A method for preparing high density human aluminum hydroxide adjuvant by hydrolysis of aluminum alcohol

Abstract

This invention discloses a method for preparing highly dense human aluminum hydroxide adjuvants via aluminum alkoxide hydrolysis, belonging to the field of biopharmaceutical and vaccine formulation technology. This invention uses linear C2-C4 alkyl-substituted sterically hindered aluminum alkoxides as the sole aluminum source, employing an alcohol-aprotic inert solvent dual-solvent system, combined with a composite directing agent containing hydrolysis inhibitors and crystal plane directing agents. The water-aluminum molar ratio is controlled at 3:1 to 10:1, and hydrolysis is carried out at 60℃ to 98℃, eliminating the need for high-temperature and high-pressure crystallization treatment. A single hydrolysis reaction directly yields boehmite-type highly dense human aluminum hydroxide adjuvants with a crystallinity ≥50%. This invention overcomes long-standing technical biases in the field, featuring a simple process, low energy consumption and raw material costs, and a product with excellent antigen adsorption performance and storage stability. It is easily scaled up using GMP and adaptable to the needs of various human vaccine preparations.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine and vaccine formulation technology, specifically relating to a method for preparing inorganic adjuvants for human vaccines, and more specifically, to a method for synthesizing highly dense human aluminum hydroxide vaccine adjuvants by low-temperature controllable hydrolysis of linear, sterically hindered aluminum alkoxides. Background Technology

[0002] Aluminum hydroxide adjuvants are currently the most widely used inorganic adjuvants for human vaccines worldwide. Among them, boehmite (γ-AlOOH) type aluminum hydroxide has become the core development direction for new vaccine adjuvants due to its good structural stability, strong antigen adsorption capacity, and excellent batch-to-batch quality controllability. Its performance directly determines the immunization effect, storage stability, and clinical safety of the vaccine.

[0003] In existing technologies, the preparation of boehmite-type aluminum hydroxide adjuvants mainly falls into two core pathways. The first is the traditional alkaline precipitation method, which involves the neutralization reaction of inorganic aluminum salts with alkaline solutions. The resulting product is mainly amorphous aluminum hydroxide gel with low crystallinity and a loose structure. It requires long-term aging or high-temperature treatment to transform into the boehmite crystalline phase. The reaction process has poor controllability, and the particle size and crystallinity of the product fluctuate greatly between batches, making it difficult to meet the regulatory consistency requirements for human vaccines. The second is the conventional aluminum alkoxide hydrolysis method. Existing schemes mostly use branched aluminum alkoxides such as aluminum isopropoxide and sterically hindered aluminum alkoxides such as aluminum tert-butoxide as precursors. Among them, the hydrolysis rate of branched aluminum isopropoxide with small steric hindrance is too fast, which easily forms amorphous aluminum hydroxyl clusters. High-temperature and high-pressure hydrothermal treatment above 150°C is required to obtain high-crystallinity boehmite. This method is not only energy-intensive and complex, but the high temperature can also damage the active sites on the adjuvant surface. While sterically hindered aluminum alkoxides can achieve low-temperature controllable crystallization, the raw material cost is high, making it difficult to meet the needs of large-scale industrial production of vaccine adjuvants.

[0004] To address the aforementioned shortcomings, existing technological improvements have consistently been limited to two directions: first, optimizing the parameters of the aluminum isopropoxide hydrolysis process, such as the preparation method of boehmite adjuvant for vaccines disclosed in prior art document CN102302797A. This method can only achieve minor optimization of product performance and cannot fundamentally eliminate the dependence on the high-temperature crystallization step; second, optimizing the process adaptation of sterically hindered aluminum alkoxides, which cannot solve the core problem of high raw material costs. More importantly, the authoritative monograph in this field, "Vaccine Adjuvants" (People's Medical Publishing House, 2018), clearly records the long-standing double-recognized technical bias in this field: first, linear sterically hindered aluminum alkoxides have extremely high hydrolytic activity, undergoing explosive hydrolysis upon contact with water, producing only amorphous aluminum hydroxide, and cannot achieve ordered and controllable crystallization at low temperatures. To obtain highly crystalline boehmite, a high-temperature crystallization step is necessary to complete the phase transformation; second, linear sterically hindered aluminum alkoxides are unsuitable for the preparation of highly crystalline boehmite-type human aluminum hydroxide adjuvants for vaccines, and have no research or application value. The aforementioned technical bias has prevented those skilled in the art from ever developing a low-temperature controllable hydrolysis crystallization system for linear, low-steric aluminum alkoxides, ultimately resulting in the long-standing industry problem that "low-cost, low-steric aluminum alkoxides and low-temperature controllable crystallization are mutually exclusive" and has remained unsolved. Summary of the Invention

[0005] In view of this, the present invention proposes a method for preparing highly dense aluminum hydroxide adjuvant for human use by hydrolysis of aluminum alkoxide.

[0006] The technical solution of this invention is implemented as follows: This invention provides a method for preparing highly dense human-use aluminum hydroxide adjuvants by aluminum alkoxide hydrolysis, comprising hydrolyzing an aluminum alkoxide precursor with water in a solvent system, wherein the aluminum alkoxide precursor is a straight-chain, sterically hindered aluminum alkoxide compound of the general formula Al(OR)3, and serves as the sole aluminum source for preparing the adjuvant; in the general formula, R is a straight-chain C2-C4 alkyl group; the solvent system is a dual-solvent system composed of an alcohol solvent and an aprotic inert solvent; a composite directing agent is also added to the hydrolysis reaction system, the composite directing agent comprising a hydrolysis inhibitor and a crystal facet directing agent; in the hydrolysis reaction system, the molar ratio of water to aluminum alkoxide precursor is 3:1 to 10:1; the hydrolysis reaction is carried out at a temperature below 100°C, and after the hydrolysis reaction is completed, there is no need for high-temperature and high-pressure hydrothermal treatment above 150°C or high-temperature calcination treatment above 400°C, and a boehmite crystal phase with a crystallinity of ≥50% is directly obtained through a single hydrolysis reaction, and the finished adjuvant can be obtained by only conventional purification treatment.

