A method for preparing thiamine nitrate crystals

Abstract

The application discloses a preparation method of thiamine nitrate crystals. Specifically disclosed is a preparation method of thiamine nitrate crystals, which comprises the following steps: step (1): wet grinding is performed on a suspension liquid containing thiamine nitrate particles at 5-30 DEG C to obtain a wet grinding liquid, wherein the particle size distribution of the thiamine nitrate in the wet grinding liquid is as follows: D10: 10-100 um, D50: 100-270 um and D90: 350-720 um; step (2): temperature rising and temperature dropping cycles are performed by rising the temperature to 35-50 DEG C and then dropping the temperature to 20-40 DEG C; and step (3): thiamine nitrate crystals are obtained by temperature dropping crystallization. The thiamine nitrate particles obtained by the preparation method have the advantages of large size, good fluidity and good application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical crystallization, and particularly relates to a preparation method of thiamine nitrate crystals. BACKGROUND

[0002] Thiamine nitrate, also known as thiamine nitrate, has the English name Thiamine Nitrate, the molecular formula C 12 H 17 N5O4S, a molecular weight of 327.36, a CAS number of 532-43-4, a chemical name of 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-5-(2-hydroxyethyl)-4-methylthiazolium nitrate, and a molecular structure as shown below.

[0003]

[0004] Thiamine nitrate is a nitrate of vitamin B1, and vitamin B1 is a compound combined by a pyrimidine ring and a thiazole ring. Thiamine nitrate is also called thiamine because it contains sulfur and amine in the molecule. Vitamin B1 naturally exists in foods such as rice bran, bran, lean meat and peanut kernels, and pure products are usually prepared by chemical synthesis. Vitamin B1 is a kind of nutrient substance necessary for humans and animals, and lack of vitamin B1 can easily cause certain diseases. Commercially available vitamin B1 generally exists in the form of its nitrate (thiamine nitrate) and hydrochloride (thiamine hydrochloride). Thiamine hydrochloride is commonly used as an injection due to its strong water solubility, and is generally a pharmaceutical grade product. Thiamine nitrate is commonly used as a nutritional supplement, a food additive, a feed additive and a compound vitamin preparation.

[0005] At present, there are many domestic manufacturers producing thiamine nitrate, and most of them adopt the method of adding and neutralizing in a reaction kettle to crystallize. The particle size of the crystals obtained by crystallization is generally small, D90 is about 50-150 um, the bulk density is low (<0.6 g / ml), and the crystal morphology is long needle-shaped, thereby causing the problem of poor flowability of the product, which will seriously restrict the subsequent processing procedure of the product and affect the market competitiveness of the product.

[0006] Patent CN105384735A provides a method for improving the flowability of thiamine nitrate, that is, adding some surfactants or additives to the crystallization system to inhibit the growth of a certain crystal face of thiamine nitrate, so that the crystal morphology changes from rod-shaped or long needle-shaped to block-shaped crystals that are easy to flow. As known, adding other substances to drugs will have the risk of impurity residues, and the production of drugs or food is relatively strict in impurity control. The removal efficiency of the crystallization system for impurities or additives is affected by many factors such as process steps and operating conditions, and the addition of additives brings high risks to the expansion of production and actual application.

[0007] Patent CN107652281 A provides a method for improving the particle size and bulk density of thiamine mononitrate crystal, that is, using continuous neutralization to carry out reaction crystallization. The average particle size of thiamine mononitrate crystal can be effectively increased from 10.84 (μm) to 20.59um, and the natural bulk density can be increased from 0.35g / ml to 0.61g / ml. Although the method effectively improves the bulk density, the particle size is still small and the flowability is poor.

[0008] It can be seen that it is particularly important to develop a production process with large particle size and high bulk density. SUMMARY

[0009] The technical problem to be solved by the present application is to overcome the defects of the existing preparation method of large particle thiamine mononitrate crystal. To this end, the present application provides a preparation method of thiamine mononitrate crystal. The preparation method provided by the present application is easy to operate, the obtained product has large particle size, good flowability and good application prospect.

[0010] The present application solves the above technical problems by the following scheme.

[0011] The present application provides a preparation method of thiamine mononitrate crystal, which comprises the following steps:

[0012] Step (1) wet grinding the suspension liquid containing thiamine mononitrate particles at 5-30℃ to obtain a wet grinding liquid, the particle size distribution of thiamine mononitrate in the wet grinding liquid is: D10: 10-100um, D50: 100-270um, D90: 350-720um;

[0013] Step (2) temperature rising to 35-50℃ and temperature dropping to 20-40℃ to carry out temperature rising and dropping cycle;

[0014] Step (3) temperature dropping and crystallization to obtain thiamine mononitrate crystal.

[0015] In the step (1), the suspension liquid can be a suspension liquid of thiamine mononitrate particles and water, and the suspension liquid can also optionally contain thiamine mononitrate dissolved in water. The mass ratio of thiamine mononitrate to water can be 1:(8-20), for example 1:14, 1.005:14, 1.025:10, 1:10 or 1.005:10. The total thiamine mononitrate refers to the sum of thiamine mononitrate particles and thiamine mononitrate dissolved in water.

[0016] In the step (1), the thiamine mononitrate particles are the conventional solid form of thiamine mononitrate in the art.

[0017] In the step (1), the D10 of the particle size distribution of thiamine mononitrate in the wet grinding liquid can be 50-100um, for example 61um, 69um, 67um or 87um.

[0018] In step (1), the D50 of the particle size distribution of the thiamine nitrate in the wet milling liquid can be 150-270 um, preferably 150-250 um, such as 198 um, 200 um, 202 um or 264 um.

[0019] In step (1), the D90 of the particle size distribution of the thiamine nitrate in the wet milling liquid can be 380-720 um, preferably 380-510 um, such as 412 um, 430 um, 500 um, 495 um or 695 um.

