co-flow pH was maintained at 11, and the stirring speed was 40 Hz. After the co-flow was completed, stirring was stopped, and the emulsification pump was turned on, adjusting the emulsification speed to 16000 RPM. Emulsify for 30 minutes, disperse and emulsify, then add 12wt% sulfuric acid to adjust the pH to 7.0, reduce the pressure to 104 kPa, and age for 90 minutes at 90℃. After aging, add 12wt% sulfuric acid at the same temperature to adjust the pH to 4.0 and age for 45 minutes. After aging, pump the filter cake into a filter press frame for washing. Wash the filter cake in the following order: 80℃ pure water, 0.04wt% sodium carbonate solution, and 80℃ pure water, with a time interval ratio of 3:1:6. The washing time is 6 hours. Wash the silica slurry until the conductivity is 42 μS / cm. After washing, spray dry and air jet mill the resulting slurry to obtain macroporous silica for pharmaceutical excipients.

[0054] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 3.

[0055] Table 3

[0056]

[0057] Example 4

[0058] A method for preparing macroporous silica for pharmaceutical excipients includes the following steps:

[0059] Maintaining a temperature of 260℃ and a pressure of 1.8 MPa, solid high-purity sodium silicate was simultaneously added to reactor A for dissolution. After dissolution, the water glass was filtered through a plate filter to remove impurities by adding 4 wt% fumed silica (containing high-purity water glass). The filtered high-purity water glass was diluted to 14 wt%. After dilution, at a temperature of 150℃ and a pressure of 0.4 MPa, high-purity water glass with a silica concentration of 14 wt% and sulfuric acid with a concentration of 9 wt% were simultaneously added to reactor B. The co-flow time was 100 minutes, the co-flow pH was maintained at 10, and the stirring speed was 50 Hz. After the co-flow was completed, stirring was stopped, and the emulsification pump was turned on, adjusting the emulsification speed to 15000 RPM. Emulsify for 30 minutes, disperse and emulsify, then add 9wt% sulfuric acid to adjust the pH to 7.1, reduce the pressure to 101 kPa, and age for 90 minutes at 85℃. After aging, add 9wt% sulfuric acid at the same temperature to adjust the pH to 4.2 and age for 60 minutes. After aging, pump the filter cake into a filter press frame for washing. Wash the filter cake in the following order: 50℃ pure water, 0.03wt% sodium bicarbonate solution, and 50℃ pure water, with a time interval ratio of 3:1:6. The washing time is 7 hours. Wash the silica slurry until the conductivity is 39 μS / cm. After washing, spray dry and air jet mill the resulting slurry to obtain macroporous silica for pharmaceutical excipients.

[0060] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 4.

[0061] Table 4

[0062]

[0063] Example 5

[0064] A method for preparing macroporous silica for pharmaceutical excipients includes the following steps:

[0065] Maintaining a temperature of 430℃ and a pressure of 2 MPa, solid high-purity sodium silicate was simultaneously added to reactor A for dissolution. After dissolution, the water glass was filtered through a plate filter with diatomaceous earth containing 3.8 wt% silica to remove impurities. The filtered high-purity water glass was diluted to 19 wt%. After dilution, under conditions of 180℃ and 0.5 MPa, high-purity water glass with a silica concentration of 19 wt% and sulfuric acid with a concentration of 13 wt% were simultaneously added to reactor B. The co-flow time was 120 minutes, the co-flow pH was maintained at 12, and the stirring speed was 50 Hz. After the co-flow was completed, stirring was stopped, and the emulsification pump was turned on, adjusting the emulsification speed to 19000 RPM for emulsification. After 25 minutes of dispersion and emulsification, 13wt% sulfuric acid was added to adjust the pH to 6.9, the pressure was reduced to 102 kPa, and the temperature was reduced to 96℃. The mixture was then aged for 110 minutes. After aging, 13wt% sulfuric acid was added at the same temperature to adjust the pH to 3.5, and the mixture was aged for 60 minutes. After aging, the mixture was pumped into a filter press frame for washing. The filter cake was washed in the following order: 70℃ pure water, 0.03wt% sodium bicarbonate solution, and 70℃ pure water. The time interval ratio was 3:1:6, and the washing time was 5 hours. The silica slurry was washed until the conductivity was 46 μS / cm. After washing, the resulting slurry was spray-dried and air-jet pulverized to obtain macroporous silica for pharmaceutical excipients.

