High-concentration high-stability dibromohydantoin solution and preparation method thereof

Abstract

The invention relates to the field of dibromohydantoin, in particular to a high-concentration and high-stability dibromohydantoin solution and a preparation method thereof. The stability and solubility of the dibromohydantoin are improved by compounding the specific solubilizer and the stabilizer. Wherein the solubilizer comprises one or more of urea, acetamide, EDTA2Na or gamma-cyclodextrin, the stabilizer is a compound system of sulfamic acid and Tween 80 or polyhexamethylene biguanide, the effective bromine content of the prepared dibromohydantoin solution is greater than 4%, and through an accelerated stability test at 54 DEG C, the effective bromine content of the solution is maintained to be greater than or equal to 4.0%, and the storage life is prolonged to more than 6 months. And the pH value is stabilized at 5-7. The obtained dibromohydantoin solution has high solubility, high stability and safety, is suitable for multiple scenes such as water treatment and medical disinfection, and has remarkable commercial application value.

Description

Technical Field

[0001] The invention relates to the field of dibromohydantoin, in particular to a high-concentration and high-stability dibromohydantoin solution and a preparation method thereof. Background Art

[0002] Dibromohydantoin, also known as 1,3-dibromo-5,5-dimethylhydantoin (CAS number: 77-48-5), is a highly effective, broad-spectrum bromine-based disinfectant. It primarily exerts its oxidative bactericidal action by releasing active bromine. It is widely used in water treatment, healthcare, food processing, and agricultural production. Compared to traditional chlorine-based disinfectants, dibromohydantoin offers advantages such as rapid bactericidal activity, a wide pH range, a lack of irritating odor, and low residual activity. However, dibromohydantoin faces two major technical obstacles in its practical application: low solubility and low stability. For example, a Chinese invention patent application discloses a method for preparing a dibromohydantoin disinfectant solution. The raw materials for preparing the dibromohydantoin disinfectant, measured by weight, include 0.2-1 part dibromohydantoin, 0.2-1 part ND-301 compound releaser, and 98-99.6 parts water. Due to the low solubility of dibromohydantoin, the effective bromine concentration in the product is only 200-10,000 ppm, a relatively low level, resulting in relatively poor disinfection performance.

[0003] The effective bromine content of raw dibromohydantoin powder is approximately 50%, and its water solubility at room temperature is approximately 0.2%. Traditionally, amino- or carbonyl-containing compounds such as urea and allantoin are often used to improve solubility. For example, urea has limited solubilization effect at low concentrations, necessitating an increase in urea concentration. However, excessive urea can affect solution stability. Allantoin, however, has low solubility, with a saturation concentration of only 0.6%, making it suitable only for low-concentration dibromohydantoin systems and unable to meet high-concentration requirements. Furthermore, while cyclodextrin can improve solubility through inclusion complexation, its high cost limits its commercial application. Furthermore, dibromohydantoin solutions are prone to decomposition during storage, especially at high temperatures, resulting in a decrease in effective bromine content, discoloration, or pH fluctuations.

[0004] Dibromohydantoin disinfectants are generally required to have excellent stability. After 14 days of storage at 54°C, the available bromine content decreases by less than 10%, indicating a shelf life of at least one year under natural storage conditions. Disinfectants prepared using disinfectant tablets or powders exhibit a decrease in available bromine content of less than 10% after 3 days of storage at room temperature. Therefore, while maintaining a high available bromine content in dibromohydantoin solutions, further ensuring product storage stability is a pressing technical challenge for researchers in this field. Summary of the Invention

[0005] In order to solve the above technical problems, the first aspect of the present invention provides a high-concentration and high-stability dibromohydantoin solution, the raw materials for its preparation include dibromohydantoin, a solubilizer, a stabilizer and a solvent, and the effective bromine content of the dibromohydantoin solution is greater than 4%.

[0006] The testing principle of the effective bromine content in the present invention is as follows: in an acidic solution, dibromohydantoin is oxidized by potassium iodide to precipitate a certain amount of iodine, which is then titrated with a sodium thiosulfate standard solution.

[0007] The test procedure for effective bromine content in the present invention (reference: Section 2.2.14 of the "Technical Specifications for Hospital Disinfection") is as follows: 0.15 g of the sample to be tested is weighed and placed in a 250 mL iodine volumetric flask to which 125 mL of water and 2 g of potassium iodide (AR) have been added. The sample is stirred thoroughly on an electromagnetic stirrer to completely dissolve the sample. The sample is removed, 20 mL of sulfuric acid solution is added, the bottle mouth and bottle wall are rinsed with 20 mL of distilled water, the bottle is quickly covered and sealed, and the bottle is placed in a dark place for 5 minutes. The sample is then titrated with a sodium thiosulfate standard solution (c(Na2S2O4) 0.1 mol / L). When the solution turns light yellow, a starch indicator (5 g / L) is added and the titration is continued until the blue color disappears. The volume of the sodium thiosulfate standard titration solution consumed is recorded (a blank is also made at the same time).

[0008] Available bromine content

[0009] Wherein, V1: volume of sodium thiosulfate standard titration solution consumed in titration, mL;

[0010] V2: Volume of sodium thiosulfate standard titration solution consumed in blank titration, mL;

[0011] m: the mass of the sample, g;

[0012] 0.07991: the mass of bromine in grams equivalent to 1.0 g of sodium thiosulfate standard titration solution [c(Na2S2O4) = 1.0 mol / L];

[0013] c1: titration concentration of sodium thiosulfate standard solution, mol / L;

[0014] The unit of effective bromine content in the solution is mg / L.