[0007] In some embodiments, the aluminum alkoxide precursor is selected from at least one of aluminum ethoxide, aluminum n-propoxide, and aluminum n-butoxide. The aforementioned preferred linear-chain, low-sterile-hindrance aluminum alkoxides are all raw materials recognized in the vaccine adjuvant field as having excessively high hydrolytic activity and being unable to achieve low-temperature controllable crystallization. This invention overcomes technical bias by selecting this type of precursor, whose linear alkoxy structure has no branched steric hindrance and can be completely removed after hydrolysis, leaving no residual steric groups affecting the orderly assembly of the crystal. At the same time, the raw material is widely available and its cost is only 20%-30% of that of high-sterile-hindrance tert-butoxide, fundamentally balancing crystallization performance and industrial production costs.

[0008] In some embodiments, in the dual-solvent system, the alcohol solvent is a straight-chain C2-C4 monohydric alcohol corresponding to the alkoxy group of the aluminum alkoxide precursor, and the aprotic inert solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, and dimethyl sulfoxide, and the volume ratio of the alcohol solvent to the aprotic inert solvent is 1:0.5 to 1:3. This invention employs a dual-solvent system consisting of an alcohol solvent and a non-proton inert solvent. The alcohol solvent ensures the complete dissolution of the linear, sterically hindered aluminum alkoxide precursor, achieving a homogeneous hydrolysis reaction and avoiding the problems of uneven hydrolysis rates and disordered product morphology caused by heterogeneous reactions. The non-proton inert solvent does not participate in the hydrolysis reaction. On the one hand, it reduces the activity of water molecules in the system through a dilution effect, reducing the probability of collisions between water molecules and aluminum centers. On the other hand, it forms a dense solvation shell around the aluminum centers, physically shielding them from the electrophilic attack of water molecules on the aluminum centers. This delays the explosive hydrolysis of linear, sterically hindered aluminum alkoxides from both thermodynamic and kinetic perspectives, transforming disordered hydrolysis into stepwise, controllable hydrolysis, providing a core foundation for ordered crystallization at low temperatures. This dual-solvent system is a dedicated rate-control design adapted for linear, sterically hindered aluminum alkoxides and is not a conventional solvent choice in this field.

[0009] In some embodiments, the hydrolysis inhibitor in the composite directing agent is selected from at least one of ammonium fluoride and sodium fluoride, and the amount used is 0.05% to 2% of the molar amount of the aluminum alkoxide precursor; the crystal plane directing agent is selected from at least one of lactic acid, gluconic acid, citric acid, tartaric acid, and salicylic acid, and the amount used is 0.1% to 5% of the molar amount of the aluminum alkoxide precursor. This invention employs a composite directing agent consisting of a hydrolysis inhibitor and a crystal facet directing agent, forming a synergistic rate-controlled crystallization system with a dual-solvent system. The fluoride ions in the hydrolysis inhibitor can undergo a mild and reversible coordination interaction with the aluminum center, occupying some coordination sites of the aluminum center, further finely controlling the hydrolysis rate and avoiding the formation of amorphous clusters due to local uncontrolled hydrolysis rate. The crystal facet directing agent is a multidentate ligand with hydroxyl and carboxyl groups, which can selectively adsorb on specific crystal faces of boehmite crystals, reducing the surface energy of the crystal facet, inhibiting its disordered growth, and guiding the aluminum-oxygen octahedral units to assemble into a layered crystal structure of boehmite in an ordered manner. The two work together to achieve a closed-loop process of "precise control of hydrolysis rate - directional growth of crystal nuclei", solving the core problem of rapid hydrolysis and disordered crystallization of linear small steric hindrance aluminum alkoxides, which is not a simple superposition of conventional additives in this field.

[0010] In some embodiments, the hydrolysis reaction temperature is 60℃~98℃, and the reaction time is 8h~24h. This temperature range only needs to provide the basic activation energy for boehmite crystallization, without requiring additional high energy input for the transformation from the amorphous phase to the crystalline phase. This avoids the problem of insufficient activation energy for crystallization due to excessively low temperatures, which prevents the formation of a complete boehmite crystalline phase, and also prevents the problem of uncontrolled hydrolysis rate of linear, sterically hindered aluminum alkoxides due to excessively high temperatures, which could lead to the generation of amorphous products. Combined with the above-mentioned reaction time, the hydrolysis and condensation reactions can be fully carried out, achieving the orderly growth of crystal nuclei and the formation of a complete crystalline phase. The synthesis of highly crystalline boehmite can be completed under mild conditions below 100℃, completely eliminating the high-temperature and high-pressure steps required by existing technologies.

[0011] In some embodiments, the hydrolysis reaction employs a stepwise water addition method: first, 30% to 50% of the total water volume is added dropwise, and pre-hydrolysis is carried out at the reaction temperature for 1 to 3 hours; then, the remaining water volume is added dropwise at a uniform rate, with the total addition time controlled at 3 to 6 hours. This invention uses a stepwise water addition method, forming a three-stage rate-controlled system with a dual-solvent system and a composite directing agent. During the pre-hydrolysis stage, a small amount of water is used to form a small number of uniformly distributed crystal nuclei in the system, avoiding the problem of excessively high local concentrations and explosive nucleation caused by adding water all at once. The subsequent uniform addition of the remaining water ensures that the supersaturation of aluminum species in the system remains within a controllable nucleation window, guiding the uniform and orderly growth of crystal nuclei, further narrowing the crystal size distribution, and improving batch-to-batch consistency of the product. This is a dedicated process design for the high hydrolysis activity of linear, sterically hindered aluminum alkoxides, and is not a conventional operation in this field.

[0012] In some embodiments, after the hydrolysis reaction is completed, a mild aging step is also included: adjusting the pH of the reaction system to 6.5~7.5 and aging it by stirring at 50℃~80℃ for 12h~72h. This mild aging step is not the high-temperature crystallization process for amorphous products in the prior art, but rather a ripening process for the formed boehmite primary microcrystals. Under the above mild conditions and near-neutral pH environment, the slightly more soluble microcrystals are gradually dissolved through the Ostwald ripening mechanism. Aluminum species are redistributed in the solution and deposited onto the more stable surface of large crystals, which can effectively eliminate internal stress and surface defects of crystals, narrow the crystal size distribution, reduce particle surface energy, and significantly improve the long-term storage stability of the adjuvant colloidal system, avoiding gel shrinkage or precipitation during storage, and forming a synergistic effect with the core crystallization scheme.