[0020] In step (1), the particle size distribution of the thiamine nitrate in the wet milling liquid can be: D10: 69 um, D50: 202 um, D90: 495 um, or D10: 67 um, D50: 202 um, D90: 430 um, or D10: 61 um, D50: 198 um, D90: 412 um, or D10: 87 um, D50: 264 um, D90: 695 um.

[0021] In step (1), the particle size of the thiamine nitrate in the wet milling liquid is preferably smaller than the particle size of the thiamine nitrate particles in the suspension.

[0022] In step (1), the particle size of the thiamine nitrate particles in the suspension containing thiamine nitrate particles can be D10: 10-100 um, D50: 100-300 um, D90: 500-800 um.

[0023] In step (1), the D10 of the particle size distribution of the thiamine nitrate particles in the suspension can be 60-100 um, such as 79 um, 90 um, 93 um or 95 um.

[0024] In step (1), the D50 of the particle size distribution of the thiamine nitrate particles in the suspension can be 200-300 um, such as 220 um, 250 um, 284 um or 290 um.

[0025] In step (1), the D90 of the particle size distribution of the thiamine nitrate particles in the suspension can be 550-800 um, such as 602 um, 690 um, 737 um or 750 um.

[0026] In step (1), the particle size distribution of the thiamine nitrate particles in the suspension can be: D10: 95 um, D50: 290 um, D90: 750 um, or D10: 90 um, D50: 250 um, D90: 690 um, or D10: 79 um, D50: 220 um, D90: 602 um, or D10: 93 um, D50: 284 um, D90: 737 um.

[0027] In step (1), the temperature of the wet milling can be 5-25 °C, for example 25 °C.

[0028] In step (1), the wet milling can be performed using a shear force providing machine, for example a wet mill, an emulsifier or ultrasound, preferably a wet mill.

[0029] In step (1), when the wet milling is performed using a wet mill, the rotation speed of the wet mill can be 1000-15000 rpm, preferably 1000-5000 rpm, for example 3000 rpm, 1000 rpm, 2000 rpm or 1500 rpm.

[0030] In step (1), the wet milling step can be monitored by measuring the particle size distribution, and the wet milling can be performed until the desired particle size distribution is achieved. The wet milling time can be 0.3-1.5 h, for example 0.5 h or 1 h, preferably 0.5-1 h when performed using a wet mill at 1000-3000 rpm.

[0031] In step (2), the temperature increase can be to 40-50 °C, for example 40 °C or 45 °C.

[0032] In step (2), the temperature decrease can be to 30-38 °C, for example 35 °C.

[0033] In step (2), the temperature difference between the temperature increase and the temperature decrease (temperature difference between the end of the temperature increase and the end of the temperature decrease) can be 3-12 °C, for example 5 °C or 10 °C.

[0034] In step (2), the number of temperature increase and temperature decrease cycles can be 1.

[0035] In step (2), the temperature increase rate can be conventional in the art, for example 3-20 °C / h, for example 10 °C / h.

[0036] In step (2), the temperature decrease rate can be 5-15 °C / h, for example 10 °C / h or 5 °C / h.

[0037] In step (2), after the temperature increase, the temperature can be maintained before the temperature decrease, preferably for 0.3-2 h, for example 0.5 h or 1 h.

[0038] In step (2), preferably, the ammonium nitrate aqueous solution is added after the temperature is lowered, for example, 40%-60% mass content (mass of ammonium nitrate / mass of the solution) of ammonium nitrate aqueous solution, preferably 50% mass content of ammonium nitrate aqueous solution, 40% mass content of ammonium nitrate aqueous solution.

[0039] In step (2), the volume-mass ratio (V / m) of the ammonium nitrate aqueous solution to the thiamine nitrate can be (0.5-5): 1 mL / g, preferably (1-5): 1 mL / g, for example, 3: 1 mL / g, 1: 1 mL / g, 1: 1.005 mL / g, 1.5: 1 mL / g, or 1.5: 1.025 mL / g, and those skilled in the art can adjust the addition rate of the ammonium nitrate aqueous solution according to the uniformity of the obtained thiamine nitrate crystal particles, preferably, the volume of the ammonium nitrate aqueous solution added per hour is 1-5 (V / m) / h, for example, 1 (V / m) / h or 3 (V / m) / h, wherein V / m is the volume-mass ratio of the ammonium nitrate aqueous solution to the thiamine nitrate, in mL / g.

[0040] In step (2), the ammonium nitrate aqueous solution can be added dropwise, and the dropwise addition time can be 1 h or 0.5 h.

[0041] In step (2), the ammonium nitrate aqueous solution can be added at the end temperature of the temperature lowering in step (2) (for example, 20-40°C).

[0042] In step (3), the temperature lowering and crystallization can be temperature lowering to 0-10°C for crystallization, for example, 5°C, and further preferably, the temperature lowering rate is 5-15°C / h (for example, 10°C / h or 5°C / h).

[0043] Step (3) can further comprise the following post-treatment steps: filtration, washing, and drying to obtain the thiamine nitrate crystals. The washing can be performed using an alcohol solvent, for example, methanol and / or ethanol. The drying can be vacuum drying, preferably, vacuum drying at 40-70°C (for example, 40°C or 50°C).

[0044] In the preparation method, in step (3), the particle size distribution of the thiamine nitrate crystals can be: D10: 80-200 um, D50: 200-500 um, D90: 800-1200 m, for example, D10: 128 um, D50: 371 um, D90: 1010 um, or D10: 108 um, D50: 327 um, D90: 893 um, or D10: 112 um, D50: 313 um, D90: 870 um.

[0045] In the step (3), the D10 of the crystal size distribution of the thiamine nitrate can be 100-150 um, such as 128 um, 108 um or 112 um.

[0046] In the step (3), the D50 of the crystal size distribution of the thiamine nitrate can be 300-400 um, such as 313 um, 327 um or 371 um.

[0047] In the step (3), the D90 of the crystal size distribution of the thiamine nitrate can be 850-1100 um, such as 870 um, 893 um or 1010 um.

[0048] In the preparation method, in the step (3), the angle of repose of the thiamine nitrate crystal can be 30-35°, such as 30°, 33° or 35°.