[0015] As an implementable example, the solubilizer includes one or more of urea, allantoin, thiourea, amide, cyclodextrin, EDTA derivative or organic acid sodium salt.

[0016] As an implementable case, the mass ratio of dibromohydantoin to urea is 10:(5-10).

[0017] Furthermore, the mass ratio of dibromohydantoin to urea is 10:10.

[0018] As an implementable case, the mass ratio of dibromohydantoin to allantoin is 1:(0.1-0.5).

[0019] Furthermore, the mass ratio of dibromohydantoin to allantoin is 1:0.5.

[0020] As an implementable example, the amidate includes acetamide or nicotinamide.

[0021] Furthermore, the amidate is acetamide.

[0022] Furthermore, the mass ratio of acetamide to dibromohydantoin is (10-15):10.

[0023] As an implementable example, the cyclodextrin includes one or more of α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.

[0024] Furthermore, the mass ratio of the gamma-cyclodextrin to dibromohydantoin is 10:(15-40).

[0025] As an implementable case, the EDTA derivative includes one or more of EDTA2Na, EDTA4Na, EDTAFeNa or EDTACuNa.

[0026] Furthermore, the EDTA derivative includes EDTA2Na.

[0027] As an implementable case, the organic acid sodium salt includes one of sodium benzoate, sodium salicylate, and sodium p-aminobenzoate.

[0028] Furthermore, the solubilizing agent includes at least one of urea, EDTA2Na, acetamide or gamma-cyclodextrin.

[0029] The solubilization mechanism of urea for dibromohydantoin is primarily based on its intermolecular interaction. The amino group (-NH2) in the urea molecule acts as a hydrogen bond donor, while the carbonyl group (-CO-) acts as a hydrogen bond acceptor, forming a hydrogen bond network with polar groups in the dibromohydantoin molecule. This effectively disrupts the original crystalline structure of dibromohydantoin, weakening its intermolecular packing. Furthermore, it enhances its hydrophilicity by forming a soluble urea-dibromohydantoin complex. However, low urea levels are less effective in solubilizing high concentrations of dibromohydantoin.

[0030] The amino group (-NH2) of acetamide acts as a hydrogen bond donor, and the carbonyl group (-CO-) as a hydrogen bond acceptor, forming multiple hydrogen bond interactions with bromine atoms, amide groups, or carbonyl groups in the dibromohydantoin molecule. This weakens the hydrophobic stacking or van der Waals forces between dibromohydantoin molecules, destabilizing their crystal structure. Simultaneously, it enhances the molecule's hydrophilicity by forming an acetamide-dibromohydantoin polar complex. Furthermore, acetamide, as a small molecule cosolvent, can reduce the aggregation tendency of dibromohydantoin molecules in the solvent through molecular dispersion, thereby synergistically improving the solubility and dispersibility of dibromohydantoin. However, single-component acetamide has a poor solubilization effect on dibromohydantoin, primarily due to the limitations of its molecular structure, which prevents it from forming a stable acetamide-dibromohydantoin polar complex with dibromohydantoin. Furthermore, acetamide lacks synergistic effects with other solubilizing agents and cannot provide sufficient hydrogen bonding or polar interactions to significantly enhance the solubility of dibromohydantoin. Even if acetamide can partially solubilize dibromohydantoin, the resulting system is unstable and cannot maintain a good solubility effect in practical applications.

[0031] The multiple carboxyl groups and amino functional groups in the EDTA2Na molecule can specifically bind to metal ions in the solution to form a stable water-soluble complex. In addition, the potential binding of metal ions to polar groups in the dibromohydantoin molecule can be effectively eliminated during the reaction process, avoiding the formation of insoluble metal-dibromohydantoin complex precipitation. At the same time, EDTA2Na reduces the concentration of free metal ions in the solution, reducing the interference of metal ions on the intermolecular interactions of dibromohydantoin, thereby improving the hydrophilicity and dispersibility of dibromohydantoin, and ultimately significantly improving its solubility in the solvent system. However, single-component EDTA2Na is difficult to achieve the ideal solubilization effect and usually needs to be compounded with other solubilizing agents, such as urea and cyclodextrin, to further improve solubility. Therefore, the present invention successfully achieves a mass concentration of dibromohydantoin solution of 10wt% by compounding hydrogen-bonding solubilizing agents such as urea and acetamide with EDTA2Na. The effective bromine content in the dibromohydantoin solution is greater than 4%, significantly higher than the original powder solubility of 0.2g / 100mL, meeting the performance requirements of high-concentration disinfectant preparations.

[0032] The solubilization mechanism of γ-cyclodextrin for dibromohydantoin is primarily based on its unique cyclic cavity structure and inclusion complex. γ-cyclodextrin is a cyclic oligosaccharide composed of multiple glucose units. Its hydrophobic cavity selectively incorporates hydrophobic or non-polar groups in dibromohydantoin molecules through van der Waals forces and hydrophobic interactions, while the hydrophilic hydroxyl groups on the outside form hydrogen bonds with water molecules, significantly increasing the hydrophilicity of the complex. This inclusion complex disperses and stabilizes dibromohydantoin molecules in aqueous solution, reducing the tendency for intermolecular aggregation. At the same time, by forming a water-soluble γ-cyclodextrin-dibromohydantoin inclusion complex, it effectively destroys the drug's original crystalline structure, thereby significantly improving its solubility and solution stability. However, the price of γ-cyclodextrin raw materials is relatively high, and its large-scale use will lead to a significant increase in production costs. A combination of γ-cyclodextrin and EDTA2Na significantly improves the solubility of dibromohydantoin, particularly at a mass ratio of 10:(10-15):2. This is primarily due to the hydrophobic interior and hydrophilic exterior of γ-cyclodextrin, which can encapsulate the hydrophobic portions of dibromohydantoin molecules to form inclusion complexes, reducing intermolecular forces and aggregation, thereby enhancing solubility. Simultaneously, EDTA2Na, as a ligand, coordinates with the bromine atoms in dibromohydantoin to form stable water-soluble complexes, altering the solution's ionic strength and polarity, further promoting dissolution. Furthermore, the synergistic effect of γ-cyclodextrin and EDTA2Na optimizes the dissolution environment, enhances intermolecular interactions, and further improves the solubility of dibromohydantoin. This complex system effectively enhances the solubility of dibromohydantoin through inclusion, coordination, and synergistic effects, and has promising application prospects.

