Thiothiamine crystal, preparation method and application thereof

Abstract

The present invention relates to a thiothiamine crystal and a preparation method thereof and a method for using the thiothiamine crystal. 12 H 16 N4OS2, molecular weight 296.41, the crystallographic characteristics of the thiothiamine include: space group P-1, unit cell parameters a=8.97618(18), b=12.2371(3), c=13.8492(2), α=113.5261(19), β=90.871(15)4, γ=99.5043(18), and unit cell volume of 1370.09(5). The thiothiamine crystals obtained by the present invention are a new crystal form, which improves the filtration performance of the product and has good hygroscopicity, and can significantly reduce water consumption, which has great significance for product performance and subsequent processing.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis and drug crystallization, and specifically relates to a thiothiamine crystal, a preparation method and application thereof, and in particular relates to a new thiothiamine crystal form, a preparation method and application thereof. Background Art

[0002] Polymorphism, the ability of a compound to exist in multiple crystalline forms, is crucial in pharmaceutical manufacturing. Different crystal forms vary in packing, molecular conformation, and lattice energy, affecting a range of properties, including solubility, dissolution rate, hardness, bulk density, melting point, tableting performance, and crystal habit. Therefore, the study of polymorphs plays an indispensable role in the development of drugs, materials, pesticides, and foods. The study of polymorphs is a crucial branch of crystal engineering, enabling the manipulation of the physical and chemical properties of active pharmaceutical ingredients (APIs) without altering their primary chemical formula or mechanism of action.

[0003] Vitamin B1 is a crucial nutrient, and the human body requires sufficient intake to maintain normal life. A vitamin B1 deficiency can lead to a range of problems, including purple fingers, shortness of breath, indigestion, abdominal distension, nausea and vomiting, loss of appetite, and weakness in the limbs. However, the production of vitamin B1 presents a series of challenges, notably the production of the intermediate product, thiothiamine. During production, thiothiamine is prepared by reactive crystallization. Due to reactive crystallization and the properties of the substance, thiothiamine exhibits a needle-shaped crystal habit. In actual production, these needle-shaped crystals are difficult to filter, have a high moisture content, and exhibit poor fluidity, making subsequent processing difficult. Consequently, large amounts of water are required for washing, resulting in significant water consumption and resource consumption.

[0004] Therefore, it is very necessary to develop a new thiothiamine crystal form. Summary of the Invention

[0005] The present invention aims to provide a thiothiamine crystal, a preparation method and application thereof. Compared with other existing crystal forms, the thiothiamine crystal greatly improves the product's performance and has low hygroscopicity. At the same time, it can significantly reduce the use of water, which has a great significance for product performance and post-processing, and expands its industrial production application. In addition, the present application adopts a suspension reaction crystallization method or a neutralization reaction crystallization method for preparation, which has a simple process and good repeatability.

[0006] One of the purposes of the present invention is to provide a thiothiamine crystal, wherein the molecular formula of the thiothiamine crystal is C 12 H 16 N4OS2, molecular mass 296.41, chemical structure is as follows:

[0007]

[0008] The crystallographic characteristics of the thiothiamine (such as Figure 2 The structure of the lattice structure is shown in Figure 2 (shown), including space group P-1, unit cell parameters a=8.97618(18), b=12.2371(3), c=13.8492(2), α=113.5261(19), β=90.871(15)4, γ=99.5043(18), and unit cell volume is 1370.09(5).

[0009] Preferably, the thiothiamine crystals have an X-ray powder diffraction pattern (e.g., Figure 1 The diffraction angles expressed in 2θ degrees are 6.98±0.2°, 8.02±0.2°, 8.22±0.2°, 12.6±0.2°, 13.64±0.2°, 13.98±0.2°, 16.48±0.2°, 20.12±0.2°, 21.92±0.2°, 22.56±0.2°, 22.92±0.2°23.52±0.2°, 27.68±0.2°, and 28.02±0.2°, respectively;

[0010] Preferably, the X-ray powder diffraction of the thiothiamine crystals measured using Cu-Kα radiation has a diffraction angle expressed in 2θ of 10.02±0.2°, 11.7±0.2°, 12.28±0.2°, 13.64±0.2°, 16.06±0.2°, 17.42±0.2°, 17.96±0.2°, 18.80±0.2°, 19.1±0.2°, 20.72±0.2°, 20.94±0.2°. .2°, 21.54±0.2°, 24.2±0.2°, 24.7±0.2°, 25.5±0.2°, 26.14±0.2°, 26.88±0.2°, 27.46±0.2°, 28.92±0.2°, 29.8±0.2°, 30.22±0.2°, 30.6±0.2°, 30.98±0.2°, 31.56±0.2°, and 32.46±0.2° also have characteristic peaks.