[0049] In the preparation method, in the step (3), the bulk density of the thiamine nitrate crystal can be 0.7-0.9 g / mL, such as 0.83 g / mL, 0.81 g / mL, 0.77 g / mL or 0.79 g / mL.

[0050] In the preparation method, in the step (3), the aspect ratio of the thiamine nitrate crystal can be 2:1-10:1, such as 5:1, 4:1, 6:1 or 8:1.

[0051] The preparation method can further comprise a preparation method of the thiamine nitrate particle suspension, comprising the following steps:

[0052] The mixture A of thiamine nitrate and water is mixed with the crystal seed at 40-60 °C, and crystallization is carried out to obtain the thiamine nitrate particle-containing suspension.

[0053] In the mixture A of thiamine nitrate and water, the mass ratio of the thiamine nitrate to water can be 1:(10-20), such as 1:14 or 1:10.

[0054] In the preparation method of the thiamine nitrate particle suspension, the mixing can be carried out at 40-50 °C, such as 45 °C or 50 °C.

[0055] In the preparation method of the thiamine nitrate particle suspension, the crystal seed is a thiamine nitrate particle (such as a crystal) with a particle size distribution of D90: 400-600 um, D50: 150-250 um and D10: 50-100 um.

[0056] In the preparation method of the thiamine nitrate particle suspension, the D10 of the particle size distribution of the crystal seed can be 80-100 um, such as 87 um.

[0057] In the method for preparing the suspension of thiamine nitrate particles, the D50 of the particle size distribution of the crystal seeds can be 200-220 μm, for example, 207 μm.

[0058] In the method for preparing the suspension of thiamine nitrate particles, the D90 of the particle size distribution of the crystal seeds can be 480-50 μm, for example, 487 μm.

[0059] In the method for preparing the suspension of thiamine nitrate particles, the particle size distribution of the crystal seeds can be: D10: 87 μm, D50: 207 μm, and D90: 487 μm.

[0060] In the method for preparing the suspension of thiamine nitrate particles, the mass ratio of the crystal seeds to the thiamine nitrate can be conventional in the art, for example, (0.3-10): 100, for example, (0.3-3): 100, preferably 0.5: 100 or 2.5: 100.

[0061] In the method for preparing the suspension of thiamine nitrate particles, the crystallization step can comprise two stages; the first stage is carried out (for example, stirring) at 40-50°C (for example, 45°C, 50°C), and the crystallization time of the first stage can be 1-2 hours; the second stage is cooling crystallization. Preferably, the temperature is lowered to the temperature of the wet grinding, and the cooling rate is 3-15°C / h, for example, 10°C / h or 5°C / h.

[0062] The method can further comprise a method for preparing the mixture A of thiamine nitrate and water, which comprises the following steps: dissolving thiamine nitrate and water at 50-70°C to obtain the mixture A of thiamine nitrate and water;

[0063] In the method for preparing the mixture A of thiamine nitrate and water, the amount of the thiamine nitrate and water can be as described in any of the embodiments of the present application.

[0064] In the method for preparing the mixture A of thiamine nitrate and water, the temperature of the mixing can be 50-60°C, for example, 55°C or 65°C.

[0065] Preferably, the method for preparing the thiamine nitrate crystals comprises the following steps:

[0066] Step (s1) dissolving thiamine nitrate and water at 50-70°C to obtain the mixture A of thiamine nitrate and water;

[0067] Step (s2) mixing the mixture A of thiamine nitrate and water with crystal seeds at 40-60°C to obtain a mixture of thiamine nitrate particles and water;

[0068] Step (1) wet grinding the mixture of thiamine nitrate particles and water at 5-30℃ to obtain a wet grinding liquid, wherein the thiamine nitrate particle size distribution is: D10: 10-100um, D50: 100-270um, D90: 350-720um.

[0069] Step (2) temperature rise to 35-50℃, temperature drop to 20-40℃ to carry out temperature rise and drop cycle.

[0070] Step (3) temperature drop crystallization to obtain thiamine nitrate crystals.

[0071] The application provides a water suspension liquid containing thiamine nitrate particles, wherein the thiamine nitrate particle size distribution is: D10: 10-100um, D50: 100-270um, D90: 350-720um.

[0072] The water suspension liquid containing thiamine nitrate particles can be a water suspension liquid of thiamine nitrate crystals obtained by wet grinding.

[0073] In the water suspension liquid containing thiamine nitrate particles, the thiamine nitrate particle size distribution can be as described in any of the schemes of the application.

[0074] In the mixture, the mass ratio of thiamine nitrate to water can be 1:(8-20), for example 1:14, 1.005:14, 1.025:10, 1:10 or 1.005:10.

[0075] The application provides the use of the above-mentioned water suspension liquid containing thiamine nitrate particles in the preparation of thiamine nitrate crystals by temperature drop crystallization. Preferably, the thiamine nitrate crystals, the temperature drop crystallization are as described in any of the schemes of the application.

[0076] The application provides a thiamine nitrate crystal prepared by the above-mentioned preparation method.

[0077] The application provides a thiamine nitrate crystal, which is a rod-shaped crystal, and the particle size distribution is D10: 80-200um, D50: 200-500um, D90: 800-1200m.

[0078] The D10 of the thiamine nitrate crystal particle size distribution can be 100-150um, for example 128um, 108um or 112um.

[0079] The D50 of the thiamine nitrate crystal particle size distribution can be 300-400um, for example 313um, 327um or 371um.

[0080] The D90 of the thiamine nitrate crystal particle size distribution can be 800-1100um, for example 870um, 893um or 1010um.

[0081] The resting angle of the thiamine nitrate crystals can be 30-35°, for example 30°, 33° or 35°.

[0082] The bulk density of the thiamine nitrate crystals can be 0.7-0.9 g / mL, for example 0.83 g / mL, 0.81 g / mL, 0.77 g / mL or 0.79 g / mL.

[0083] The aspect ratio of the thiamine nitrate crystals can be 2:1-10:1, for example 5:1, 4:1, 6:1 or 8:1.