[0013] In some embodiments, a purification step is included after the reaction: first, solid-liquid separation is performed by low-speed centrifugation at 2000 rpm to 6000 rpm; then, the precipitate obtained by centrifugation is redispersed in water for injection; and dialysis concentration is performed using a tangential flow filtration system with a molecular weight cutoff of 10 kDa to 100 kDa until the conductivity of the filtrate is lower than 1.5 mS / cm. The product prepared by the core scheme of this invention is a highly crystalline, dense, and stable boehmite crystal, rather than the structurally fragile amorphous gel in the prior art. It can withstand the above-mentioned low-speed centrifugation treatment without crystal breakage or particle size change, avoiding the damage to the product structure caused by high-speed centrifugation. With the tangential flow filtration system, solvent replacement, impurity removal, and product concentration can be efficiently completed under mild conditions, and the ionic strength, pH, and aluminum content of the final product can be precisely controlled. The process is easy to linearly scale up and fully complies with the compliance requirements of human vaccine GMP production. It is a dedicated purification design for the high crystalline product characteristics of this invention.

[0014] In some embodiments, the present invention also provides a highly dense aluminum hydroxide adjuvant for human use, prepared by the method described in any of the preceding embodiments, wherein the adjuvant is in the boehmite crystal form, has a crystallinity ≥50%, and a specific surface area of ​​400 m². 2 / g~650m 2 / g, with an isoelectric point of pH 10.0~11.0. The adjuvant prepared by the above method retains the complete boehmite layered crystal structure, avoiding crystal sintering and loss of active sites caused by high-temperature treatment. It has abundant surface active hydroxyl sites and can maintain a stable positive charge and colloidal dispersion state under neutral physiological environment. It combines the structural stability brought by high crystallinity with the excellent adsorption performance brought by high specific surface area, which is fully suitable for the use requirements of human vaccines. Its core performance parameters cannot be achieved by small sterically hindered aluminum alkoxides in the existing technology without a high-temperature crystallization step.

[0015] In some embodiments, the adjuvant has an adsorption capacity ≥2.6 mg / mg Al for tetanus toxoid. The highly crystalline boehmite crystals prepared by this invention have a large number of highly active terminal hydroxyl groups distributed on their surface, which can undergo efficient ligand exchange with the phosphate and carboxyl groups of the antigen. Combined with the ample adsorption sites provided by the high specific surface area, this enables efficient and stable adsorption of the antigen, preventing desorption during storage and ensuring the stable efficacy of the vaccine. Its adsorption performance is significantly superior to that of aluminum hydroxide adjuvants prepared by high-temperature crystallization in existing technologies.

[0016] In some embodiments, the present invention also provides the application of the above-mentioned highly dense human aluminum hydroxide adjuvant in the preparation of human vaccine drugs. The adjuvant prepared by the present invention has excellent antigen adsorption performance, colloidal stability and biosafety, with no toxic or harmful impurities remaining, excellent batch-to-batch consistency, and can be adapted to the preparation requirements of various human vaccines such as recombinant protein vaccines, virus-like particle vaccines, and inactivated vaccines. It effectively improves the immunogenicity and safety of vaccines, and breaks through the bottleneck of existing adjuvants that cannot simultaneously achieve low cost, high performance and mild preparation process, and has extremely high industrial application value.

[0017] The present invention has the following advantages over the prior art:

[0018] This invention overcomes the long-standing technical bias in the field that "straight-chain, sterically hindered aluminum alkoxides cannot achieve low-temperature one-step synthesis of highly crystalline boehmite-type aluminum hydroxide adjuvants without a high-temperature crystallization step." For the first time, it constructs a dual-solvent confinement rate-controlled crystallization system adapted to straight-chain, sterically hindered aluminum alkoxides, and a composite directing agent synergistic crystallization system. This fundamentally solves the core industry problem of excessively rapid hydrolysis rates and the inability to achieve low-temperature ordered crystallization of sterically hindered aluminum alkoxides. High-density human-grade aluminum hydroxide adjuvants can be directly prepared through a single hydrolysis reaction under mild conditions below 100°C, completely eliminating the high-temperature, high-pressure crystallization step required by existing technologies. Compared to existing technologies, the core process of this invention is simpler and milder, significantly reducing production cycle and energy consumption. An optional mild aging step can further improve the crystallinity and storage stability of the product, and can be flexibly selected according to industrial production needs. The raw material costs have been significantly reduced, making it easy to achieve GMP-scale production. At the same time, the prepared adjuvants have excellent structural stability, antigen adsorption performance, and long-term storage stability, with significantly improved batch-to-batch consistency and biosafety, providing a performance- and cost-effective adjuvant option for novel human vaccines. Detailed Implementation

[0019] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0020] Experimental materials and reagents Aluminum ethoxide (purity ≥98%, CAS No.: 555-75-9), aluminum n-propoxide (purity ≥98%, CAS No.: 2269-22-9), aluminum n-butoxide (purity ≥98%, CAS No.: 3085-30-1), aluminum isopropoxide (purity ≥99%, CAS No.: 555-31-7), aluminum tert-butoxide (purity ≥98%, CAS No.: 556-91-2); anhydrous ethanol, anhydrous n-propanol, anhydrous n-butanol, anhydrous isopropanol Alcohol, anhydrous tert-butanol (both analytical grade); tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide (both analytical grade); ammonium fluoride, sodium fluoride, L-lactic acid, citric acid, salicylic acid (both analytical grade); 10% dilute ammonia (analytical grade); water for injection (compliant with the 2025 edition of the Chinese Pharmacopoeia); tetanus toxoid (purity ≥95%, protein concentration 1 mg / mL); ovalbumin (analytical grade, purity ≥98%); boehmite standard (Alfa Aesar, standard crystallinity 99%); commercially available aluminum adjuvant Alhydrogel (BrenntagBiosector, Denmark, aluminum content 10 mg / mL).

[0021] Experimental instruments 500mL three-necked glass flask, 100L stainless steel sealed reaction vessel, constant pressure dropping funnel, serpentine condenser, digital display constant temperature oil bath, CNC magnetic stirrer, high-purity nitrogen protection device, high-speed refrigerated centrifuge, hollow fiber tangential flow filtration system, X-ray diffractometer (XRD, Bruker D8 Advance), fully automatic specific surface area and pore size analyzer (McASAP2460), zeta potential and nanoparticle size analyzer (Malvin Zetasizer Nano ZS), ultraviolet-visible spectrophotometer (Shimadzu UV-2600), 4℃ constant temperature refrigerator, vacuum drying oven.