[0011] Preferably, the differential scanning calorimetry DSC spectrum of the thiothiamine crystals (such as Figure 3 ) has a characteristic endothermic peak at 133.68±2°C and a characteristic melting peak at 244.05°C.

[0012] A second object of the present invention is to provide a method for preparing thiothiamine crystals as described in the first object, wherein the preparation method is a suspension reaction crystallization method or a neutralization reaction crystallization method.

[0013] As a preferred technical solution of the present invention, the suspension reaction crystallization method comprises the following steps:

[0014] The thiothiamine raw material is mixed with a solvent, suspended for reaction and crystallization at 25-100° C. for 24-48 hours to obtain the thiothiamine crystals.

[0015] Preferably, the solvent is water or n-butanol;

[0016] Preferably, based on the addition amount of thiothiamine raw material being 0.5-2 g, the addition amount of the solvent is 20-50 mL;

[0017] Preferably, the mixing and suspension reaction crystallization are carried out under stirring conditions, and the stirring rate is 300-500 r / min.

[0018] Preferably, the preparation method further comprises sequentially performing solid-liquid separation and drying on the mixture obtained after suspension reaction crystallization;

[0019] Preferably, the solid-liquid separation method is filtration;

[0020] Preferably, the drying temperature is 25-50° C., and the drying time is 12-24 hours.

[0021] As another preferred technical solution of the present invention, the neutralization reaction crystallization method comprises the following steps:

[0022] (1) mixing aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid in a solvent, reacting at 70-90° C. for 1-2 hours to obtain a reactant;

[0023] (2) adding alkali solution to the reactant obtained in step (1) at 65-90° C. to obtain the thiothiamine crystals.

[0024] The molar ratio of the aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester to hydrochloric acid in step (1) is 1:(1-2);

[0025] Preferably, the solvent in step (1) is water;

[0026] Preferably, the amount of the solvent added in step (1) is 50-600 mL, based on the addition amount of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester being 50-70 g;

[0027] Preferably, the alkali solution in step (2) is sodium hydroxide solution;

[0028] Preferably, in step (2), alkali solution is added to a pH not lower than 4, preferably 6-8;

[0029] Preferably, the preparation method further comprises cooling the mixed solution after adding the alkali solution to 25-55°C;

[0030] Preferably, the preparation method further comprises cooling the mixture to 25-55° C., performing solid-liquid separation and drying in sequence;

[0031] Preferably, the solid-liquid separation method is filtration;

[0032] Preferably, the drying temperature is 40-60° C., and the drying time is 12-24 hours.

[0033] The third object of the present invention is to provide a use of the thiothiamine crystals as described in the first object in the preparation of vitamin B1.

[0034] As described above, the excellent effects of the present invention are:

[0035] The preparation method used in the present invention is a suspension reaction crystallization method and a neutralization reaction crystallization method, which are simple and have good reproducibility. The solvents that can be used are n-butanol and water, and the solvent can be selected according to actual conditions. The resulting new crystal product has improved product filtration performance and good hygroscopicity, while significantly reducing water consumption, which is of great significance for product performance and subsequent processing. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Powder X-ray diffraction (PXRD) pattern of the new crystalline form of thiothiamine;

[0037] Figure 2 Crystal structure (SXRD) diagram of the new crystalline form of thiothiamine;

[0038] Figure 3 Thermogravimetric analysis (TG) and differential scanning calorimetry (DSC) diagrams of the new crystalline form of thiothiamine;

[0039] Figure 4 Comparison of filtration time between the new thiothiamine crystal form and the original crystal form;

[0040] Figure 5 Comparison of the moisture-attracting properties of the new thiothiamine crystal form and the original crystal form. DETAILED DESCRIPTION

[0041] The following are specific embodiments of the novel thiothiamine crystal form, but this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0042] Example 1

[0043] 60g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 500ml crystallizer in a molar ratio of 1:1.5, 263.3ml of water was added, and the temperature was raised to 85 degrees over 1.2 hours and reacted for half an hour. 30% by mass of alkaline sodium hydroxide was added dropwise thereto while maintaining the temperature at 85 degrees until the pH was greater than 7, and then cooled to 50°C to obtain white crystals. After filtration, the crystals were washed with water and dried in a 50-degree air drying oven to obtain a white powder.