[0033] In actual production, a multi-component compounding technical solution is often adopted, in which at least two of urea, EDTA2Na, acetamide or gamma-cyclodextrin are selected to solubilize through the synergistic effect between the components. This significantly improves the solubility and formulation stability of dibromohydantoin while ensuring safety and cost control. This allows the technical effects of achieving a mass concentration of 10wt% of the dibromohydantoin solution, an effective bromine content of greater than 4%, and excellent heat resistance and stability.

[0034] As an implementable example, the stabilizer includes one or more of sulfamic acid, sulfamic acid derivatives, Tween emulsifiers, ammonium sulfate or polyhexamethylene biguanide.

[0035] As an implementable example, the aminosulfonic acid derivative includes one or more of methylaminosulfonate, ethylaminosulfonate, propylaminosulfonate or ammonium sulfamate.

[0036] As an implementable case, the Tween emulsifier includes one or more of Tween 20, Tween 40, Tween 60 or Tween 80.

[0037] Furthermore, the stabilizer includes at least one of aminosulfonic acid, Tween 80 or polyhexamethylene biguanide.

[0038] Furthermore, when the stabilizer is aminosulfonic acid and Tween 80, the mass ratio of dibromohydantoin to aminosulfonic acid and Tween 80 is 10: (0.2-2): (2.5-10).

[0039] Furthermore, when the stabilizer is aminosulfonic acid and Tween 80, and the solubilizer includes urea and EDTA2Na, the mass ratio of dibromohydantoin to urea to EDTA2Na to aminosulfonic acid and Tween 80 is 10:10:2:(0.5-1):10 or 10:10:2:(1.5-2):7.5.

[0040] Furthermore, when the stabilizer is aminosulfonic acid and Tween 80, and the solubilizer includes acetamide and EDTA2Na, the mass ratio of dibromohydantoin to acetamide to EDTA2Na to aminosulfonic acid and Tween 80 is 10:10:2:(0.2-1):(2.5-10).

[0041] Furthermore, when the stabilizer is aminosulfonic acid and Tween 80, and the solubilizer includes γ-cyclodextrin and EDTA2Na, the mass ratio of dibromohydantoin to γ-cyclodextrin and EDTA2Na to aminosulfonic acid and Tween 80 is 10:15:2:(0.2-1.5):(2-10).

[0042] Furthermore, when the stabilizer is aminosulfonic acid and polyhexamethylene biguanide, the mass ratio of dibromohydantoin to aminosulfonic acid and polyhexamethylene biguanide is 10:(0.2-2):(0.1-2).

[0043] Furthermore, when the stabilizers are aminosulfonic acid and polyhexamethylene biguanide; the solubilizers are urea and EDTA2Na; the mass ratio of dibromohydantoin and aminosulfonic acid, polyhexamethylene biguanide, urea and EDTA2Na is 10:(0.5-2):(0.1-1.5):10:2.

[0044] Furthermore, when the stabilizers are aminosulfonic acid and polyhexamethylene biguanide; the solubilizers are acetamide and EDTA2Na; the mass ratio of dibromohydantoin and aminosulfonic acid, polyhexamethylene biguanide, acetamide and EDTA2Na is 10:(0.5-1.5):(0.5-1.5):10:2.

[0045] Furthermore, when the stabilizers are aminosulfonic acid and polyhexamethylene biguanide; the solubilizers are γ-cyclodextrin and EDTA2Na; the mass ratio of dibromohydantoin and aminosulfonic acid, polyhexamethylene biguanide, γ-cyclodextrin and EDTA2Na is 10:(0.2-1.5):(0.1-1.5):15:2.

[0046] As an implementable example, the solvent includes one of water, PBS buffer or citric acid.

[0047] The second aspect of the present invention provides a method for preparing a high-concentration and high-stability dibromohydantoin solution, comprising: mixing dibromohydantoin, a solubilizer, a stabilizer and a solvent, and stirring the mixture to obtain the solution.

[0048] Beneficial effects

[0049] (1) The present invention successfully achieves a mass concentration of 10% dibromohydantoin solution by combining hydrogen-bonding solubilizers such as urea and acetamide with EDTA2Na. The effective bromine content in the dibromohydantoin solution is greater than 4%, which is significantly higher than the solubility of the original powder of 0.2g / 100mL, meeting the performance requirements of high-concentration disinfectant preparations.

[0050] (2) The present invention selects a combination of aminosulfonic acid and polyhexamethylene biguanide as a stabilizer, and further limits the mass ratio of dibromohydantoin to aminosulfonic acid and polyhexamethylene biguanide to 10: (0.2-2): (0.1-2). The prepared dibromohydantoin solution maintains an effective bromine content of ≥4.0% in an accelerated stability test at 54°C, and the shelf life is extended to more than 6 months, meeting the requirements for commercial long-term storage.