[0084] The particle size distribution of the thiamine nitrate crystals is, for example, D10: 128 um, D50: 371 um, D90: 1010 um, or D10: 108 um, D50: 327 um, D90: 893 um, or D10: 112 um, D50: 313 um, D90: 870 um.

[0085] Explanation of terms:

[0086] In the present application, D 90 Refers to the cumulative distribution percentage of the particle size distribution, when the cumulative distribution percentage reaches 90% from small to large, the corresponding particle size value.

[0087] In the present application, D 50 Refers to the cumulative distribution percentage of the particle size distribution, when the cumulative distribution percentage reaches 50% from small to large, the corresponding particle size value.

[0088] In the present application, D 10 Refers to the cumulative distribution percentage of the particle size distribution, when the cumulative distribution percentage reaches 10% from small to large, the corresponding particle size value.

[0089] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be arbitrarily combined, i.e. to obtain each preferred example of the present application.

[0090] The reagents and raw materials used in the present application are commercially available.

[0091] The positive progress effect of the present application is:

[0092] 1. The particle size of thiamine nitrate is increased, the morphology of thiamine nitrate is improved, the product obtained has the characteristics of good flowability and high bulk density, and the introduction of foreign impurities is avoided, which can well meet the requirements of subsequent preparations.

[0093] 2. The preparation process of the thiamine nitrate crystals is simple in condition, easy to control, good in stability and convenient for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0094] Figure 1 The polarizing microscope photo of the short rod-shaped thiamine nitrate crystals obtained in Example 1.

[0095] Figure 2 Particle size distribution of the short rod-like thiamine nitrate crystal obtained in Example 1.

[0096] Figure 3 Polarizing microscope photograph of the short rod-like thiamine nitrate crystal obtained in Example 2.

[0097] Figure 4 Polarizing microscope photograph of the long rod-like thiamine nitrate crystal obtained in Comparative Example 1.

[0098] Figure 5 Polarizing microscope photograph of the thiamine nitrate crystal obtained in Example 3.

[0099] Figure 6 Polarizing microscope photograph of the thiamine nitrate crystal obtained in Comparative Example 2.

[0100] Figure 7 Polarizing microscope photograph of the thiamine nitrate crystal obtained in Comparative Example 3.

[0101] Figure 8 Polarizing microscope photograph of the thiamine nitrate crystal obtained in Comparative Example 4.

[0102] Figure 9 Polarizing microscope photograph of the thiamine nitrate crystal obtained in Example 4.

[0103] Figure 10 Polarizing microscope photograph of the thiamine nitrate crystal obtained in Comparative Example 5. DETAILED DESCRIPTION

[0104] The present application will be further described in the following by way of examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, for which no specific conditions are mentioned, are selected according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0105] The flowability is represented by the powder repose angle, according to the Guiding Principles for Determination of Powder Flowability, and is tested by a conventional detection method in the art, such as the fixed funnel method, in which the excess of the powder to be tested is added into a container with a fixed diameter bottom, and when the powder flows out from the center hole of the bottom of the container, a sliding slope (the vertical shear plane is triangular) of the powder flow out is formed at the orifice of the inner bottom of the container, and the angle formed by the sliding slope and the horizontal bottom is the repose angle.

[0106] Bulk density: The bulk density of the powder was determined according to the general test methods of the fourth edition of the Pharmacopoeia, using a conventional test method in the art such as the fixed mass method. The test method was as follows: about 100 g of the sample powder to be tested (if necessary, the sample powder was passed through a sieve with a mesh size of 1.0 mm to fully disperse the lumps formed during storage. The sieving operation should be gentle to avoid changing the properties of the powder) was accurately weighed, slowly poured into a glass graduated cylinder, carefully scraped flat on the top of the cylinder, the apparent volume was recorded to the nearest scale line, and the bulk density was calculated.

[0107] Example 1

[0108] (1) 100 g of thiamine nitrate (CAS: 532-43-4) powder, 1400 ml of water were added to a reaction kettle, and the temperature was raised to 55°C for dissolution, then the temperature was lowered to 45°C, 0.5 g of seed crystals (preparation method, see Comparative Example 3, D10: 87 um; D50: 207 um; D90: 487 um) were added, and the crystals were grown for 2 h;

[0109] (2) After cooling at a rate of 10°C / h to 25°C, the particle size distribution of the slurry was D10: 95 um, D50: 290 um, D90: 750 um. The slurry was wet milled at 25°C for 0.5 h using a wet mill with the following parameters: 2P4M, 1000 rpm, and the particle size distribution of the slurry after wet milling was D10: 69 um, D50: 202 um, D90: 495 um;

[0110] (3) After wet milling, the temperature was raised to 40°C at a rate of 10°C / h and maintained for 0.5 h, then the temperature was lowered to 35°C at a rate of 10°C / h;

[0111] (4) 100 ml of a 50 wt% ammonium nitrate solution was slowly added at 35°C, and the addition time was 1 h;

[0112] (5) The temperature was continued to be lowered to 5°C at a rate of 10°C / h;

[0113] (6) The temperature was maintained at 5°C for 1-2 h, then the product was filtered, washed with methanol, and dried at 40°C under vacuum to obtain 93 g of thiamine nitrate solid.

[0114] The polarized light microscope photograph of the product obtained is shown in Figure 1 ( Figures 1 to 10 The particle morphology was short rod-like. The particle size distribution is shown in Figure 2 The sample particle size was tested using a Malvern particle size distribution tester, and the results were D10: 128 um, D50: 371 um, D90: 1010 um. The angle of repose was 30 degrees, the bulk density was 0.83 g / ml, the purity was 99.7%, and the aspect ratio was about 5:1.