[0044] The product obtained in this example was characterized by powder X-ray diffraction pattern (see Figure 1 ), it can be seen that: it has characteristic diffraction peaks at 6.98±0.2°, 8.02±0.2°, 8.22±0.2°, 12.6±0.2°, 13.64±0.2°, 13.98±0.2°, 16.48±0.2°, 20.12±0.2°, 21.92±0.2°, 22.56±0.2°, 22.92±0.2°, 23.52±0.2°, 27.68±0.2°, and 28.02±0.2°, in addition, there are characteristic diffraction peaks at 10.02±0.2°, 11.7±0.2°, 12.28±0.2°, 13.64±0.2°, 16.06±0.2°, There are also auxiliary weak characteristic peaks at 17.42±0.2°, 17.96±0.2°, 18.80±0.2°, 19.1±0.2°, 20.72±0.2°, 20.94±0.2°, 21.54±0.2°, 24.2±0.2°, 24.7±0.2°, 25.5±0.2°, 26.14±0.2°, 26.88±0.2°, 27.46±0.2°, 28.92±0.2°, 29.8±0.2°, 30.22±0.2°, 30.6±0.2°, 30.98±0.2°, 31.56±0.2°, and 32.46±0.2°.

[0045] The product obtained in this example was subjected to crystallographic characterization (see Figure 2 ) and found that its crystallographic characteristics are: space group P-1, unit cell parameters are a=8.97618(18), b=12.2371(3), c=13.8492(2), α=113.5261(19), β=90.871(15)4, γ=99.5043(18), and unit cell volume is 1370.09(5).

[0046] The product obtained in this example was characterized by differential scanning calorimetry (see Figure 3 ), and found that its DSC spectrum had a characteristic endothermic peak at 132.39 °C and a characteristic melting peak at 244.05 °C.

[0047] From the above characterization results, it can be seen that the product obtained in this example is a new crystal form of thiothiamine crystals.

[0048] The filtration performance and moisture absorption performance of the thiothiamine crystals of the crystal form obtained in this example and the thiothiamine crystals of the existing crystal form on the market were tested. The test methods and test results are as follows:

[0049] (1) Filtration performance test: 5 g of the thiothiamine crystals obtained in this example and 5 g of the conventional thiothiamine crystals on the market were weighed and suspended in 200 g of water. The suspension was filtered under a pressure of -0.025 MPa and the filtration time was measured. The test results are shown in Table 1. Figure 4 It can be found that the filtration time of conventional thiothiamine crystals (i.e., the original crystal form) on the market is 5 minutes and 11 seconds, while the filtration time of thiothiamine crystals (i.e., the new crystal form) obtained in this embodiment is 1 minute and 3 seconds. It can be seen that the filtration time of the new crystal form is shortened by 80% compared with the original crystal form, greatly improving the production efficiency.

[0050] (2) Hygroscopicity test: Weigh about 10 mg of the thiothiamine crystals obtained in this example and the conventional thiothiamine crystals on the market, and pre-dry them with dry nitrogen at 25°C; the relative humidity in the temperature cycle range is increased from 0% to 95% in steps of 5%, and then returned to 0% in steps of 5%. Weight gain balance standard: The balance is set to a weight change rate (dm / dt) of less than 0.01% within 5 minutes of each relative humidity step, and the maximum balance time is 30 minutes. The weight change is calculated using the corresponding dry sample. The results show (see Figure 5 ), at a relative humidity of 95%, the weight of the original thiothiamine crystal form increased by 0.89%, and the weight of the new crystal form increased by 0.64%.

[0051] Example 2

[0052] 60g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 500ml crystallizer in a molar ratio of 1:1.5, 211.6ml of water was added, and the temperature was raised to 85 degrees over 1.5 hours and reacted for half an hour. 30% by mass of alkaline sodium hydroxide was added dropwise thereto while maintaining the temperature at 85 degrees until the pH was greater than 7, and then cooled to 25°C to obtain white crystals. After filtration, the crystals were washed with water and dried in a 50-degree air drying oven to obtain a white powder.

[0053] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in Example 2 was the same new crystal form as in Example 1.

[0054] The product obtained in this example was subjected to product performance testing using the same testing method as in Example 1. It was found that the filtration performance and moisture absorption performance of the product prepared in Example 2 were superior to those of conventional crystalline products on the market.

[0055] Example 3

[0056] 60g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 500ml crystallizer in a molar ratio of 1:1.2, 314.9ml of water was added, and the temperature was raised to 80 degrees in 1 hour and reacted for half an hour. At 65 degrees, 30% by mass fraction of alkaline sodium hydroxide was added dropwise until the pH was greater than 7 to obtain white crystals, which were then cooled to 55°C, filtered, washed with water, and dried in a 60-degree air drying oven to obtain a white powder.