[0051] (3) The present invention selects a combination of aminosulfonic acid and Tween 80 as stabilizers, and further limits the mass ratio of dibromohydantoin to aminosulfonic acid and Tween 80 to 10: (0.2-2): (2.5-10). The prepared dibromohydantoin solution maintains an effective bromine content of ≥4.0% in an accelerated stability test at 54°C, and the shelf life is extended to more than 6 months, meeting the requirements for commercial long-term storage.

[0052] (IV) Through a large number of screening experiments, the present invention found that some solubilizers have a high risk factor. Therefore, the use of solubilizers with violent reactions, such as EDTAFeNa and ammonium polyphosphate, was avoided. Instead, the solubilizers and stabilizers most suitable for dibromohydantoin, such as acetamide and urea, were selected as safe ingredients to reduce production risks. In addition, a suitable solvent was selected to stabilize the pH of the compound system at 5-7, reduce side reactions and bromine gas emission problems, and make the operation safer.

[0053] (5) The dibromohydantoin solution provided by the present invention can dynamically adjust the solution polarity, ionic strength and metal interference, is compatible with different pH and temperature conditions, and is suitable for diverse scenarios such as industrial water treatment and medical disinfection, thereby expanding the application range of dibromohydantoin. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 Schematic diagram of the appearance of the light yellow dibromohydantoin solution in experimental groups 11-16.

[0055] Figure 2 Schematic diagram of the appearance of the light orange dibromohydantoin solution in experimental groups 11-16.

[0056] Figure 3 Schematic diagram of the appearance of the orange-red dibromohydantoin solution in experimental groups 11-16. DETAILED DESCRIPTION

[0057] 1. Solubilizer Screening Experiment

[0058] Experimental group 1, urea and allantoin solubilization experiment

[0059] Experimental group 1.1 Urea solubilization experiment

[0060] Experimental Group 1.1 The first aspect provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, urea and water, and the amounts of raw materials are shown in Table 1.

[0061] The second aspect of experimental group 1.1 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, urea, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin after 30 minutes, and recording the dissolution effect in Table 1.

[0062] Table 1

[0063]

[0064]

[0065] From the experimental results in Table 1, it can be seen that when the mass ratio of dibromohydantoin, urea and water is 10:10:80, corresponding to Example 1.5#, the solubilization effect of dibromohydantoin is better, and the mass concentration of dibromohydantoin reaches 10 wt%.

[0066] Experimental group 1.2 Urea solubilization experiment

[0067] Experimental group 1.2 first provided a dibromohydantoin solution, the raw materials for preparation included dibromohydantoin, allantoin and water, and the amounts of the raw materials were shown in Table 2.

[0068] The second aspect of experimental group 1.2 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, allantoin and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 2.

[0069] Table 2

[0070] Example 1.6# 1.7# 1.8# Dibromohydantoin (parts) 1 1 1 Allantoin (part) 0.1 0.5 1 Water (parts) 98.9 98.5 98 Dissolution effect of dibromohydantoin The solubilization effect is not obvious Completely dissolved Not completely dissolved

[0071] From the experimental results in Table 2, it can be seen that due to the low solubility of allantoin itself, it can only be used as a solubilizer for low-concentration dibromohydantoin, and the saturated mass concentration of allantoin is 0.6 wt%.

[0072] When the mass ratio of dibromohydantoin, allantoin and water is 1:0.5:98.5, corresponding to Example 1.7#, the solubilization effect of dibromohydantoin is better, and the mass concentration of dibromohydantoin reaches 1wt%.

[0073] Experimental group 2, acetamide solubilization experiment

[0074] The first aspect of experimental group 2 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, acetamide and water, and the amounts of raw materials are shown in Table 3.

[0075] The second aspect of Experimental Group 2 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, acetamide, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 3.

[0076] Table 3

[0077]

[0078]

[0079] From the experimental results in Table 3, it can be seen that when acetamide is used as a solubilizing agent, when the mass ratio of dibromohydantoin to acetamide is 10:(10-15), corresponding to Examples 2.5# and 2.6#, the dissolution effect of dibromohydantoin is good, and the mass concentration can reach 10wt%. In addition, the use of acetamide is safe and easy to operate.

[0080] Experimental group 3, cyclodextrin solubilization experiment

[0081] Experimental group 3.1, α-cyclodextrin solubilization experiment

[0082] Experimental Group 3.1 The first aspect provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, α-cyclodextrin and water, and the amounts of the raw materials are shown in Table 4.

[0083] The second aspect of Experimental Group 3.1 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, α-cyclodextrin, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 4.

[0084] Table 4

[0085] Example 3.1# 3.2# 3.3# 3.4# 3.5# 3.6# Dibromohydantoin (parts) 10 10 10 10 10 10 α-cyclodextrin (parts) 2.5 6.6 10 15 30 56.6 Water (parts) 87.5 83.4 80 75 60 33.4 Dissolution effect of dibromohydantoin Not completely dissolved Not completely dissolved Not completely dissolved A small amount of undissolved Completely dissolved Completely dissolved

[0086] Conclusion: α-cyclodextrin itself has relatively poor solubility and poor inclusion properties for dibromohydantoin. However, when the mass ratio of dibromohydantoin to α-cyclodextrin is 10:(30-56.6), it can be completely dissolved. For Examples 3.5# and 3.6#, the mass concentration of dibromohydantoin can reach 10wt%. However, the solubility performance is better for 2wt% dibromohydantoin, and it can basically be dissolved.

[0087] The pretreatment process of cyclodextrin is as follows: 0.5 kg of cyclodextrin and grinding balls are mixed in a mass ratio of 1:1, added into a 2.5 L ball mill, and ball milled for 6 hours at a stirring speed of 600 rpm.