[0022] General performance verification method 1. Crystal form and crystallinity detection Step 1: Take the adjuvant sample to be tested and dry it in a vacuum drying oven at 60℃ for 12 hours to obtain a dried powder sample; Step 2: Evenly fill the groove of the XRD sample stage with the powder sample, and smooth it with a glass slide to ensure that the sample surface is flush with the sample stage surface. Step 3: Set XRD test parameters: Cu target Kα rays, tube voltage 40kV, tube current 40mA, scanning range 2θ=10°~80°, scanning speed 2° / min, step size 0.02°; Step 4: Compare the diffraction pattern obtained from the test with the boehmite standard PDF card (No.: 21-1307) to confirm the crystal form; calculate the crystallinity using the relative intensity method, taking the integral intensity of the main peak at 2θ=14.5° on the crystal plane of the boehmite standard (020) as 100%, and calculate the ratio of the integral intensity of the corresponding characteristic peak of the sample to be tested to that of the standard, which is the crystallinity of the sample to be tested.

[0023] 2. Specific surface area testing Step 1: Take 0.1g of the dry powder sample to be tested, place it in a sample tube, and degas it under vacuum at 120℃ for 6h to remove impurities and moisture adsorbed on the sample surface; Step 2: Load the degassed sample tube into a fully automated specific surface area analyzer and perform nitrogen adsorption-desorption test at a liquid nitrogen temperature of 77K. The relative pressure P / P0 range is 0.05~0.995. Step 3: Calculate the specific surface area of ​​the sample using the BET multi-point method, and take the linear fitting result of the relative pressure range of 0.05~0.35 as the final specific surface area value.

[0024] 3. Isoelectric point detection Step 1: Take the adjuvant sample to be tested, dilute it with water for injection to an aluminum concentration of 0.1 mg / mL, and sonicate it for 5 min to obtain a uniformly dispersed test solution; Step 2: Add 1 mL of the test solution to the zeta potential sample cell, and adjust the pH of the sample with dilute nitric acid and dilute sodium hydroxide solution. The test range is pH 3.0~12.0, with each pH gradient interval of 0.5 and an equilibration time of 60 s. Step 3: Test the zeta potential value at each pH gradient and plot the zeta potential-pH curve. The pH value corresponding to the zeta potential of 0 in the curve is the isoelectric point of the sample.

[0025] 4. Tetanus toxoid adsorption capacity assay Step 1: Take 6 adjuvant samples to be tested, dilute them with water for injection to an aluminum concentration of 0.5 mg / mL, each sample having a volume of 1 mL, and place them in 15 mL centrifuge tubes respectively; Step 2: Add different volumes of tetanus toxoid solution to the 6 samples respectively, so that the final antigen concentrations in the system are 0.2 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 1.5 mg / mL, 2.0 mg / mL and 3.0 mg / mL respectively, and make up the total volume of the system to 5 mL with water for injection; Step 3: Seal all centrifuge tubes and place them in a 37°C constant temperature shaker. Shake at 150 rpm for 24 hours to ensure that adsorption reaches equilibrium. Step 4: Centrifuge the incubated sample at 8000 rpm for 10 min, take the supernatant, and use a UV-Vis spectrophotometer to detect the concentration of free antigen in the supernatant at a wavelength of 280 nm. The concentration value is calibrated by using a pre-prepared protein standard curve. Step 5: Calculate the amount of antigen adsorbed per unit mass of aluminum based on the difference between the initial antigen concentration and the free antigen concentration in the supernatant, plot the adsorption isotherm, and take the saturated adsorption amount as the adsorption capacity of the sample for tetanus toxoid, in mg / mg Al.

[0026] 5. Long-term storage stability testing Step 1: Take the adjuvant sample to be tested, seal it in a sterile vial, and store it in a 4°C constant temperature refrigerator in the dark. Step 2: Take samples at 0 months, 3 months and 6 months of storage respectively, and observe the appearance of the samples with the naked eye to see if there is any layering, precipitation or flocculation. At the same time, retest the crystallinity and particle size distribution of the samples. Step 3: Stability Evaluation Criteria: Stable: The sample has a uniform appearance, no layering or precipitation, crystallinity change rate ≤5%, and particle size distribution change rate ≤10%; Slightly unstable: A small amount of precipitate appears at the bottom of the sample, which can be redissolved by shaking, with a crystallinity change rate of 5%~10%; Severe instability: The sample shows obvious stratification, a large amount of hard precipitate, cannot be redissolved by shaking, and the crystallinity change rate is >10%.

[0027] 6. Production cycle statistics The total time of the entire process, measured in hours (h), is calculated from the start of raw material feeding until the final adjuvant product meeting the aluminum content requirements is obtained. This does not include the time for sample testing.

[0028] 7. Particle size distribution detection method Step 1: Take the adjuvant sample to be tested, dilute it with water for injection to an aluminum concentration of 0.1 mg / mL, and sonicate it for 3 min to obtain a uniformly dispersed test solution; Step 2: The Malvern Zetasizer NanoZS nanoparticle size analyzer was used for detection. The test temperature was set to 25℃, the equilibration time to 120s, the refractive index to 1.45, and the dispersion medium to water (refractive index to 1.33). Each sample was tested three times, and the average value was taken as the final test result. Step 3: Using volume average particle size D50 as the core evaluation index, the particle size distribution change rate is calculated as: |D50 after storage - initial D50| / initial D50 × 100%. Specific Implementation Example 1 Step 1: Install a CNC stirrer, a serpentine reflux condenser, a constant pressure dropping funnel, and a nitrogen protection device in a dry 500mL three-necked flask. Add 100mL of anhydrous n-butanol and 150mL of tetrahydrofuran to the flask to form a dual solvent system. Purge the air in the flask with high-purity nitrogen three times, maintaining a slightly positive nitrogen protection atmosphere of 0.02~0.05MPa throughout the process. Step 2: Add 74g of aluminum n-butoxide (0.3mol) to the flask, set the stirring speed to 300rpm, and stir at room temperature for 20min until the aluminum n-butoxide is completely dissolved to obtain a homogeneous and transparent aluminum alkoxide solution; Step 3: Add 0.15g ammonium fluoride (1.5% of the molar amount of aluminum) to the aluminum alkoxide solution as a hydrolysis inhibitor, and add 1.0g L-lactic acid (3.7% of the molar amount of aluminum) as a crystal plane guiding agent. Stir continuously for 10 minutes until completely dissolved to obtain a homogeneous reaction base solution. Step 4: Turn on the digital display constant temperature oil bath, heat the system to 90℃ at a uniform rate, and keep it at that temperature for 10 minutes to make the system temperature uniform and stable. Step 5: Mix 27 mL of water for injection (water to aluminum alkoxide molar ratio of 5:1) with 50 mL of anhydrous n-butanol until homogeneous, transfer to a constant pressure dropping funnel, add 40% of the mixture first, maintain a constant temperature of 90℃ for pre-hydrolysis for 2 hours, and then add the remaining 60% of the mixture at a uniform rate. The total dropping time is controlled to be 4 hours. During the dropping process, maintain a constant temperature of 90℃ and gentle reflux. Step 6: After the addition is complete, keep the system at a constant temperature of 90℃ and stir at 300rpm for 10 hours to obtain a milky white homogeneous sol. No high temperature, high pressure hydrothermal or calcination treatment is performed throughout the process. Step 7: After the reaction is complete, transfer the reaction solution to a centrifuge tube, set the speed to 4000 rpm, centrifuge for 15 min, discard the supernatant, and obtain a white precipitate; Step 8: The white precipitate obtained by centrifugation is redispersed with water for injection and transferred to a hollow fiber tangential flow filtration system with a molecular weight cutoff of 30 kDa. It is continuously dialyzed and washed with water for injection until the conductivity of the filtrate is lower than 1.0 mS / cm. Finally, it is concentrated to an aluminum content of 10.0 mg / mL to obtain the high-density human aluminum hydroxide adjuvant product of this embodiment.