[0057] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0058] The product obtained in this example was subjected to a product performance test using the same testing method as in Example 1. It was found that the filtration performance and moisture absorption performance of the product prepared in this example were superior to those of conventional crystalline products on the market.

[0059] Example 4

[0060] 12 g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 250 ml crystallizer in a molar ratio of 1:2, 100 mL of water was added, the temperature was raised to 90 degrees and the reaction was carried out for 1 hour, and an alkali solution with a mass fraction of 18.7% was added dropwise thereto while maintaining the temperature at 90 degrees until the pH was greater than 7, and then cooled to 40 ° C to obtain white crystals, which were filtered and washed with water. The crystals were dried in a 40-degree air drying oven to obtain a white powder.

[0061] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0062] The product obtained in this example was subjected to a product performance test using the same testing method as in Example 1. It was found that the filtration performance and moisture absorption performance of the product prepared in this example were superior to those of conventional crystalline products on the market.

[0063] Example 5

[0064] 12 g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 250 ml crystallizer in a molar ratio of 1:1, 90 ml of water was added, the temperature was raised to 85 degrees for half an hour, and 18.7% alkali solution was added dropwise at 70 degrees until the pH was greater than 4 to obtain white crystals. After filtration, the crystals were washed with water and dried in a 40-degree air drying oven to obtain a white powder.

[0065] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0066] Example 6

[0067] 12 g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 250 ml crystallizer in a molar ratio of 1:2, 60 ml of water was added, the temperature was raised to 70 degrees for half an hour, and an alkali solution with a mass fraction of 18.7% was added dropwise at 65 degrees until the pH was greater than 5 to obtain white crystals. After filtration, the crystals were washed with water and dried in a 60-degree air drying oven to obtain a white powder.

[0068] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0069] Example 7

[0070] 12 g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 250 ml crystallizer in a molar ratio of 1:1.2, 115 ml of water was added, the temperature was raised to 90 degrees for half an hour, and 30% by mass of alkali solution was added dropwise thereto while maintaining the temperature at 90 degrees until the pH was greater than 6 to obtain white crystals. After filtration, the crystals were washed with water and dried in a 50-degree air drying oven to obtain a white powder.

[0071] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0072] Example 8

[0073] 12 g of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid were added to a 250 ml crystallizer in a molar ratio of 1:2, 100 ml of water was added, the temperature was raised to 85 degrees and the reaction was carried out for half an hour, and 30% by mass of alkali solution was added dropwise thereto while maintaining the temperature at 85 degrees until the pH was greater than 7 to obtain white crystals. After filtration, the crystals were washed with water and dried in a 50-degree air drying oven to obtain a white powder.

[0074] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0075] Example 9

[0076] 0.5 g of the original thiothiamine crystal was placed in a 20 ml sample bottle, 20 ml of n-butanol solvent was added, and the suspension reaction crystallization was carried out by stirring at 25 degrees. After 48 hours, white crystals were obtained by suction filtration. The crystals were dried in a 50 degree air drying oven to obtain white powder.

[0077] The product obtained in this example was subjected to product characterization testing using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0078] Example 10

[0079] Place 0.5 g of the original thiothiamine crystal in a 20 ml sample bottle, add 20 ml of water solvent, stir at 60 degrees for suspension reaction crystallization, filter after 48 hours to obtain white crystals, and dry the crystals in a 50 degree air drying oven to obtain white powder.

[0080] The product obtained in this example was subjected to a product performance test using the same testing method as in Example 1. It was found that the product prepared in this example was a new crystal form identical to that in Example 1.

[0081] The technical solutions proposed and disclosed in the present invention can be implemented by those skilled in the art by drawing on the content herein and appropriately changing the conditions, routes, and other aspects. Although the methods and preparation techniques of the present invention have been described through preferred embodiments, it is obvious that those skilled in the art can modify or recombine the methods and technical routes described herein without departing from the content, spirit, and scope of the present invention to achieve the ultimate preparation technology. It is particularly important to point out that all similar substitutions and modifications that are obvious to those skilled in the art are considered to be included in the spirit, scope, and content of the present invention.

Claims

1. A thiothiamine crystal, characterized in that: The molecular formula of the thiothiamine crystal is C 12 H 16 N4OS2, molecular mass 296.41, chemical structure is as follows: ； The crystallographic characteristics of the thiothiamine include: space group P-1, unit cell parameters a=8.97618(18), b=12.2371(3), c=13.8492(2), α=113.5261(19), β=90.871(15)4, γ=99.5043(18), and unit cell volume of 1370.09(5).