[0088] Experimental group 3.2, β-cyclodextrin solubilization experiment

[0089] The first aspect of Experimental Group 3.2 provides a dibromohydantoin solution. The raw materials for preparation include dibromohydantoin, β-cyclodextrin and water. The amounts of the raw materials are shown in Table 5.

[0090] The second aspect of experimental group 3.2 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, β-cyclodextrin, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 5.

[0091] Table 5

[0092] Example 3.7# 3.8# 3.9# 3.10# 3.11# Dibromohydantoin (parts) 10 10 10 10 10 β-cyclodextrin (parts) 6.6 10 15 23.3 40 Water (parts) 83.4 80 75 66.7 50 Dissolution effect of dibromohydantoin Mostly insoluble Mostly insoluble A small part is insoluble A small part is insoluble partially insoluble

[0093] Conclusion: The solubility of β-cyclodextrin itself is relatively poor, and its inclusion property for dibromohydantoin is not good. However, it has good solubility for 1wt% dibromohydantoin and can basically dissolve it, so its cost-effectiveness is low.

[0094] Experimental group 3.3, γ-cyclodextrin solubilization experiment

[0095] The first aspect of experimental group 3.3 provided a dibromohydantoin solution, the raw materials for preparation included dibromohydantoin, γ-cyclodextrin and water, and the amounts of the raw materials were shown in Table 6.

[0096] The second aspect of experimental group 3.3 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, γ-cyclodextrin, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 6.

[0097] Table 6

[0098]

[0099] Conclusion: The molecular cavity of γ-cyclodextrin is large, and its inclusion effect on dibromohydantoin is ideal. When the mass ratio of dibromohydantoin to γ-cyclodextrin is 10:(15-40), the solubilization effect is excellent, but its price is high. Therefore, the mass ratio of dibromohydantoin to γ-cyclodextrin is limited to 10:(10-15) as the optimal solution.

[0100] Experimental group 4, sodium salicylate solubilization experiment

[0101] The first aspect of experimental group 4 provided a dibromohydantoin solution, the raw materials for preparation included dibromohydantoin, sodium salicylate and water, and the amounts of raw materials were shown in Table 7.

[0102] The second aspect of Experimental Group 4 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, sodium salicylate, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 7.

[0103] Table 7

[0104]

[0105] Experimental group 5, sodium benzoate solubilization experiment

[0106] The first aspect of experimental group 5 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, sodium benzoate and water, and the amounts of raw materials are shown in Table 8.

[0107] The second aspect of experimental group 5 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, sodium benzoate and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of dibromohydantoin, and recording the dissolution effect in Table 8.

[0108] Table 8

[0109]

[0110] Experimental group 6, EDTA2Na solubilization experiment

[0111] The first aspect of experimental group 6 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, EDTA2Na and water, and the raw material amounts are shown in Table 9.

[0112] The second aspect of Experimental Group 6 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, EDTA2Na and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of dibromohydantoin, and recording the dissolution effect in Table 9.

[0113] Table 9

[0114]

[0115] Conclusion: The solubilization effect of dibromohydantoin using EDTA2Na alone is average, and the solubilization effect will be improved when used with other components of solubilizers.

[0116] Experimental group 7, EDTAFeNa solubilization experiment

[0117] Mix 10 parts of dibromohydantoin, 10 parts of EDTAFeNa and 80 parts of water. A violent reaction occurs as soon as the three components are mixed. The solution immediately turns red and bromine gas escapes. This may be due to the reduction of iron in EDTAFeNa, which leads to the failure of the experiment and the experiment is relatively dangerous.

[0118] Experimental group 8, PEPA solubilization experiment

[0119] The first aspect of experimental group 8 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, PEPA (pentaerythritol phosphate) and water, and the raw material amounts are shown in Table 10.

[0120] The second aspect of Experimental Group 8 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, PEPA, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 10.

[0121] Table 10

[0122]

[0123]

[0124] Conclusion: The solubilization effect of PEPA is poor, the cost performance is poor, and the experiment fails.

[0125] Experimental group 9, polyphosphate solubilization experiment

[0126] Experimental Group 9.1, ammonium polyphosphate solubilization experiment

[0127] Experimental Group 9.1 provides a dibromohydantoin solution. The raw materials for preparation include dibromohydantoin, ammonium polyphosphate and water. The amounts of raw materials are shown in Table 11.

[0128] The second aspect of Experimental Group 9.1 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, ammonium polyphosphate, and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of the dibromohydantoin, and recording the dissolution effect in Table 11.

[0129] Table 11

[0130]

[0131] Experimental Group 9.2: Sodium tripolyphosphate solubilization experiment

[0132] The first aspect of experimental group 9 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, sodium tripolyphosphate and water, and the raw material amounts are shown in Table 12.

[0133] The second aspect of Experimental Group 9 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, sodium tripolyphosphate and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of dibromohydantoin, and recording the dissolution effect in Table 12.

[0134] Table 12

[0135]

[0136]

[0137] Conclusion: The solubilizing effect of sodium tripolyphosphate is insufficient and it can be used together with other solubilizers.

[0138] Experimental group 10, dimethylhydantoin solubilization experiment

[0139] The first aspect of experimental group 10 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, dimethylhydantoin and water, and the amounts of raw materials are shown in Table 13.

[0140] The second aspect of experimental group 10 provides a method for preparing a dibromohydantoin solution, comprising: stirring and mixing dibromohydantoin, dimethylhydantoin and water in certain mass fractions to obtain a dibromohydantoin solution, observing the dissolution of dibromohydantoin, and recording the dissolution effect in Table 13.

[0141] Table 13

[0142]

[0143] Conclusion: The effect of dimethylhydantoin as a solubilizer is average when used alone and it needs to be used in combination with other solubilizers.