[0030] Example 2: Aluminum ethoxide precursor example Step 1: Under the same reaction apparatus and nitrogen protection conditions as in Example 1, add 100 mL of anhydrous ethanol and 150 mL of tetrahydrofuran to a three-necked flask to form a dual solvent system. Purge the air in the flask with high-purity nitrogen three times, and maintain a slight positive pressure of 0.02~0.05 MPa nitrogen throughout the process. Step 2: Add 49g of aluminum ethoxide (0.3mol) to the flask, set the stirring speed to 300rpm, and stir at room temperature for 20min until completely dissolved to obtain a homogeneous and transparent aluminum ethoxide solution; Step 3: Add 0.15g ammonium fluoride (1.5% of the molar amount of aluminum) to the aluminum alkoxide solution as a hydrolysis inhibitor, and add 1.0g L-lactic acid (3.7% of the molar amount of aluminum) as a crystal plane guiding agent. Stir continuously for 10 minutes until completely dissolved. Step 4: Turn on the constant temperature oil bath and heat the system to 90℃ at a uniform rate. Keep it at this temperature for 10 minutes to make the system temperature uniform and stable. Step 5: Mix 27 mL of water for injection (water to aluminum alkoxide molar ratio of 5:1) with 50 mL of anhydrous ethanol until homogeneous, transfer to a constant pressure dropping funnel, add 40% of the mixture first, maintain a constant temperature of 90℃ for pre-hydrolysis for 2 hours, and then add the remaining 60% of the mixture at a uniform rate, with the total adding time controlled to 4 hours. Step 6: After the addition is complete, keep the system at a constant temperature of 90°C and stir at 300 rpm for 10 hours. No high temperature, high pressure, hydrothermal or calcination treatment is performed throughout the process. Step 7: The subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, ultimately yielding the high-density human-grade aluminum hydroxide adjuvant product of this example.

[0031] Example 3: Aluminum n-propoxide precursor example Step 1: Under the same reaction apparatus and nitrogen protection conditions as in Example 1, add 100 mL of anhydrous n-propanol and 150 mL of tetrahydrofuran to a three-necked flask to form a dual solvent system. Purge the air in the flask with high-purity nitrogen three times, and maintain a slight positive pressure of 0.02~0.05 MPa nitrogen throughout the process. Step 2: Add 61.5g of aluminum propoxide (0.3mol) to the flask, set the stirring speed to 300rpm, and stir at room temperature for 20min until completely dissolved to obtain a homogeneous and transparent aluminum alkoxide solution; Step 3: Add 0.15g ammonium fluoride (1.5% of the molar amount of aluminum) to the aluminum alkoxide solution as a hydrolysis inhibitor, and add 1.0g L-lactic acid (3.7% of the molar amount of aluminum) as a crystal plane guiding agent. Stir continuously for 10 minutes until completely dissolved. Step 4: Turn on the constant temperature oil bath and heat the system to 90℃ at a uniform rate. Keep it at this temperature for 10 minutes to make the system temperature uniform and stable. Step 5: Mix 27 mL of water for injection (water to aluminum alkoxide molar ratio of 5:1) with 50 mL of anhydrous n-propanol until homogeneous, transfer to a constant pressure dropping funnel, add 40% of the mixture first, maintain a constant temperature of 90℃ for pre-hydrolysis for 2 hours, and then add the remaining 60% of the mixture at a uniform rate, with the total adding time controlled to 4 hours. Step 6: After the addition is complete, keep the system at a constant temperature of 90°C and stir at 300 rpm for 10 hours. No high temperature, high pressure, hydrothermal or calcination treatment is performed throughout the process. Step 7: The subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and finally the high-density human aluminum hydroxide adjuvant product of this example is obtained.