[0115] Example 2

[0116] (1) 100 g of thiamine nitrate powder and 1000 ml of water were added to a reactor, and the mixture was dissolved by heating to 65°C, and then the temperature was decreased to 50°C. 2.5 g of seed crystals (D10: 87 um; D50: 207 um; D90: 487 um) were added, and the seed crystals were aged for 1 h;

[0117] (2) After the temperature was decreased to 25°C at a rate of 5°C / h, the particle size distribution of the slurry was D10: 90 um, D50: 250 um, and D90: 690 um. The slurry was circulated for 1 h using a wet mill (2000 rpm) at 25°C, and the particle size distribution of the slurry was D10: 67 um, D50: 202 um, and D90: 430 um;

[0118] (3) After the wet milling, the temperature was increased to 45°C at a rate of 10°C / h, and the temperature was maintained for 1 h. Then, the temperature was decreased to 35°C at a rate of 5°C / h;

[0119] (4) 150 ml of a 40 wt% ammonium nitrate solution was slowly added to the slurry at 35°C, and the addition was performed over a period of 0.5 h;

[0120] (5) The temperature was continuously decreased to 5°C at a rate of 5°C / h;

[0121] (6) The temperature was maintained at 5°C for 1-2 h, and the product was filtered, washed with ethanol, and dried at 50°C under vacuum to obtain 97 g of thiamine nitrate solid.

[0122] The polarized light microscope photograph of the obtained product is shown in Figure 3 , and the particle morphology was similar to that of Example 1. The particle size of the sample was measured using a Malvern particle size distribution tester, and the D10 was 108 um, the D50 was 327 um, and the D90 was 893 um. The angle of repose was 33 degrees, the bulk density was 0.81 g / ml, the purity was 99.7%, and the aspect ratio was about 4:1.

[0123] Example 3

[0124] (1) 100 g of thiamine nitrate powder and 1000 ml of water were added to a reactor, and the mixture was dissolved by heating to 65°C, and then the temperature was decreased to 50°C. 2.5 g of seed crystals (D10: 87 um; D50: 207 um; D90: 487 um) were added, and the seed crystals were aged for 1 h;

[0125] (2) After the temperature was decreased to 25°C at a rate of 5°C / h, the particle size distribution of the slurry was D10: 79 um, D50: 220 um, and D90: 602 um. The slurry was circulated for 1 h using a wet mill (1500 rpm) at 25°C, and the particle size distribution of the slurry was D10: 61 um, D50: 198 um, and D90: 412 um;

[0126] (3) After the wet milling, the temperature was increased to 45°C at a rate of 10°C / h, and the temperature was maintained for 1 h. Then, the temperature was decreased to 35°C at a rate of 5°C / h;

[0127] (4) continue to cool down to 5°C at a rate of 5°C / h;

[0128] (5) keep at 5°C for 1-2h, filter, wash with ethanol, and dry at 50°C under vacuum to obtain 75g of thiamine nitrate solid.

[0129] The polarized light microscope photo of the product obtained is as follows Figure 5 The sample particle size was tested using a Malvern particle size distribution tester, D10: 112um, D50: 313um, D90: 870um. The angle of repose was 35 degrees, the bulk density was 0.79g / ml, the purity was 99.6%, and the aspect ratio was ~ 6:1.

[0130] Example 4

[0131] (1) add 100g of thiamine nitrate powder and 1400ml of water into a reaction kettle, heat to 55°C to dissolve, then cool down to 45°C, add 2.5g of seed crystal (D10: 87um; D50: 207um; D90: 487um), and crystallize for 2h;

[0132] (2) after cooling down to 25°C at a rate of 10°C / h, the slurry particle size distribution is D10: 93um, D50: 284um, D90: 737um, wet mill for ~ 10min at 25°C using a wet mill with parameters 2P4M, 1500rpm, and the slurry particle size distribution is D10: 87um, D50: 264um, D90: 695um;

[0133] (3) after wet milling, heat up to 40°C at a rate of 10°C / h, keep for 0.5h, then cool down to 35°C at a rate of 10°C / h;

[0134] (4) slowly add 100ml of 50wt% ammonium nitrate solution at 35°C, and the addition time is 1h;

[0135] (5) continue to cool down to 5°C at a rate of 10°C / h;

[0136] (6) keep at 5°C for 1-2h, filter, wash with methanol, and dry at 40°C under vacuum to obtain 92g of thiamine nitrate solid.

[0137] The polarized light microscope photo of the product obtained is as follows Figure 9 The obtained particles are relatively long and thin, the angle of repose is 33 degrees, the bulk density is 0.77g / ml, and the aspect ratio is ~ 8:1.

[0138] Comparative Example 1

[0139] (1) Add 100 g of thiamine nitrate powder and 1400 ml of water into a reaction kettle, heat to 55°C to dissolve, then cool to 50°C, add 2.5 g of seed crystals (D10: 87 um; D50: 207 um; D90: 487 um), and crystallize for 1 h to obtain a feed liquid with a particle size distribution of D10: 90 um, D50: 250 um, and D90: 690 um.

[0140] (2) Slowly add 150 ml of a 40 wt% ammonium nitrate solution at 35°C, with a drop time of 0.5 h

[0141] (3) Continue to cool to 5°C at a rate of 5°C / h

[0142] (4) Maintain at 5°C for 1-2 h, filter, wash with ethanol, and dry at 50°C under vacuum to obtain 96.5 g of thiamine nitrate solid.

[0143] The polarizing microscope photograph of the product obtained is shown in Figure 4 The angle of repose is 40 degrees, and the bulk density is 0.67 g / ml. It can be seen that the particle morphology of Comparative Example 1 is long rod-shaped, and the particle size is uneven, with a purity of 99.5%, D10: 36 um, D50: 229 um, and D90: 864 um.

[0144] Comparative Example 2

[0145] Crystallization of thiamine nitrate was carried out in the manner disclosed in CN107652281 A:

[0146] (1) Mix 500 mL of thiamine sulfate oxidation liquor and 100 mL of thiamine nitrate aqueous solution in a mixing kettle;

[0147] (2) Pump the mixed oxidation liquor and 14% ammonia water into a static mixing crystallizer by controlling the flow rate to make the pH value 6.5-7.0;

[0148] (3) After the material obtained in step (2) is reacted and crystallized in the static mixing crystallizer, it flows into a thiamine nitrate cooling centrifuge kettle, and the temperature of the material in the reaction kettle is controlled at about 30°C. After a batch of material has completely passed through the static mixing crystallizer, the crystallized material is cooled to below 10°C, filtered, washed, and dried.