[0144] 2. Screening of high-concentration and high-stability dibromohydantoin solutions

[0145] Experimental Group 11

[0146] In this experimental group, aminosulfonic acid + Tween 80 and urea + EDTA2Na raw materials were used as the compound system to test the dissolution effect of dibromohydantoin.

[0147] The first aspect of experimental group 11 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, urea, EDTA2Na, aminosulfonic acid, Tween 80 and PBS buffer, the total mass parts of the raw materials are 100, and the raw material amounts are shown in Tables 14-15.

[0148] The second aspect of experimental group 11 provides a method for preparing a dibromohydantoin solution, wherein dibromohydantoin, urea, EDTA2Na, aminosulfonic acid, Tween 80 and PBS buffer are mixed according to a certain mass fraction, and the total mass fraction of the raw materials is ensured to be 100 parts to obtain a dibromohydantoin solution.

[0149] Table 14

[0150]

[0151] When PBS buffer was added to the system in 100 parts by mass, the pH of the final dibromohydantoin solution was between 5 and 7. The pH of the solution in 11.10# was too low after 100 parts of PBS buffer were added. Further addition of PBS buffer until the pH reached 6 decreased the dissolution efficiency of dibromohydantoin.

[0152] Table 15

[0153]

[0154] When PBS buffer is added to the system to a mass fraction of 100, the pH value of the dibromohydantoin solution is between 5 and 7.

[0155] Samples numbered 11.11# to 11.18# were placed in opaque sealed bottles and placed in a 54°C constant temperature box for 14 days. After 14 days, the appearance, pH value, and content (effective bromine content) were tested. The experimental results are detailed in Table 16.

[0156] Table 16

[0157]

[0158]

[0159] Conclusion: From the experimental results in Table 11, it can be seen that the stabilizing effect of aminosulfonic acid is excellent for the dibromohydantoin solution with a relative mass concentration of 10wt%, and the stabilizing effect is optimal when the mass concentration of aminosulfonic acid is 0.1-1wt%. The stabilizing effect is further improved by adding Tween 80, and the optimal mass concentration of Tween 80 is 5-10wt%.

[0160] A comprehensive analysis of the dissolution effect of dibromohydantoin showed that Examples 11.7#, 11.8#, 11.9#, 11.17#, and 11.18# had the best dissolution effect. However, further consideration of the thermal storage stability showed that the solutions of Examples 11.17# and 11.18# changed color after being kept in a 54°C constant temperature box for 14 days, and the effective bromine content was less than 4%. Therefore, Examples 11.7#, 11.8#, and 11.9# were selected as the optimal implementation cases. At this time, the mass ratio of dibromohydantoin, urea, EDTA2Na, aminosulfonic acid, and Tween 80 was 10:10:2:(0.5-1):10.

[0161] Experimental group 12

[0162] In this experimental group, aminosulfonic acid + Tween 80 and acetamide + EDTA2Na were used as the compound systems to test the dissolution effect of dibromohydantoin.

[0163] The first aspect of experimental group 12 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, acetamide, EDTA2Na, aminosulfonic acid, Tween 80 and PBS buffer, the total mass parts of the raw materials are 100, and the raw material amounts are shown in Tables 17-18.

[0164] The second aspect of experimental group 12 provides a method for preparing a dibromohydantoin solution, wherein dibromohydantoin, acetamide, EDTA2Na, aminosulfonic acid, Tween 80 and PBS buffer are mixed according to certain mass parts, and the total mass parts of the raw materials are ensured to be 100 parts to obtain a dibromohydantoin solution.

[0165] Table 17

[0166]

[0167] After PBS buffer is added to the system to a mass fraction of 100, the pH value of the dibromohydantoin solution is between 5 and 7.

[0168] Table 18

[0169]

[0170] After PBS buffer is added to the system to a mass fraction of 100, the pH value of the dibromohydantoin solution is between 5 and 7.

[0171] Samples 12.1# to 12.16# were placed in opaque sealed bottles and then placed in a 54°C constant temperature box for 14 days. After 14 days, the appearance, pH value, and content (effective bromine content) were tested. The experimental results are detailed in Table 19.

[0172] Table 19

[0173]

[0174]

[0175] Conclusion: The experimental results in Table 19 show that in the sulfamic acid + Tween 80 and acetamide + EDTA2Na compound systems, the optimal concentrations are 0.2-1wt% sulfamic acid and 2.5-10wt% Tween 80. Samples 12.13# to 12.16# exhibit slightly poor dissolution performance due to the low pH value achieved by adding 1.5wt% sulfamic acid. Furthermore, the experimental group consisting of dibromohydantoin + urea + EDTA2Na + sulfamic acid + Tween 80 exhibits better stability than the experimental group consisting of dibromohydantoin + acetamide + EDTA2Na + sulfamic acid + Tween 80.

[0176] A comprehensive analysis of the dissolution effect of dibromohydantoin revealed that Examples 12.3#-12.12# had the best dissolution effect. Further consideration of the thermal storage stability revealed that the solutions of Examples 12.3#-12.12# did not change color after being kept in a 54°C constant temperature box for 14 days, and the effective bromine content was still higher than 4%. Therefore, Examples 12.3#-12.12# were selected as the optimal implementation cases. At this time, the mass ratio of dibromohydantoin, acetamide, EDTA2Na, aminosulfonic acid, and Tween 80 was 10:10:2:(0.2-1):(5-10).

[0177] Experimental Group 13

[0178] In this experimental group, aminosulfonic acid + polyhexamethylene biguanide and urea + EDTA2Na raw materials were used as the compound system to test the dissolution effect of dibromohydantoin.