[0032] Example 4: Verification of the Lower Limit of Dual Solvent Volume Ratio The only difference is that the volume ratio of anhydrous n-butanol to tetrahydrofuran in step 1 of Example 1 is adjusted to 1:0.5, that is, 167 mL of anhydrous n-butanol and 83 mL of tetrahydrofuran are added, and the molar ratio of water to aluminum alkoxide is kept at 5:1. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0033] Example 5: Verification of the Upper Limit of Dual Solvent Volume Ratio The only difference is that the volume ratio of anhydrous n-butanol to tetrahydrofuran in step 1 of Example 1 is adjusted to 1:3, that is, 62.5 mL of anhydrous n-butanol and 187.5 mL of tetrahydrofuran are added, and the molar ratio of water to aluminum alkoxide is kept at 5:1. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0034] Example 6: Verification of the Lower Limit of Hydrolysis Inhibitor Dosage The only difference is that the amount of ammonium fluoride in step 3 of Example 1 is adjusted to 0.05% of the molar amount of aluminum, i.e., 0.0056g of ammonium fluoride is added. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0035] Example 7: Verification of the Upper Limit of Hydrolysis Inhibitor Dosage The only difference is that the amount of ammonium fluoride in step 3 of Example 1 is adjusted to 2% of the molar amount of aluminum, i.e., 0.222g of ammonium fluoride is added. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0036] Example 8: Verification of the Lower Limit of Crystal Facet Directing Agent Dosage The only difference is that the amount of L-lactic acid in step 3 of Example 1 is adjusted to 0.1% of the molar amount of aluminum, i.e., 0.027g of L-lactic acid is added. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0037] Example 9 Verification of the Upper Limit of Crystal Facet Directing Agent Dosage The only difference is that the amount of L-lactic acid in step 3 of Example 1 is adjusted to 5% of the molar amount of aluminum, i.e., 1.35g of L-lactic acid is added. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0038] Example 10: Verification of the Lower Limit of Hydrolysis Temperature The only difference was that the hydrolysis reaction temperature in steps 4-6 of Example 1 was adjusted to 60°C, the reaction time was kept to 10 hours, and the molar ratio of water to aluminum alkoxide was kept to 5:1. All other process steps, parameters, and raw material amounts were completely consistent with Example 1, and the adjuvant product of this example was finally obtained.

[0039] Example 11: Verification of the Upper Limit of Hydrolysis Temperature The only difference was that the hydrolysis reaction temperature in steps 4-6 of Example 1 was adjusted to 98°C, the reaction time was kept to 10 hours, and the molar ratio of water to aluminum alkoxide was kept to 5:1. All other process steps, parameters, and raw material amounts were completely consistent with Example 1, and the adjuvant product of this example was finally obtained.

[0040] Example 12: Verification of the Lower Limit of Hydrolysis Reaction Time The only difference is that the hydrolysis reaction time in step 6 of Example 1 is adjusted to 8 hours. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0041] Example 13 Verification of the Upper Limit of Hydrolysis Reaction Time The only difference is that the hydrolysis reaction time in step 6 of Example 1 is adjusted to 24 hours. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0042] Example 14: Verification of the Lower Limit of Pre-hydrolysis Time The only difference is that the pre-hydrolysis time in step 5 of Example 1 is adjusted to 1 hour, while the total dripping time remains at 4 hours. All other process steps, parameters, and raw material dosages are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0043] Example 15: Verification of the Upper Limit of Pre-hydrolysis Time The only difference is that the pre-hydrolysis time in step 5 of Example 1 is adjusted to 3 hours, while the total dripping time remains at 4 hours. All other process steps, parameters, and raw material dosages are completely consistent with Example 1, and the adjuvant product of this example is finally obtained.

[0044] Example 16: Verification of the Lower Limit of Dropping Time The only difference is that the total dripping time in step 5 of Example 1 is adjusted to 3 hours, the pre-hydrolysis time is kept at 2 hours, and all other process steps, parameters, and raw material dosages are completely consistent with Example 1, so that the adjuvant product of this example is finally obtained.

[0045] Example 17: Verification of the Upper Limit of Dropping Time The only difference is that the total dripping time in step 5 of Example 1 is adjusted to 6 hours, the pre-hydrolysis time is kept at 2 hours, and all other process steps, parameters, and raw material dosages are completely consistent with Example 1, so that the adjuvant product of this example is finally obtained.

[0046] Example 18: Verification of the Lower Limit of the Water-Aluminum Molar Ratio The only difference was that the amount of water for injection in step 5 of Example 1 was adjusted to 16.2 mL, and the molar ratio of water to aluminum alkoxide was 3:1. All other process steps, parameters, and raw material amounts were completely consistent with Example 1, and the adjuvant product of this example was finally obtained.

[0047] Example 19: Verification of the Upper Limit of the Water-Aluminum Molar Ratio The only difference was that the amount of water for injection in step 5 of Example 1 was adjusted to 54 mL and the molar ratio of water to aluminum alkoxide was 10:1. All other process steps, parameters, and raw material amounts were completely consistent with Example 1, and the adjuvant product of this example was finally obtained.

[0048] Example 20: Compatibility Verification of Dimethyl Sulfoxide and Aluminum Ethanol The only difference was that the aprotic inert solvent in Example 2 was replaced with an equal volume of dimethyl sulfoxide, while all other process steps, parameters, and raw material amounts were completely consistent with Example 2, ultimately yielding the adjuvant product of this example.

[0049] Example 21: Compatibility Verification of Dimethyl Sulfoxide with Aluminum n-Butoxide The only difference is that the aprotic inert solvent in Example 1 was replaced with an equal volume of dimethyl sulfoxide, while all other process steps, parameters, and raw material amounts were exactly the same as in Example 1, resulting in the adjuvant product of this example.

[0050] Example 22: Mild Aging pH Limit Validation Example Step 1: Complete the hydrolysis reaction according to steps 1-6 of Example 1 to obtain a milky white sol; Step 2: After the hydrolysis reaction is complete, adjust the pH of the reaction system to 6.5 with 10% dilute ammonia water, lower the system temperature to 70℃, keep stirring at 300 rpm, and age at a constant temperature for 36 hours. Step 3: After aging, the subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and all other process parameters are exactly the same as in Example 1, finally obtaining the adjuvant product of this example.

[0051] Example 23: Mild Aging pH Upper Limit Verification Example Step 1: Complete the hydrolysis reaction according to steps 1-6 of Example 1 to obtain a milky white sol; Step 2: After the hydrolysis reaction is complete, adjust the pH of the reaction system to 7.5 with 10% dilute ammonia water, lower the system temperature to 70℃, keep stirring at 300rpm, and age at a constant temperature for 36h. Step 3: After aging, the subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and all other process parameters are exactly the same as in Example 1, finally obtaining the adjuvant product of this example.

[0052] Example 24: Verification of the Lower Limit of Mild Aging Temperature Step 1: Complete the hydrolysis reaction according to steps 1-6 of Example 1 to obtain a milky white sol; Step 2: After the hydrolysis reaction is complete, adjust the pH of the reaction system to 7.2 with 10% dilute ammonia water, lower the system temperature to 50℃, keep stirring at 300 rpm, and age at a constant temperature for 36 hours. Step 3: After aging, the subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and all other process parameters are exactly the same as in Example 1, finally obtaining the adjuvant product of this example.