[0066] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 5.

[0067] Table 5

[0068]

[0069] Example 6

[0070] A method for preparing macroporous silica for pharmaceutical excipients includes the following steps:

[0071] Maintaining a temperature of 300℃ and a pressure of 2 MPa, solid high-purity sodium silicate was simultaneously added to reactor A for dissolution. After dissolution, the water glass was filtered through a plate filter with 4.2 wt% silica gel to remove impurities. The filtered high-purity water glass was diluted to 17 wt%. After dilution, under conditions of 200℃ and 0.6 MPa, high-purity water glass with a silica concentration of 17 wt% and sulfuric acid with a concentration of 11 wt% were simultaneously added to reactor B. The co-flow time was 100 minutes, the co-flow pH was maintained at 11, and the stirring speed was 50 Hz. After the co-flow was completed, stirring was stopped, the emulsification pump was turned on, and the emulsification speed was adjusted to 17000 RPM for emulsification. After 20 minutes of dispersion and emulsification, 11 wt% sulfuric acid was added to adjust the pH to 6.8, the pressure was reduced to 105 kPa, and the temperature was reduced to 84°C. The mixture was then aged for 110 minutes. After aging, 11 wt% sulfuric acid was added at the same temperature to adjust the pH to 3.5, and the mixture was aged for 50 minutes. After aging, the mixture was pumped into a filter press frame for washing. The filter cake was washed in the following order: 80°C pure water, 0.05 wt% sodium bicarbonate solution, and 80°C pure water. The time interval ratio was 3:1:6, and the washing time was 7 hours. The silica slurry was washed until the conductivity was 33 μS / cm. After washing, the resulting slurry was spray-dried and air-jet pulverized to obtain macroporous silica for pharmaceutical excipients.

[0072] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 6.

[0073] Table 6

[0074]

[0075] Comparative Example 1

[0076] The difference from Example 1 is that diatomaceous earth with a silica content of 5w% and no high-purity water glass is added, and the water glass is filtered through a plate filter to remove impurities. Other operations are the same as in Example 1.

[0077] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 7.

[0078] Table 7

[0079]

[0080]

[0081] Comparative Example 2

[0082] The difference from Example 1 is that, under conditions of 220°C and 0.7 MPa, high-purity water glass with a silica concentration of 20 wt% and sulfuric acid with a concentration of 15 wt% were simultaneously added to reactor B with stirring and flow. Other operations were the same as in Example 1. The physicochemical properties of the products were tested using the same methods and standards as in Example 1. The physicochemical properties of the seven parallel products are shown in Table 8.

[0083] Table 8

[0084]

[0085] Comparative Example 3

[0086] The difference from Example 1 is that the concurrent flow pH is 9.1, while other operations are the same as in Example 1. The testing methods and standards for the physicochemical properties of the products are the same as in Example 1, and the physicochemical properties of the seven parallel products are shown in Table 9.

[0087] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 9.

[0088] Table 9

[0089]

[0090] Comparative Example 4

[0091] The difference from Example 1 is that, after the co-flow is completed, the speed of the emulsifying pump is adjusted to 9000 RPM; other operations are the same as in Example 1. The test methods and standards for the physicochemical properties of the products are the same as in Example 1, and the physicochemical properties of the seven parallel products are shown in Table 10.

[0092] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 10.

[0093] Table 10

[0094]

[0095]

[0096] Comparative Example 5

[0097] The difference from Example 1 is that 15 wt% sulfuric acid was added after dispersion and emulsification to adjust the pH to 6.1; other operations were the same as in Example 1. The physicochemical properties of the product were tested using the same methods and standards as in Example 1. The physicochemical properties of the seven parallel products are shown in Table 11.

[0098] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 11.