[0179] The first aspect of experimental group 13 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, urea, EDTA2Na, aminosulfonic acid, polyhexamethylene biguanide and PBS buffer, the total mass parts of the raw materials are 100, and the raw material amounts are shown in Tables 20-21.

[0180] The second aspect of experimental group 13 provides a method for preparing dibromohydantoin solution, wherein dibromohydantoin, urea, EDTA2Na, aminosulfonic acid, polyhexamethylene biguanide and PBS buffer are mixed according to certain mass parts, and the total mass parts of the raw materials are ensured to be 100 parts to obtain dibromohydantoin solution.

[0181] Table 20

[0182]

[0183] Table 21

[0184]

[0185] After PBS buffer is added to the system to a mass fraction of 100, the pH value of the dibromohydantoin solution is between 5 and 7.

[0186] The samples corresponding to serial numbers 13.1# to 13.16# were placed in opaque sealed bottles and then placed in a 54°C constant temperature box for 14 days. After 14 days, the appearance, pH value, and content (effective bromine content) were tested. The experimental results are detailed in Table 22.

[0187] Table 22

[0188]

[0189]

[0190] Among them, the 13.13# to 13.16# samples had a slightly poorer dissolution effect because the added concentration of aminosulfonic acid was 2 wt%, resulting in a lower pH value of the final solution.

[0191] Conclusion: From the experimental results in Table 22, it can be seen that in the composite systems of aminosulfonic acid + polyhexamethylene biguanide and urea + EDTA2Na, the mass concentration of aminosulfonic acid is 0.2-1wt%, and the mass concentration of polyhexamethylene biguanide is 0.2-1wt%, which is the best, and the stability of dibromohydantoin solution is better.

[0192] The appearance of the dibromohydantoin solutions shows that after the hot storage test, the products of Examples 13.3#-13.10# and 13.13#-13.16# still have a light orange appearance and an effective bromine content greater than 4%. Therefore, the mass ratios of dibromohydantoin, urea, EDTA2Na, aminosulfonic acid, and polyhexamethylene biguanide are 10:10:2:0.5:(1-1.5), 10:10:2:(1-1.5):(0.1-1.5), and 10:10:2:2:(1-1.5).

[0193] Experimental group 14

[0194] In this experimental group, aminosulfonic acid + polyhexamethylene biguanide and acetamide + EDTA2Na raw materials were used as the compound system to test the dissolution effect of dibromohydantoin.

[0195] The first aspect of experimental group 14 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, acetamide, EDTA2Na, aminosulfonic acid, polyhexamethylene biguanide and PBS buffer, the total mass parts of the raw materials are 100, and the raw material amounts are shown in Tables 23-24.

[0196] The second aspect of experimental group 14 provides a method for preparing a dibromohydantoin solution, wherein dibromohydantoin, acetamide, EDTA2Na, aminosulfonic acid, polyhexamethylene biguanide and PBS buffer are mixed according to a certain mass fraction, and the total mass fraction of the raw materials is ensured to be 100 parts to obtain a dibromohydantoin solution.

[0197] Table 23

[0198]

[0199] Table 24

[0200]

[0201] After PBS buffer is added to the system to a mass fraction of 100, the pH value of the dibromohydantoin solution is between 5 and 7.

[0202] The samples corresponding to serial numbers 14.1# to 14.16# were placed in opaque sealed bottles and then placed in a 54°C constant temperature box for 14 days. After 14 days, the appearance, pH value, and content (effective bromine content) were tested. The experimental results are detailed in Table 25.

[0203] Table 25

[0204]

[0205]

[0206] Conclusion: From the experimental results in Table 25, it can be seen that in the composite system of aminosulfonic acid + polyhexamethylene biguanide and acetamide + EDTA2Na, the mass concentration of aminosulfonic acid is 0.2-1wt%, and the mass concentration of polyhexamethylene biguanide is 0.2-1wt%, which is optimal. The stability of the dibromohydantoin solution is even better. It can be seen from the effective bromine content of the dibromohydantoin solution after being kept in a constant temperature box at 54°C for 14 days that the effective bromine content of Examples 14.3#, 14.4#, 14.7#, 14.8#, 14.10#, 14.11#, 14.12#, and 14.16# is still greater than 4%, indicating better high temperature stability. Comparing experimental groups 11-12 and 13-14, it can be seen that polyhexamethylene biguanide has a better solubilization effect than Tween 80, but the cost of polyhexamethylene biguanide is higher, and the cost and dissolution effect can be comprehensively considered when using it.

[0207] Experimental group 15

[0208] In this experimental group, aminosulfonic acid + Tween 80 and γ-cyclodextrin + EDTA2Na were used as the compound system to test the dissolution effect of dibromohydantoin.

[0209] The first aspect of experimental group 15 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, γ-cyclodextrin, EDTA2Na, aminosulfonic acid, Tween 80 and PBS buffer, the total mass parts of the raw materials are 100, and the raw material amounts are shown in Tables 26-27.

[0210] The second aspect of experimental group 15 provides a method for preparing dibromohydantoin solution, wherein dibromohydantoin, γ-cyclodextrin, EDTA2Na, aminosulfonic acid, Tween 80 and PBS buffer are mixed according to certain mass parts, and the total mass parts of the raw materials are ensured to be 100 parts to obtain dibromohydantoin solution.

[0211] The pretreatment process of γ-cyclodextrin is as follows: 0.5 kg of γ-cyclodextrin and grinding balls are mixed at a mass ratio of 1:1, added into a 2.5 L ball mill, and ball milled for 6 h at a stirring speed of 600 rpm.