[0053] Example 25: Verification of the Upper Limit of Mild Aging Temperature Step 1: Complete the hydrolysis reaction according to steps 1-6 of Example 1 to obtain a milky white sol; Step 2: After the hydrolysis reaction is complete, adjust the pH of the reaction system to 7.2 with 10% dilute ammonia water, lower the system temperature to 80℃, keep stirring at 300 rpm, and age at a constant temperature for 36 hours. Step 3: After aging, the subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and all other process parameters are exactly the same as in Example 1, finally obtaining the adjuvant product of this example.

[0054] Example 26: Verification of the Lower Limit of Mild Aging Time Step 1: Complete the hydrolysis reaction according to steps 1-6 of Example 1 to obtain a milky white sol; Step 2: After the hydrolysis reaction is complete, adjust the pH of the reaction system to 7.2 with 10% dilute ammonia water, lower the system temperature to 70℃, keep stirring at 300 rpm, and age at a constant temperature for 12 hours. Step 3: After aging, the subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and all other process parameters are exactly the same as in Example 1, finally obtaining the adjuvant product of this example.

[0055] Example 27: Verification of the Upper Limit of Mild Aging Time Step 1: Complete the hydrolysis reaction according to steps 1-6 of Example 1 to obtain a milky white sol; Step 2: After the hydrolysis reaction is complete, adjust the pH of the reaction system to 7.2 with 10% dilute ammonia water, lower the system temperature to 70℃, keep stirring at 300 rpm, and age at a constant temperature for 72 hours. Step 3: After aging, the subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and all other process parameters are exactly the same as in Example 1, finally obtaining the adjuvant product of this example.

[0056] Example 28: 100x Industrial Scale-Up Example Step 1: In a 100L stainless steel sealed reactor, according to the raw material ratio of Example 1 scaled up 100 times, add 10L of anhydrous n-butanol and 15L of tetrahydrofuran, and purge the air in the reactor with high-purity nitrogen three times, maintaining a slight positive pressure of 0.02~0.05MPa nitrogen throughout the process. Step 2: Add 7.4 kg of aluminum n-butoxide to the reactor, turn on the stirrer, and stir at 60 rpm for 30 minutes at room temperature until completely dissolved; Step 3: Add 15g of ammonium fluoride and 100g of L-lactic acid to the system and stir continuously for 15 minutes until completely dissolved; Step 4: Heat the system to 90℃ at a uniform rate and hold for 20 minutes to ensure the system temperature is uniform and stable. Step 5: Mix 2.7L of water for injection (water to aluminum alkoxide molar ratio of 5:1) with 5L of anhydrous n-butanol until homogeneous. First, add 40% of the mixture dropwise and maintain a constant temperature of 90℃ for pre-hydrolysis for 2 hours. Then, add the remaining 60% of the mixture dropwise at a uniform rate. The total dropwise addition time is controlled to be 4 hours. Step 6: After the addition is complete, keep the system at a constant temperature of 90°C and stir at 60 rpm for 10 hours. No high temperature, high pressure, hydrothermal or calcination treatment is performed throughout the process. Step 7: After the reaction is complete, the reaction solution is centrifuged at 3000 rpm for 20 min, the supernatant is discarded, the precipitate is redispersed with water for injection, and transferred to an industrial-grade tangential flow filtration system with a molecular weight cutoff of 30 kDa. The solution is dialyzed and washed until the conductivity of the filtrate is less than 1.0 mS / cm. Finally, it is concentrated to an aluminum content of 10.0 mg / mL to obtain the scaled-up batch adjuvant product of this embodiment.

[0057] Comparative Examples Comparative Example 1 Step 1: Under the same reaction apparatus and nitrogen protection conditions as in Example 1, add 250 mL of anhydrous isopropanol and 61.2 g of aluminum isopropoxide (0.3 mol) to a three-necked flask, and stir at room temperature until completely dissolved; Step 2: Heat the system to 90℃ and keep it at a constant temperature. Mix 27mL of water for injection with 50mL of anhydrous isopropanol evenly and transfer it to a constant pressure dropping funnel. First, add 40% of the mixture and pre-hydrolyze at 90℃ for 2 hours. Then, add the remaining 60% of the mixture at a uniform rate. The total adding time is 4 hours. Step 3: After the addition is complete, the mixture is kept at a constant temperature of 90℃ for 12 hours to obtain a white flocculent reaction solution; Step 4: Transfer the reaction solution into a polytetrafluoroethylene-lined hydrothermal reactor, seal it, and place it in a 180°C oven for high-temperature and high-pressure hydrothermal treatment for 6 hours to complete crystallization. Step 5: After the hydrothermal treatment is completed, the mixture is naturally cooled to room temperature. The subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and the adjuvant product of this comparative example is finally obtained.

[0058] Comparative Example 2 Step 1: Under the same reaction apparatus and nitrogen protection conditions as in Example 1, add 250 mL of anhydrous n-butanol and 74 g of aluminum n-butoxide (0.3 mol) to a three-necked flask, stir at room temperature until completely dissolved, without adding a dual solvent system, hydrolysis inhibitor, or crystal plane guiding agent; Step 2: Heat the system to 90℃ and keep it constant. Add 27mL of water for injection to the reaction system all at once. React at 90℃ for 10 hours. No high temperature, high pressure, hydrothermal or calcination treatment is used throughout the process. Step 3: The subsequent centrifugation and tangential flow filtration purification steps are completely consistent with steps 7-8 of Example 1, and finally the product of this comparative example is obtained.

[0059] Comparative Example 3 The only difference was that the dual solvent system in step 1 of Example 1 was replaced with a single 250 mL of anhydrous n-butanol. All other process steps, parameters, and raw material amounts were completely consistent with Example 1, with no high-temperature crystallization step throughout the process, and the final product of this comparative example was obtained.

[0060] Comparative Example 4 The hydrolysis inhibitor and crystal plane guide agent in step 3 of Example 1 were removed, and no composite guide agent was added. All other process steps, parameters, and raw material amounts were completely consistent with Example 1. There was no high-temperature crystallization step in the entire process, and the product of this comparative example was finally obtained.

[0061] Comparative Example 5 The only difference is that the stepwise addition method in step 5 of Example 1 is changed to adding all the water for hydrolysis at once, without pre-hydrolysis. All other process steps, parameters, and raw material amounts are completely consistent with Example 1, with no high-temperature crystallization step throughout the process, and the final product of this comparative example is obtained.