2. The thiothiamine crystal according to claim 1, characterized in that The X-ray powder diffraction of the thiothiamine crystal measured using Cu-Kα radiation has characteristic peaks at diffraction angles expressed in 2θ degrees at 6.98±0.2°, 8.02±0.2°, 8.22±0.2°, 12.6±0.2°, 13.64±0.2°, 13.98±0.2°, 16.48±0.2°, 20.12±0.2°, 21.92±0.2°, 22.56±0.2°, 22.92±0.2°, 23.52±0.2°, 27.68±0.2°, and 28.02±0.2°.

3. The thiothiamine crystal according to claim 1, characterized in that The X-ray powder diffraction of the thiothiamine crystals measured using Cu-Kα radiation has diffraction angles expressed in 2θ of 10.02±0.2°, 11.7±0.2°, 12.28±0.2°, 13.64±0.2°, 16.06±0.2°, 17.42±0.2°, 17.96±0.2°, 18.80±0.2°, 19.1±0.2°, 20.72±0.2°, 20.94±0.2°. There are also characteristic peaks at 21.54±0.2°, 24.2±0.2°, 24.7±0.2°, 25.5±0.2°, 26.14±0.2°, 26.88±0.2°, 27.46±0.2°, 28.92±0.2°, 29.8±0.2°, 30.22±0.2°, 30.6±0.2°, 30.98±0.2°, 31.56±0.2°, and 32.46±0.2°.

4. The thiothiamine crystal according to claim 1, characterized in that The differential scanning calorimetry (DSC) spectrum of the thiothiamine crystals has a characteristic endothermic peak at 133.68±2° C. and a characteristic melting peak at 244.05° C.

5. The method for preparing thiothiamine crystals according to any one of claims 1 to 4, characterized in that: The preparation method is a suspension reaction crystallization method or a neutralization reaction crystallization method; The suspension reaction crystallization method comprises the following steps: mixing the thiothiamine raw material with a solvent, and performing suspension reaction crystallization at 25-100° C. for 24-48 hours to obtain the thiothiamine crystals; the solvent is water or n-butanol; The neutralization reaction crystallization method comprises the following steps: (1) mixing aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester and hydrochloric acid in a solvent, reacting at 70-90° C. for 1-2 hours to obtain a reactant; the solvent is water; (2) adding alkali solution to the reactant obtained in step (1) at 65-90° C. to obtain the thiothiamine crystals; the alkali solution is sodium hydroxide solution.

6. The preparation method according to claim 5, characterized in that In the suspension reaction crystallization method, based on the addition amount of thiothiamine raw material being 0.5-2 g, the addition amount of the solvent is 20-50 mL.

7. The preparation method according to claim 5, characterized in that In the suspension reaction crystallization method, the mixing and suspension reaction crystallization are carried out under stirring conditions, and the stirring rate is 300-500 r / min.

8. The preparation method according to claim 5, characterized in that The suspension reaction crystallization method further includes sequentially performing solid-liquid separation and drying on the mixture obtained after the suspension reaction crystallization.

9. The preparation method according to claim 8, characterized in that The solid-liquid separation method is filtration.

10. The preparation method according to claim 8, characterized in that The drying temperature is 25-50° C., and the drying time is 12-24 hours.

11. The preparation method according to claim 5, characterized in that In the neutralization reaction crystallization method, the molar ratio of the aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester to hydrochloric acid in step (1) is 1:(1-2).

12. The preparation method according to claim 5, characterized in that In the neutralization reaction crystallization method, the amount of the solvent added in step (1) is 50-600 mL, based on the addition amount of aminodithioic acid [(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-acetyl-3-hydroxypropyl ester being 50-70 g.

13. The preparation method according to claim 5, characterized in that In the neutralization reaction crystallization method, in step (2), alkaline solution is added until the pH is not less than 4.

14. The preparation method according to claim 13, characterized in that In the neutralization reaction crystallization method, alkali solution is added to a pH of 6-8.

15. The preparation method according to claim 5, characterized in that In the neutralization reaction crystallization method, the preparation method further comprises cooling the mixed solution after adding the alkali solution to 25-55°C.

16. The preparation method according to claim 5, characterized in that In the neutralization reaction crystallization method, the preparation method further comprises cooling the mixture to 25-55° C. and sequentially performing solid-liquid separation and drying.

17. The preparation method according to claim 16, characterized in that The drying temperature is 40-60° C., and the drying time is 12-24 hours.

18. Use of the thiothiamine crystals according to claim 1 in the preparation of vitamin B1.

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