[0099] Table 11

[0100]

[0101] Comparative Example 6

[0102] The difference from Example 1 is that the washing sequence of the filter cake was 80°C pure water, 0.05wt% sodium carbonate solution, and 80°C pure water, with a time interval ratio of 2:2:6. Other operations were the same as in Example 1. The physicochemical properties of the product were tested using the same methods and standards as in Example 1, and the physicochemical properties of the seven parallel products are shown in Table 12.

[0103] The testing methods and standards for the physical and chemical properties of the products are the same as in Example 1. The physical and chemical properties of the seven parallel products are shown in Table 12.

[0104] Table 12

[0105]

[0106] Results Analysis

[0107] The test data from the above six embodiments show that the physical properties of the products produced according to the technical solution of the present invention are basically similar, indicating that the technical solution is stable in production.

[0108] Comparative Example 1 shows that when diatomaceous earth without 5% silica is used to filter water glass through a plate filter to remove impurities, the silica content and porosity of the product in the example are significantly lower, while the total number of aerobic bacteria, sulfate, and the number of spots are significantly increased. This indicates that diatomaceous earth can mainly adsorb insoluble impurities and trace elements in high-purity water glass. Without diatomaceous earth, the amount of impurities increases, and the growth of silica pore volume is limited to a certain extent.

[0109] In addition, compared with Example 1, when the pressure of reactor B was increased to 0.7 MPa and the temperature was increased to 220°C, the porosity of the product was significantly reduced, while the total number of aerobic bacteria and the number of spots were significantly increased. This indicates that under the conditions of exceeding the limit of temperature and pressure, the total volume of the primary silica pore structure becomes smaller, which leads to a decrease in porosity and thus reduces the adsorption efficiency of the formed silica particles themselves.

[0110] Comparative Example 3 reduced the co-current pH value to 9.1, which is below the lower limit of the specified conditions. The porosity of the product decreased significantly, while the total number of aerobic bacteria and the number of spots increased significantly. The main reason is that the strength of the alkalinity of the pH value reflects the concentration of hydroxide ions in the solution. Hydroxide ions will react with hydrogen ions. Within a certain concentration range, hydroxide ions cause silica to expand its pores, making its porosity larger. However, if the concentration of hydroxide ions is too high or too low, it will cause shrinkage.

[0111] Comparative Example 4 reduced the emulsifying pump speed to 9000 RPM. The porosity of the product decreased slightly, while the total number of aerobic bacteria and the number of spots increased slightly. However, the sulfate concentration increased significantly. This indicates that when the speed of the emulsifying pump is lower than the lower limit of the specified speed, the collision efficiency between primary silica particles decreases, which in turn triggers the porosity effect of secondary particles. Sulfate in the solution is more sensitive to the pore volume structure of secondary silica particles, and sulfate impurities will penetrate into it, ultimately leading to an increase in sulfate concentration.

[0112] In Comparative Example 5, after dispersion and emulsification, 15 wt% sulfuric acid was added to adjust the pH to 6.1. The porosity of the product decreased, the total number of aerobic bacteria and the number of spots increased slightly, and the sulfate concentration increased significantly. This was mainly because the silica particles formed under this pH condition were smaller, the silica particle production rate was slower, and the resulting porosity was smaller. Under this condition, the washing difficulty increased, leading to a significant increase in sulfate concentration.

[0113] Comparative Example 6 had time intervals of 2:2:6. The amount of edible alkali used was doubled compared to the previous amount. The porosity and number of spots of the product were not significantly affected, and the total number of aerobic bacteria was further reduced. However, the pH of the product was significantly increased. This was mainly because the amount of edible alkali used was increased, which greatly increased the pH of the solution. In addition, the silica pores formed were larger. Under the condition that the sulfate level met the standard, some of the alkali solution would remain in the silica pores, which ultimately caused the pH of the silica to exceed the standard.

[0114] By comparing the physicochemical properties of the embodiments and comparative examples, it can be seen that only the synergistic combination of various conditions can achieve the technical effect of the present invention.