[0212] Table 26

[0213]

[0214] Table 27

[0215]

[0216] After PBS buffer is added to the system to a mass fraction of 100, the pH value of the dibromohydantoin solution is between 5 and 7.

[0217] Samples 15.1# to 15.16# were placed in opaque sealed bottles and then placed in a 54°C constant temperature box for 14 days. After 14 days, the appearance, pH value, and content (effective bromine content) were tested. The experimental results are detailed in Table 28.

[0218] Table 28

[0219]

[0220]

[0221] Conclusion: From the experimental results in Table 28, it can be seen that in the composite systems of aminosulfonic acid + Tween 80 and γ-cyclodextrin + EDTA2Na, the stability of the dibromohydantoin solution is relatively excellent. From the effective bromine content of the dibromohydantoin solution after being kept in a constant temperature box at 54°C for 14 days, it can be seen that the effective bromine content of Examples 15.2#, 15.3#, 15.4#, 15.6#-15.8#, 15.10#-15.12#, and 15.16# is still greater than 4%, indicating better high-temperature stability.

[0222] Experimental group 16

[0223] In this experimental group, aminosulfonic acid + polyhexamethylene biguanide and γ-cyclodextrin + EDTA2Na were used as the compound system to test the dissolution effect of dibromohydantoin.

[0224] The first aspect of experimental group 16 provides a dibromohydantoin solution, the raw materials for preparation include dibromohydantoin, γ-cyclodextrin, EDTA2Na, aminosulfonic acid, polyhexamethylene biguanide and PBS buffer, the total mass parts of the raw materials are 100, and the raw material amounts are shown in Tables 29-30.

[0225] The second aspect of experimental group 16 provides a method for preparing a dibromohydantoin solution, wherein dibromohydantoin, γ-cyclodextrin, EDTA2Na, aminosulfonic acid, polyhexamethylene biguanide and PBS buffer are mixed in certain parts by mass, and the total mass of the raw materials is ensured to be 100 parts to obtain a dibromohydantoin solution.

[0226] The pretreatment process of γ-cyclodextrin is as follows: 0.5 kg of γ-cyclodextrin and grinding balls are mixed at a mass ratio of 1:1, added into a 2.5 L ball mill, and ball milled for 6 h at a stirring speed of 600 rpm.

[0227] Table 29

[0228]

[0229]

[0230] Table 30

[0231]

[0232] After PBS buffer is added to the system to a mass fraction of 100, the pH value of the dibromohydantoin solution is between 5 and 7.

[0233] Samples 16.1# to 16.16# were placed in opaque sealed bottles and then placed in a 54°C constant temperature box for 14 days. After 14 days, the appearance, pH value, and content (effective bromine content) were tested. The experimental results are detailed in Table 31.

[0234] Table 31

[0235]

[0236]

[0237] Conclusion: The experimental results in Table 31 show that the stability of dibromohydantoin solutions in the aminosulfonic acid + polyhexamethylene biguanide and gamma-cyclodextrin + EDTA2Na systems is also excellent. The effective bromine content of dibromohydantoin solutions after 14 days in a 54°C incubator indicates that Examples 16.1#-16.3#, 16.5#-16.7#, 16.9#-16.11#, and 16.15# still exceed 4%, indicating improved high-temperature stability. While gamma-cyclodextrin exhibits excellent solubilization effects, its high cost should be considered when using it.

[0238] The appearance diagram of the light yellow dibromohydantoin solution in experimental groups 11-16 is as follows Figure 1 shown.

[0239] The appearance diagram of the light orange dibromohydantoin solution in experimental groups 11-16 is as follows Figure 2 shown.

[0240] The appearance diagram of the orange-red dibromohydantoin solution in experimental groups 11-16 is as follows Figure 3 shown.

Claims

1. A high-concentration and high-stability dibromohydantoin solution, characterized in that: The preparation raw materials include dibromohydantoin, a solubilizer, a stabilizer and a solvent; The effective bromine content of the dibromohydantoin solution is greater than 4%.

2. The high-concentration and high-stability dibromohydantoin solution according to claim 1, characterized in that: The solubilizer includes one or more of urea, allantoin, thiourea, amidate, cyclodextrin, EDTA derivative or organic acid sodium salt.

3. The high-concentration and high-stability dibromohydantoin solution according to claim 2, characterized in that: The mass ratio of dibromohydantoin to urea is 10:(5-10).

4. The high-concentration and high-stability dibromohydantoin solution according to claim 2, characterized in that: The amidates include acetamide or nicotinamide.

5. The high-concentration and high-stability dibromohydantoin solution according to claim 4, wherein the mass ratio of acetamide to dibromohydantoin is (10-15):

10.

6. The high-concentration and high-stability dibromohydantoin solution according to claim 5, characterized in that: The cyclodextrin includes one or more of α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.

7. The high-concentration and high-stability dibromohydantoin solution according to claim 6, characterized in that: The mass ratio of the gamma cyclodextrin to dibromohydantoin is (15-40):

10.

8. The high-concentration and high-stability dibromohydantoin solution according to any one of claims 1 to 7, characterized in that: The stabilizer includes one or more of sulfamic acid, sulfamic acid derivatives, Tween 20, Tween 40, Tween 60, Tween 80, ammonium sulfate or polyhexamethylene biguanide.

9. The high-concentration and high-stability dibromohydantoin solution according to claim 1, characterized in that: The solvent includes one of water, PBS buffer or citric acid.

10. A method for preparing a high-concentration and high-stability dibromohydantoin solution according to any one of claims 1 to 9, characterized in that: include: Mix dibromohydantoin, a solubilizer, a stabilizer and a solvent, and stir them evenly to obtain a dibromohydantoin solution.

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