[0149] The polarizing microscope photograph of the product obtained is shown in Figure 6 The angle of repose is 48 degrees, and the bulk density is 0.60 g / ml. It can be seen that the particle size of Comparative Example 2 is very small, and the flowability is poor.

[0150] Comparative Example 3

[0151] (1) 100 g of thiamine nitrate powder and 1400 ml of water were added to a reaction kettle, and the mixture was dissolved by heating to 55°C, and then the temperature was lowered to 45°C, 0.1 g of seed crystal (D10: 16 um, D50: 62 um, D90: 183 um, source of Comparative Example 2) was added, and the seed crystal was aged for 1 h;

[0152] (2) After the temperature was lowered to 25°C at a rate of 10°C / h, the particle size distribution of the slurry was D10: 72 um, D50: 189 um, and D90: 411 um, and the slurry was wet milled at 25°C for 0.5 h, and the particle size distribution of the slurry was D10: 63 um, D50: 132 um, and D90: 327 um;

[0153] (3) After wet milling, the temperature was increased to 40°C at a rate of 10°C / h, and the temperature was maintained for 0.5 h, and then the temperature was lowered to 35°C at a rate of 10°C / h;

[0154] (4) 100 ml of 50 wt% ammonium nitrate solution was slowly added at 35°C, and the addition time was 1 h;

[0155] (5) The temperature was continuously lowered to 5°C at a rate of 10°C / h;

[0156] (6) The temperature was maintained at 5°C for 1-2 h, and the product was filtered, washed with methanol, and dried at 40°C under vacuum to obtain 92 g of thiamine nitrate solid.

[0157] The polarizing microscope photograph of the obtained product is as shown in Figure 7 , the particles were short rod-shaped, the particle size was small, and the purity was 99.5%. The particle size of the sample was tested using a Malvern particle size distribution tester, D10: 87 um, D50: 207 um, D90: 487 um, angle of repose 38 degrees, and bulk density 0.71 g / ml.

[0158] Comparative Example 4

[0159] (1) 100 g of thiamine nitrate powder and 1400 ml of water were added to a reaction kettle, and the mixture was dissolved by heating to 55°C, and then the temperature was lowered to 45°C, 5 g of small particle seed crystal (D10: 16 um, D50: 62 um, D90: 183 um) was added, and the seed crystal was aged for 2 h;

[0160] (2) After the temperature was lowered to 25°C at a rate of 10°C / h, the particle size distribution of the slurry was D10: 36 um, D50: 95 um, and D90: 239 um, and the slurry was wet milled at 25°C for 0.5 h, and the particle size distribution of the slurry was D10: 27 um, D50: 72 um, and D90: 184 um;

[0161] (3) After wet milling, the temperature was increased to 40°C at a rate of 10°C / h, and the temperature was maintained for 0.5 h, and then the temperature was lowered to 35°C at a rate of 10°C / h;

[0162] (4) slowly add 100 ml of 50 wt% ammonium nitrate solution at 35 °C, the dropwise addition time is 1 h;

[0163] (5) continue to cool to 5 °C, the cooling rate is 10 °C / h;

[0164] (6) keep at 5 °C for 1-2 h, filter, wash with methanol, and vacuum dry at 40 °C to obtain 93 g of thiamine nitrate solid.

[0165] The polarizing microscope photo of the obtained product is as follows Figure 8 . The purity is 99.4%. The sample particle size is tested by using a Malvern particle size distribution tester, D10: 80, D50: 190, D90: 475 um. The rest angle is 42 degrees, and the bulk density is 0.63 g / ml. The product particle size is made smaller and the flowability is made worse by using small particle seeds.

[0166] Comparative Example 5:

[0167] (1) add 100 g of thiamine nitrate powder, 1400 ml of water into the reaction kettle, heat to 55 °C to dissolve, then cool to 45 °C, add 2.5 g of seeds (D10: 87 um; D50: 207 um; D90: 487 um), and crystallize for 2 h;

[0168] (2) after cooling to 25 °C at 10 °C / h, the slurry particle size distribution is D10: 93 um, D50: 284 um, D90: 737 um, wet mill for 1 h at 25 °C by using a wet mill with parameters 2P4M6F, 15000 rpm, to obtain a slurry particle size distribution of D10: 17 um, D50: 96 um, D90: 212 um;

[0169] (3) after wet milling, heat to 40 °C at 10 °C / h, keep for 0.5 h, then cool to 35 °C at a rate of 10 °C / h;

[0170] (4) slowly add 100 ml of 50 wt% ammonium nitrate solution at 35 °C, the dropwise addition time is 1 h;

[0171] (5) continue to cool to 5 °C, the cooling rate is 10 °C / h;

[0172] (6) keep at 5 °C for 1-2 h, filter, wash with methanol, and vacuum dry at 40 °C to obtain 91 g of thiamine nitrate solid.

[0173] The polarizing microscope photo of the obtained product is as follows Figure 10 . This comparative example is over-wet milled, and the obtained particles are relatively small, D10: 76, D50: 255, D90: 568 um; the rest angle is 35 degrees, the bulk density is 0.72 g / ml, and the flowability is not as good as that of Examples 1-3.