[0115] Application performance testing

[0116] The performance indicators of three pharmaceutical excipient silica products 1-3, 3-3, and 5-3 prepared using the present invention, and comparative examples 1-3, 3-3, and 5-3, were compared with those of Grace 244FP:

[0117] Table 12

[0118]

[0119]

[0120] Comparing the three samples of Examples 1-3, 3-3, and 5-3, the three samples of Comparative Examples 1-3, 3-3, and 5-3, and Grace 244FP, the silica for pharmaceutical excipients synthesized by the method of this invention has a porosity and pH close to that of Grace 244FP. Among them, the experimental product has better control of aerobic bacteria count, lower sulfate content, fewer spots, and higher silica content, and can be better applied in the pharmaceutical field.

[0121] Obviously, the above embodiments of the present invention are merely examples to clearly illustrate the technical solution of the present invention, and are not intended to limit the specific implementation of the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the claims of the present invention should be included within the protection scope of the claims of the present invention.

Claims

1. A method for preparing macroporous silica for pharmaceutical excipients, characterized in that, Includes the following steps: S1. Under the conditions of temperature of 200℃~500℃ and pressure of 1 MPa~2 MPa, solid high-purity water glass is dissolved in reaction vessel A, inorganic treatment agent is added and filtered, and then water is added to dilute to obtain water glass solution. S2. Heat reactor B to 120℃~200℃ and pressure to 0.3 MPa~0.6 MPa. Add the water glass solution obtained in step S1 and sulfuric acid to reactor B simultaneously and stir in parallel. Adjust the pH value to be alkaline. After the parallel flow is completed, stop stirring and then disperse and emulsify to form silica gel. S3. Add sulfuric acid to the silica gel obtained in step S2 to adjust the pH value to neutral. After depressurizing and cooling the reactor B, age it. After aging, add sulfuric acid to adjust the pH value to acidic and age it. Then wash to obtain silica slurry. S4. Spray dry and pulverize the silica slurry obtained in step S3 to obtain the final product. In step S1, the high-purity water glass has a modulus of 3.00~3.30, an Fe element content of ≤15 ppm, an Al element content of ≤1 ppm, a Ca element content of ≤1 ppm, a Mg element content of ≤1 ppm, and a solid water glass solubility of ≥99.8%. The inorganic treatment agent mentioned in step S1 is one of diatomaceous earth, precipitated silica, fumed silica, and silica gel, and the amount used is 2 wt%-5 wt% of the silica content of water glass. In step S2, the pH value is adjusted to an alkaline value of 10-12, the emulsification speed is 10000 rpm-20000 rpm, and the emulsification time is 10 min-30 min. Step S3 involves adjusting the pH to a neutral value of 6.8-7.2 and an acidic value of 3.0-5.

0. The washing process in step S3 involves using pure water at a temperature of 50℃~80℃ and an edible alkali solution with a concentration of 0.01 wt%~0.05 wt%. The washing time is controlled at 5h~8h, and the washing is performed in the order of pure water, edible alkali solution, and pure water, with a time interval ratio of 3:1:

6. The edible alkali is either sodium carbonate or sodium bicarbonate. The washing continues until the conductivity is below 50 μS / cm.

2. The preparation method according to claim 1, characterized in that, The silica concentration of the water glass solution in step S2 is 10 wt%~20 wt%, and the sulfuric acid concentration is 5 wt%~15 wt%.

3. The preparation method according to claim 1, characterized in that, The stirring frequency in step S2 is 40~50Hz, and the co-current time is 90 min~120 min.

4. The preparation method according to claim 1, characterized in that, Step S3 involves depressurizing to 101 Kpa~105 Kpa, cooling to 80℃~100℃, aging for 90 min~120 min, and maturing for 30 min~60 min.

5. A macroporous silica for pharmaceutical excipients prepared by the method of claim 1, characterized in that, The silica content is greater than 99.5%, and the porosity is 2.00~2.30 cm³. 3 / g, pH 6.0~8.0, total aerobic bacteria count less than 200 cfu / g, sulfate content less than 0.5%, spots less than 5 / dm³ 2 .

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