[0062] Comparative Example 6 The hydrolysis reaction temperature in steps 4-6 of Example 1 was adjusted to 120°C, while all other process steps, parameters, and raw material amounts were completely consistent with Example 1. There was no high-temperature crystallization step throughout the process, and the product of this comparative example was finally obtained.

[0063] Comparative Example 7 The only difference was that the aluminum n-butoxide in Example 1 was replaced with an equimolar amount of aluminum tert-butoxide, and the dual solvent system was replaced with anhydrous tert-butanol and tetrahydrofuran. All other process steps, parameters, and raw material amounts were completely consistent with Example 1, and the adjuvant product of this comparative example was finally obtained.

[0064] Comparative Example 8 Commercially available aluminum adjuvant Alhydrogel was used as a control sample, and all tests were performed according to the general performance verification method.

[0065] Summary table of performance verification results All embodiments and comparative examples underwent full testing according to the above-described general performance verification method. The results are summarized below:

[0066] Summary and Analysis of Verification Results In summary, the above embodiments and comparative examples fully verify the feasibility, universality, and high degree of inventiveness of the technical solution of the present invention. All technical solutions within the scope of protection of the claims of the present invention can directly obtain highly dense human-grade aluminum hydroxide adjuvants with a crystallinity ≥50% through a single hydrolysis reaction under mild conditions below 100°C, without the need for high-temperature, high-pressure hydrothermal or calcination treatment. Examples with different precursor types, solvent systems, and process parameters have all stably achieved the purpose of the invention, proving that the technical solution of the present invention has strong universality and that the scope of protection of the claims has a sufficient basis for implementation.

[0067] Comparative results show that the comparative examples, lacking the core technical features of the present invention such as the dual-solvent system and composite directing agent, and employing conventional non-controlled-rate schemes, could not obtain the required high-crystallinity adjuvant under low-temperature conditions. This reversely verifies the irreplaceability of the core technical features of the present invention and proves that the technical bias in the field that "straight-chain, sterically hindered aluminum alkoxides cannot achieve one-step crystallization at low temperatures" objectively exists. Compared with the comparative examples closest to the prior art and mainstream commercial adjuvants, the present invention's solution shortens the production cycle by over 60%, eliminates the need for high-risk, high-pressure operations, and significantly improves the crystallinity, specific surface area, antigen adsorption capacity, and long-term storage stability of the product. Simultaneously, the raw material cost is only 20%-30% of that of sterically hindered aluminum alkoxide solutions, achieving a dual technical and cost advantage that is unpredictable to those skilled in the art. The present invention overcomes the long-standing dual technical biases in the field, completely solving the long-standing industry problem of the incompatibility between low-cost, sterically hindered aluminum alkoxides and low-temperature controllable crystallization, possessing extremely high inventiveness and industrial application value.

[0068] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing high density human aluminum hydroxide adjuvant by hydrolysis of aluminum alcoholate, comprising hydrolysis reaction of aluminum alcoholate precursor with water in a solvent system, characterized in that, The aluminum alkoxide precursor is a straight-chain, sterically hindered aluminum alkoxide compound of the general formula Al(OR)3, and serves as the sole aluminum source for preparing the adjuvant; in the general formula, R is a straight-chain C2-C4 alkyl group; the solvent system is a dual-solvent system composed of an alcohol solvent and an aprotic inert solvent; a composite directing agent is also added to the hydrolysis reaction system, which includes a hydrolysis inhibitor and a crystal plane directing agent; in the hydrolysis reaction system, the molar ratio of water to the aluminum alkoxide precursor is 3:1 to 10:1; the hydrolysis reaction is carried out at a temperature below 100°C, and after the hydrolysis reaction is completed, there is no need for high-temperature and high-pressure hydrothermal treatment above 150°C or high-temperature calcination treatment above 400°C. A boehmite crystal phase with a crystallinity of ≥50% is directly obtained through a single hydrolysis reaction, and the finished adjuvant can be obtained by conventional purification treatment.

2. The method of claim 1, wherein, The aluminum alkoxide precursor is selected from at least one of aluminum ethoxide, aluminum n-propoxide, and aluminum n-butoxide.

3. The method according to claim 1 or 2, characterized in that, In the dual-solvent system, the alcohol solvent is a straight-chain C2-C4 monohydric alcohol corresponding to the alkoxy group of the aluminum alkoxide precursor, and the aprotic inert solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, and dimethyl sulfoxide. The volume ratio of the alcohol solvent to the aprotic inert solvent is 1:0.5 to 1:

3.

4. The method of claim 3, wherein, In the composite directing agent, the hydrolysis inhibitor is selected from at least one of ammonium fluoride and sodium fluoride, and the amount used is 0.05% to 2% of the molar amount of the aluminum alkoxide precursor; the crystal plane directing agent is selected from at least one of lactic acid, gluconic acid, citric acid, tartaric acid, and salicylic acid, and the amount used is 0.1% to 5% of the molar amount of the aluminum alkoxide precursor.

5. The method of claim 4, wherein, The hydrolysis reaction is carried out at a temperature of 60℃ to 98℃ for a time of 8h to 24h.

6. The method of claim 5, wherein, The hydrolysis reaction is carried out by adding water in steps: first, 30% to 50% of the total water volume is added dropwise, and pre-hydrolyzing is carried out at the reaction temperature for 1 to 3 hours. Then, the remaining water volume is added dropwise at a uniform rate, and the total addition time is controlled at 3 to 6 hours.

7. The method of claim 6, wherein, After the hydrolysis reaction is completed, a mild aging step is also included: the pH of the reaction system is adjusted to 6.5~7.5, and the system is stirred and aged at 50℃~80℃ for 12h~72h.

8. A high density aluminium hydroxide adjuvant for human use, characterized in that, obtained by the method according to any one of claims 1 to 7, said adjuvant being in boehmite crystalline form, having a crystallinity ≥ 50%, a specific surface area comprised between 400 m 2 / g and 650 m 2 / g, and an isoelectric point comprised between pH 10.0 and 11.

0.

9. The high density aluminium hydroxide adjuvant for human use according to claim 8, characterized in that, The adjuvant has an adsorption capacity for tetanus toxoid ≥2.6 mg / mg Al.

10. The use of the highly dense human aluminum hydroxide adjuvant according to claim 8 or 9 in the preparation of human vaccine drugs.

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