Claims

1. A process for the preparation of crystalline thiamine mononitrate characterized in that, It comprises the following steps: Step (s1): dissolving thiamine nitrate and water at 50-70℃ to obtain a mixture A of thiamine nitrate and water; Step (s2): mixing the mixture A of thiamine nitrate and water with crystal seeds at 40-60℃ to obtain a suspension containing thiamine nitrate particles; the crystal seeds are thiamine nitrate particles with a particle size distribution of D90: 400-600um, D50: 150-250um, and D10: 50-100um; Step (1): wet grinding the suspension containing thiamine nitrate particles at 5-30℃ to obtain a wet grinding liquid, wherein the particle size distribution of thiamine nitrate in the wet grinding liquid is D10: 50-100um, D50: 150-270um, and D90: 380-720um; In the step (1), the particle size of thiamine nitrate in the wet grinding liquid is smaller than that of the thiamine nitrate particles in the suspension; In the step (1), the wet grinding is performed by a wet grinder with a rotation speed of 1000-5000rpm; Step (2): temperature rising to 35-50℃ and temperature dropping to 20-40℃ for temperature rising and dropping cycles; In the step (2), adding an aqueous ammonium nitrate solution after temperature dropping; Step (3): temperature dropping and crystallization to obtain thiamine nitrate crystals.

2. The method for preparing thiamine nitrate crystals according to claim 1, wherein: It meets one or more of the following conditions: (1) In the step (1), the temperature of the wet grinding is 5-25℃; (2) In the step (1), the wet grinding time is 0.3-1.5 hours; (3) In the step (2), the temperature rising is rising to 40-50℃; (4) In the step (2), the temperature dropping is dropping to 30-38℃; (5) In the step (2), the temperature difference between the temperature rising and the temperature dropping is 3-12℃; (6) In the step (2), the number of temperature rising and dropping cycles is 1; (7) In the step (2), the temperature rising rate is 3-20℃ / h; (8) In the step (2), the temperature dropping rate is 5-15℃ / h; (9) In the step (2), after the temperature rising is completed, the temperature is maintained and then dropped; (10) In the step (2), the volume-to-mass ratio of the aqueous ammonium nitrate solution to the thiamine nitrate is (0.5-5): 1mL / g; (11) In the step (2), the addition rate of the aqueous ammonium nitrate solution is 1-5mL / g / h, wherein mL / g is the volume-to-mass ratio of the aqueous ammonium nitrate solution to the thiamine nitrate; (12) In the step (2), the aqueous ammonium nitrate solution is added dropwise; (13) In the step (2), the aqueous ammonium nitrate solution is added at the terminal temperature of the temperature dropping in the step (2); (14) In the step (3), the temperature dropping and crystallization is temperature dropping to 0-10℃ for crystallization; (15) In the step (3), the temperature dropping rate for the temperature dropping and crystallization is 5-15℃ / h; (16) The step (3) further comprises the following post-processing steps: filtration, washing, and drying to obtain the thiamine nitrate crystals. (17) In the step (3), the thiamine nitrate crystals satisfy the following particle size distribution conditions: D10: 80-200 um, D50: 200-500 um, D90: 800-1200 m; (18) In the step (3), the thiamine nitrate crystals have a rest angle of 30-35°; (19) In the step (3), the thiamine nitrate crystals have a bulk density of 0.7-0.9 g / mL; (20) In the step (3), the thiamine nitrate crystals have an aspect ratio of 2:1-10:

1.

3. The method for preparing thiamine nitrate crystals according to claim 2, wherein: It satisfies one or more of the following conditions: (1) In the step (1), the mass ratio of thiamine nitrate to water in the suspension is 1:(8-20) based on the total thiamine nitrate, wherein the total thiamine nitrate refers to the sum of thiamine nitrate particles and thiamine nitrate dissolved in water; (2) In the step (1), the D50 of the particle size distribution of the thiamine nitrate in the wet grinding liquid is 150-250 um; (3) In the step (1), the D90 of the particle size distribution of the thiamine nitrate in the wet grinding liquid is 380-510 um; (4) In the step (1), the D10 of the particle size distribution of the thiamine nitrate particles in the suspension is 60-100 um; (5) In the step (1), the D50 of the particle size distribution of the thiamine nitrate particles in the suspension is 200-300 um; (6) In the step (1), the D90 of the particle size distribution of the thiamine nitrate particles in the suspension is 550-800 um; (7) In the step (1), the temperature of the wet grinding is 25°C; (8) In the step (1), the wet grinding time is 0.5 h or 1 h; (9) In the step (2), the temperature is raised to 40°C or 45°C; (10) In the step (2), the temperature is lowered to 35°C; (11) In the step (2), the temperature difference between the temperature rise and the temperature drop is 5°C or 10°C; (12) In the step (2), the temperature rise rate is 10°C / h; (13) In the step (2), the temperature drop rate is 10°C / h or 5°C / h; (14) In the step (2), after the temperature rise is completed, the temperature is maintained for 0.3-2 h, and then the temperature is lowered; (15) In the step (2), after the temperature is lowered, 40%-60% mass content ammonium nitrate aqueous solution is added; (16) In the step (2), the volume-to-mass ratio of the ammonium nitrate aqueous solution to the thiamine nitrate is (1-5):1 mL / g; (17) In the step (2), the addition rate of the ammonium nitrate aqueous solution is 1 or 3 mL / g / h, wherein mL / g is the volume-to-mass ratio of the ammonium nitrate aqueous solution to the thiamine nitrate; (18) In the step (2), the dropping time of the ammonium nitrate aqueous solution is 1 h or 0.5 h; (19) In the step (3), the temperature drop crystallization is a temperature drop to 5°C for crystallization; (20) In the step (3), the temperature drop rate of the temperature drop crystallization is 5 or 10°C / h; (21) In step (3), in the post-processing step, the washing is washing with an alcohol solvent; (22) In step (3), in the post-processing step, the drying is vacuum drying; (23) In step (3), the D10 of the crystal particle size distribution of thiamine nitrate is 100-150 um (24) In step (3), the D50 of the crystal particle size distribution of thiamine nitrate is 300-400 um (25) In step (3), the D90 of the crystal particle size distribution of thiamine nitrate is 850-1100 um.

4. The method of claim 3, wherein the thiamine nitrate crystals are prepared by the process of: It meets one or more of the following conditions: ​ (1) In step (1), in the wet grinding liquid, the D10 of the particle size distribution of thiamine nitrate is 61 um, 69 um, 67 um or 87 um; (2) In step (1), in the wet grinding liquid, the D50 of the particle size distribution of thiamine nitrate is 198 um, 200 um, 202 um or 264 um; (3) In step (1), in the wet grinding liquid, the D90 of the particle size distribution of thiamine nitrate is 412 um, 430 um, 500 um, 495 um or 695 um; (4) In step (1), in the suspension liquid, the D10 of the particle size distribution of thiamine nitrate is 79 um, 90 um, 93 um or 95 um; (5) In step (1), in the suspension liquid, the D50 of the particle size distribution of thiamine nitrate is 220 um, 250 um, 284 um or 290 um; (6) In step (1), in the suspension liquid, the D90 of the particle size distribution of thiamine nitrate is 602 um, 690 um, 737 um or 750 um; (7) In step (1), in the suspension liquid, the mass ratio of thiamine nitrate to water based on the total thiamine nitrate is 1:14, 1.005:14, 1.025:10, 1:10 or 1.005:10; (8) In step (1), when the wet grinding is performed using a wet grinder at 1000-3000 rpm, the wet grinding time is 0.5-1 h; (9) In step (2), after the temperature is raised, the temperature is maintained for 0.5 h or 1 h, and then the temperature is lowered; (10) In step (2), after the temperature is lowered, 50% or 40% mass content ammonium nitrate aqueous solution is added; (11) In step (2), the volume to mass ratio of the ammonium nitrate aqueous solution to the thiamine nitrate is 3:1 mL / g, 1:1 mL / g, 1.5:1 mL / g or 1.5:1.025 mL / g; (12) In step (3), in the post-processing step, the alcohol solvent is methanol and / or ethanol; (13) In step (3), in the post-processing step, the drying is vacuum drying at 40-70°C; (14) The D10 of the crystal particle size distribution of thiamine nitrate is 128 um, 108 um or 112 um; (15) The D50 of the crystal particle size distribution of thiamine nitrate is 313 um, 327 um or 371 um; (16) The D90 of the crystal particle size distribution of the thiamine nitrate is 870 um, 893 um or 1010 um.

5. The method for preparing thiamine nitrate crystals according to claim 4, wherein: It meets one or more of the following conditions: (1) In the step (1), in the wet grinding liquid, the particle size distribution of the thiamine nitrate is: D10: 69 um, D50: 202 um, D90: 495 um, or D10: 67 um, D50: 202 um, D90: 430 um, or D10: 61 um, D50: 198 um, D90: 412 um, or D10: 87 um, D50: 264 um, D90: 695 um; (2) In the step (1), in the suspension, the particle size distribution of the thiamine nitrate particles is: D10: 95 um, D50: 290 um, D90: 750 um, or D10: 90 um, D50: 250 um, D90: 690 um, or D10: 79 um, D50: 220 um, D90: 602 um, or D10: 93 um, D50: 284 um, D90: 737 um; (3) In the step (3), the crystal of thiamine nitrate meets the following particle size distribution conditions: D10: 128 um, D50: 371 um, D90: 1010 um, or D10: 108 um, D50: 327 um, D90: 893 um, or D10: 112 um, D50: 313 um, D90: 870 um; (4) In the step (3), the rest angle of the crystal of thiamine nitrate is 30°, 33° or 35° (5) In the step (3), the bulk density of the crystal of thiamine nitrate is 0.83 g / mL, 0.81 g / mL, 0.77 g / mL or 0.79 g / mL; (6) In the step (3), the aspect ratio of the crystal of thiamine nitrate is 5:1, 4:1, 6:1 or 8:1; (7) In the step (1), when the wet grinding is treated by a wet grinder, the rotation speed of the wet grinder is 3000 rpm, 1000 rpm, 2000 rpm or 1500 rpm.

6. The production method according to claim 1, wherein The step (s2) in the preparation method meets one or more of the following conditions: (1) In the mixture A containing thiamine nitrate and water, the mass ratio of thiamine nitrate to water is 1: (10-20); (2) The mixing is carried out at 40-50°C; (3) The mass ratio of the crystal seed to the thiamine nitrate is (0.3-10):100; (4) The crystallization step includes two stages; the first stage is carried out at 40-50°C; the second stage is carried out by cooling crystallization.

7. The production method according to claim 6, wherein The step (s2) in the preparation method meets one or more of the following conditions: (1) In the mixture A containing thiamine nitrate and water, the mass ratio of thiamine nitrate to water is 1:14 or 1:10; (2) The mixing is carried out at 45°C or 50°C; (3) The mass ratio of the crystal seed to the thiamine nitrate is 0.5:100 or 2.5:100; (4) the crystallization step comprises two stages; the first stage is carried out at 40-50℃, and the crystallization time of the first stage is 1-2 hours; the second stage is temperature reduction crystallization; the temperature reduction crystallization is temperature reduction to the temperature of the wet grinding, and the temperature reduction rate is 3-15℃ / h.

8. The production method according to claim 6, wherein In step (s2), the crystallization step comprises two stages; the first stage is carried out at 40-50℃, and the crystallization time of the first stage is 1-2 hours; the second stage is temperature reduction crystallization; the temperature reduction crystallization is temperature reduction to the temperature of the wet grinding, and the temperature reduction rate is 10℃ / h or 5℃ / h.

9. The production method according to claim 6, wherein The step (s2) in the preparation method satisfies one or more of the following conditions: (1) the D10 of the particle size distribution of the seed crystal is 80-100 um; (2) the D50 of the particle size distribution of the seed crystal is 200-220 um; (3) the D90 of the particle size distribution of the seed crystal is 480-600 um.

10. The production method according to claim 6, wherein The step (s2) in the preparation method satisfies one or more of the following conditions: (1) the D10 of the particle size distribution of the seed crystal is 87 um; (2) the D50 of the particle size distribution of the seed crystal is 207 um; (3) the D90 of the particle size distribution of the seed crystal is 487 um.

11. The production method according to claim 1, wherein In step (s1) of the preparation method, the temperature of the mixing is 50-60℃.

12. The production method according to claim 11, wherein In step (s1) of the preparation method, the temperature of the mixing is 55℃ or 65℃.

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